the dynamic architecture of photoreceptor ribbon synapses

REVIEW ARTICLE

The dynamic architecture of photoreceptor ribbon synapses:Cytoskeletal, extracellular matrix, and intramembrane proteins

AARON J. MERCER1,2AND WALLACE B. THORESON1,2

1Department of Ophthalmology & Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska2Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska

(RECEIVED June 6, 2011; ACCEPTED September 6, 2011)

Abstract

Rod and cone photoreceptors possess ribbon synapses that assist in the transmission of graded light responses to second-orderbipolar and horizontal cells of the vertebrate retina. Proper functioning of the synapse requires the juxtaposition of presynapticrelease sites immediately adjacent to postsynaptic receptors. In this review, we focus on the synaptic, cytoskeletal, andextracellular matrix proteins that help to organize photoreceptor ribbon synapses in the outer plexiform layer. We examine theproteins that foster the clustering of release proteins, calcium channels, and synaptic vesicles in the presynaptic terminals ofphotoreceptors adjacent to their postsynaptic contacts. Although many proteins interact with one another in the presynapticterminal and synaptic cleft, these protein–protein interactions do not create a static and immutable structure. Instead,photoreceptor ribbon synapses are remarkably dynamic, exhibiting structural changes on both rapid and slow time scales.

Keywords: Cone, Rod, Outer retina, Neurotransmission, Cytoskeleton

Introduction

Synapses are highly specialized contacts between neurons thathave evolved to transmit signals efficiently and reliably throughoutthe nervous system. At chemical synapses, changes in the electricalpotential of a cell are converted into a chemical signal. Theclassical mechanism involves a depolarization-induced Ca2+ influxcausing SNARE proteins to intertwine and pull vesicles to theplasma membrane (Pang & Südhof, 2010). The subsequent fusionevent results in vesicles emptying their neurotransmitter contentsinto the synaptic cleft to signal through receptors on postsynapticneurons. Synapses require a highly organized placement of pre-synaptic exocytotic proteins, endocytotic proteins, calcium chan-nels, postsynaptic receptors, and other associated proteins. Inphotoreceptor terminals, synapses are organized around a largeelectron-dense structure known as the ribbon. In this review, weexamine the molecular architecture of ribbon synapses in photore-ceptor terminals with a focus on interactions with the cytoskeletonand extracellular matrix (ECM). We also summarize studiesshowing that photoreceptor ribbon synapses are not static structuresbut can be altered dynamically on both fast and slow time scales.

CaV channels cluster at the active zone

Physiological experiments have established that the voltage-gatedcalcium (CaV) channels in rod and cone photoreceptors are high

voltage-activated L-type channels (Bader et al., 1982; Corey et al.,1984; Barnes&Hille, 1989; Lasater&Witkovsky, 1991;Wilkinson&Barnes, 1996). There is no evidence for non-L-type CaV channels inphotoreceptors. Freeze-fracture electron micrographs of photore-ceptor terminals show a random array of hexagonal-shaped particlesat the apex of the synaptic ridge that are thought to be CaV channels(Raviola & Gilula, 1975; Schaeffer et al., 1982). Terminals of rodsand cones in the outer plexiform layer (OPL) label with antibodies topore-forming CaV1.2 (a1C), CaV1.3 (a1D), and CaV1.4 (a1F) subunitisoforms (Nachman-Clewner et al., 1999; Firth et al., 2001;Henderson et al., 2001; Morgans, 2001; Morgans et al., 2001, 2005;Wu et al., 2003; Mansergh et al., 2005; tom Dieck et al., 2005; Xiaoet al., 2007; Specht et al., 2009; Kersten et al., 2010; Mercer et al.,2011a,b). High levels of CaV1.3 and CaV1.4 messenger RNA(mRNA) are present in retina (Bech-Hansen et al., 1998; Stromet al., 1998; Xiao et al., 2007) but only low levels of CaV1.2 mRNA(Kamphuis & Hendriksen, 1998), suggesting that the labeling ofphotoreceptors by CaV1.2 antibodies may be nonspecific. Mutationsin CaV1.4 greatly diminish the electroretinogram (ERG) b-wave inknockout mice, produce malformed ribbons, and cause congenitalstationary night blindness (CSNB) in humans. Combined withimmunohistochemical evidence, these findings suggest thatCaV1.4 is the principle CaV channel subtype in rods (Bech-Hansenet al., 1998; Strom et al., 1998; Mansergh et al., 2005; Chang et al.,2006; Striessnig et al., 2010).

The contribution of CaV1.3 at photoreceptor synapses is lessclear. Immunoelectron micrographs show labeling for antibodies toCaV1.3 at the base of ribbons in mouse retina (Kersten et al., 2010).However, CaV1.3 mutations in mouse retina do not significantly

Address correspondence and reprint requests to: Wallace B. Thoreson,Department of Ophthalmology & Visual Sciences, University of NebraskaMedical Center, 4050 Durham Research Center, Omaha, NE 68198-5840.E-mail: [email protected]

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Visual Neuroscience (2011), 28, 453–471.Copyright � Cambridge University Press, 2011 0952-5238/11 $25.00doi:10.1017/S0952523811000356

diminish the b-wave (Wu et al., 2007), and b-waves of CaV1.3/CaV1.4 double mutants do not appear to differ from those of CaV1.4single mutants (McCall & Gregg, 2008). It may be that CaV1.3channels are present only in a subpopulation of cones. For example,CaV1.3 antibodies label M cones but not S cones in the tree shrewretina (Morgans, 1999). Subtype differences among cones alsooccur in salamander retina where protein kinase A (PKA) inhibitsCa2+ currents in rods and short wavelength-sensitive small singlecones but enhances Ca2+ currents of long wavelength-sensitive largesingle cones (Stella & Thoreson, 2000). PKA activation alsoenhances currents from heterologously expressed CaV1.3 channels(Qu et al., 2005; Liang & Tavalin, 2007). The pharmacologicalproperties of Ca2+ currents, including partial block by omega-conotoxin,are consistentwith the presence of CaV1.3 channels in salamander cones(Wilkinson & Barnes, 1996). Antibodies to a2d4 subunits labelphotoreceptor terminals (Mercer et al., 2011a), and mutations in b2 ora2d4 subunits cause diminished ERG b-waves and CSNB, suggestingthat these are the principle CaV channel accessory subunits in photo-receptors (Ball et al., 2002; Wycisk et al., 2006a,b).

Excision of the synaptic terminal diminishes rod calciumcurrents by 95%, indicating that most of the CaV channels arelocated in the terminal (Xu & Slaughter, 2005). As illustrated inFig. 1, sites of intraterminal Ca2+ influx also colocalize with synapticribbons in rod photoreceptor terminals. In this example, changes inintracellular Ca2+ levels were visualized in a salamander rod usingthe Ca2+-sensitive dye, Oregon Green BAPTA-6F, (Invitrogen,Carlsbad, CA) (KD 5 3 lM Ca2+), and the ribbon was labeled witha rhodamine-conjugated consensus peptide that binds selectivelyto the ribbon protein, ribeye (Zenisek et al., 2004). Both dyes wereintroduced into the rod through a patch-clamp pipette. Sites of Ca2+ influx and ribbons are also colocalized in cones (Choi et al.,2008). Consistent with close proximity between CaV channels andthe ribbon, immunohistochemical studies provide evidence forclusters of CaV channels at the base of the ribbon (Nachman-Clewner et al., 1999; Morgans, 2001; Morgans et al., 2005; Spechtet al., 2009; Mercer et al., 2011b). Furthermore, individual CaVchannels labeled with quantum dots conjugated to a2d4 antibodiescolocalize with fluorescently labeled ribeye consensus peptides(Mercer et al., 2011a), and immunoelectron micrographs showCaV channels along the synaptic ridge at the base of the ribbon(tom Dieck et al., 2005; Kersten et al., 2010).

Ca2+-dependent vesicle release and replenishmentat photoreceptor synapses

At most synapses, Ca2+ needs to attain high micromolar levels tostimulate release, and therefore, exocytosis is typically restricted torelease sites within nanodomains of high Ca2+ very close to CaVchannels. A Ca2+ nanodomain is defined as the 10–100 nm range inthe immediate vicinity of a Ca2+ channel where Ca2+ is not inequilibrium with fast buffers (Naraghi & Neher, 1997). Examples ofsynapses where release involves Ca2+ nanodomains include thesquid giant synapse (Adler et al., 1991), mammalian rod bipolar cell(Jarsky et al., 2010), GABAergic basket cells in the hippocampus(Bucurenciu et al., 2008), and mature calyx of Held (Fedchyshyn &Wang, 2005; Weber et al., 2010). The release mechanism in rodsand cones is much more sensitive to Ca2+ than at other synapses,and exocytosis can thus be triggered by submicromolar Ca2+

levels (Rieke & Schwartz, 1996; Thoreson et al., 2004; Shenget al., 2007; Duncan et al., 2010). The high Ca2+ affinity of therelease mechanism at photoreceptor synapses suggests that releasemight involve spatially averaged Ca2+ levels in the terminal and not

the high Ca2+ levels found in nanodomains. However, experimentscomparing effects of the diffusible synthetic Ca2+ chelators ethyleneglycol tetraacetic acid (EGTA) and 1,2-bis (o-aminophenoxy) ethane,N,N,N',N'-tetraacetic acid (BAPTA) on release indicate that releasesites are within 50–100 nm of Ca2+ channels in amphibian cones(Mercer et al., 2011b). This was shown by the finding that when 0.5mM EGTA, 5 mM EGTA, or 5 mM BAPTA were introduced intocones, only 5 mM BAPTA reduced the amplitude of glutamatergicpost-synaptic currents in second-order neurons (Mercer et al., 2011b).Comparisons of the calcium current to the size of the readily releasablepool of synaptic vesicles suggest that only a few Ca2+ channelopenings accompany fusion of each vesicle during the first fewmilliseconds of release from cones (Bartoletti et al., 2010). Thus, whencones are depolarized by a light decrement, the release of vesicles istriggered by the emergence of nanodomains of [Ca2+]i beneath openCaV channels close to ribbon release sites, providing a tight couplingbetween channel opening and vesicle fusion (Mercer et al., 2011b).

In darkness, cones appear to switch from a tight couplingbetween CaV channel opening and vesicle fusion to a mode ofrelease whereby the rate of sustained release is governed by the rateof replenishment. At the dark potential, cones are depolarized toa membrane potential of approximately �40 mV, allowing the

Fig. 1. Colocalization of Ca2+ channels to ribbon release sites. A voltage-clamped rod from a salamander retinal slice preparation was loaded withOregon Green BAPTA-6F (OGB-6F) (200 lM) to visualize intracellular Ca2+

changes and a rhodamine-conjugated ribeye-binding peptide (50 lM; Zeniseket al., 2004) to visualize the ribbon. Both were introduced into the rod througha patch pipette. To activate L-type Ca2+ channels, the voltage-clamped rodwasdepolarized from �70 to �10 mV for 100 ms. Panel (A) shows a singleconfocal section (55 ms exposure) illustrating OGB-6F fluorescence in the rodprior to the test step. Panel (B) shows OGB-6F fluorescence in the sameconfocal section during the depolarizing test step. The difference image (teststep minus control) in panel (C) shows localized hot spots of Ca2+ increase atthe base of the synaptic terminal (arrows). Panel (D) shows synaptic ribbonslabeled with rhodamine-conjugated ribeye-binding peptide in the same rod.Note that locations of the ribbons match the sites of Ca2+ influx in the twoterminals of the rod. OGB-6F was imaged with 488 nm excitation and 525 nmemission filters, and rhodamine was visualized using 568 nm excitation and607 nm emission filters. Scale bar 5 10 lm.

454 Mercer & Thoreson

continued influx of Ca2+, which in turn causes a depletion of thereadily releasable pool of vesicles at the base of the ribbon (Jackmanet al., 2009; Bartoletti et al., 2010). Under these conditions, the rateof synaptic release is limited not by the rate of individual channelopenings but by the rate at which release-ready vesicles can bereplenished (Jackman et al., 2009). The replenishment process isCa2+ dependent (Babai et al., 2010) and so, even when the releasablepool is depleted in darkness, release is nonetheless regulated by Ca2+

influx through CaV channels. However, the Ca2+-dependent sitesinvolved in replenishment are.200 nm from CaV channels, furtherthan the distance between release sites and channels (Babai et al.,2010). Because these Ca2+-dependent sites of replenishment are notlocated within Ca2+ nanodomains beneath individual channels,replenishment is regulated by the spatially averaged levels of Ca2+

entering through multiple channels. In bright light, random channelopenings are rare, and individual channel openings are closelysynchronized with decrements in light intensity. Under theseconditions, close coupling between channel openings and releaseevents can provide an accurate read out of stimulus-dependentchanges in membrane potential. When cones are depolarized indarkness, many Ca2+ channel openings occur at random intervals.Controlling release under these conditions by regulating the rate ofreplenishment offers the benefit of reducing noise that can beintroduced by stochastic channel openings.

Evidence that the Ca2+-dependent replenishment mechanisminvolves sites .200 nm from CaV channel suggests that proteinsalong the ribbon may participate in this process. At the calyx ofHeld, calmodulin plays a key role in the Ca2+-dependent acceler-ation of replenishment (Sakaba & Neher, 2001). One target ofcalmodulin is the GTP-binding protein, Rab3a (Park et al., 2002),and Rab3a has been shown to play a role in replenishment (Leenderset al., 2001). Rab3a interacts with RIM2 proteins along the ribbonand has been proposed to tether vesicles to the ribbon (Fukuda,2003; Dulubova et al., 2005; tom Dieck et al., 2005; Deguchi-Tawarada et al., 2006; Uthaiah & Hudspeth, 2010). Along withcalmodulin, Rab3a is an appealing candidate for regulatingreplenishment at the cone ribbon.

Synaptic Ca2+ buffering and extrusion

Ca2+ influx can induce vesicle release and regulate replenishment,but rising [Ca2+]i levels are balanced by Ca2+ extrusion andbuffering mechanisms. One of the first studies of synaptic Ca2+

extrusion in photoreceptors was performed byMorgans et al. (1998)to determine whether the Na+/Ca2+ exchanger or the plasmamembrane Ca2+ ATPase (PMCA) tempered increases in [Ca2+]ifollowing a depolarizing stimulus. PMCA is considered critical forCa2+ handling at other synapses (Juhaszova et al., 2000; Wanaver-becq et al., 2003; Gover et al., 2007), but the Na+/Ca2+ exchangerregulates Ca2+ levels in the outer segments of rod photoreceptors(Thoreson et al., 1997; Lagnado et al., 1998; Krizaj & Copenhagen,2002). Morgans et al. (1998) demonstrated that the PMCA handledCa2+ extrusion in terminals of cone photoreceptors from the treeshrew, and that photoreceptors in the tree shrew, mouse, goldfish,and rat express a PMCA protein using a pan-PMCA channelantibody. Labeling with PMCA antibodies is found just aboveantibodies to CaV1.3 channels, colocalized with presynaptic post-synaptic density-95 (PSD-95) complexes and the Crumbs complexprotein membrane palmitoylated protein 4 (MPP4) (Yang et al.,2007; Aartsen et al., 2009). Therefore, it seems reasonable tosuggest that PMCA transporters lie some distance from synapticrelease sites to avoid quenching brief Ca2+ signals in the active zone

during dim light conditions but capable of limiting global increasesin [Ca2+]i throughout the terminal. Similar PMCA expressionpatterns are found in the retinas of mice (Krizaj et al., 2002; Ciaet al., 2005; Johnson et al., 2007), tiger salamanders (Krizaj et al.,2003, 2004), and chickens (Tolosa de Talamoni et al., 2002).However, using a C57Bl/6J mouse model, Johnson et al. (2007)found that PMCA is critical for Ca2+ extrusion in rod terminals,whereas the Na+/Ca2+ exchanger is more important for maintainingCa2+ homeostasis in cone terminals. This corroborates the findingthat PMCA2 knockout mice exhibit deficits only in rod-mediatedERG responses (Duncan et al., 2006) and calls into question the ideathat PMCAs are solely responsible for Ca2+ homeostasis in thesynaptic terminals of all photoreceptor cells.

Although Ca2+ extrusion can modulate Ca2+ homeostasis atphotororeceptor synapses, endogenous buffering systems are alsoimportant (Thoreson, 2007). Extrusion of Ca2+ through PMCA orthe Na+/Ca2+ exchanger is slow compared to the kinetics of Ca2+

buffering (Klingauf & Neher, 1997; Thoreson et al., 1997; Krizajet al., 2004; Mercer et al., 2011b). Local calcium buffering shapesdiffusion of Ca2+ influx at the active zone (Klingauf & Neher, 1997)and thereby shapes the kinetics of neurotransmission. Endogenousneuronal buffers include calbindin, calretinin, and parvalbumin(Bennis et al., 2005; Rusakov, 2006). Although there is significantspecies-to-species variability, cone photoreceptors in most speciescontain calbindin, a fast low mobility buffer, while calretinin andparvalbumin are only observed in the photoreceptors of a handfulof species.

The calcium-binding proteins CaBP4 (Haeseleer et al., 2004;Lee et al., 2007) and calmodulin (Miller, 1991; Griessmeier et al.,2009) are also present at photoreceptor synapses and can bufferrelatively high (.1 lM) increases in [Ca2+]i. CaBP4 shifts thevoltage activation range of CaV1.4 towards more negative poten-tials, allowing channels to be effectively activated by physiologicalvoltage levels below �40 mV (Haeseleer et al., 2004). CaBP4weakly inhibits calcium-dependent inactivation of CaV1.3(Cui et al., 2007) and is a phosphorylation target of intracellularkinase pathways (Lee et al., 2007).

The synaptic ribbon

A striking feature of many sensory synapses is the presence ofa large electron-dense structure known as the ribbon. Although itsfunction in vesicle release is not yet fully understood, it is believedthat the ribbon assists sensory neurons in maintaining graded tonicneurotransmission. Ribbons were initially proposed to function asconveyor belts that help transport vesicles to the active zone forexocytosis (Bunt, 1971). However, cytosolic ATP is not needed torelease vesicles that have already been primed and attached to theribbon, indicating that vesicle movement along the ribbon does notinvolve a molecular motor requiring ATP hydrolysis (Heidelberger,1998). In fact, rather than accelerating vesicle replenishment at thebase of the ribbon, the observation that vesicles are depleted fromthe base of the ribbon in darkness suggests that ribbons actually slowvesicle delivery (Jackman et al., 2009). Other proposed functionsinclude the possibility that ribbons may prime vesicles for release,act like a flytrap to capture and deliver vesicles to the active zone,assist with endocytosis of previously released vesicles, or coordinatemultivesicular release (Prescott & Zenisek, 2005).

Ribbons are found in bipolar and photoreceptor cells of theretina, pineal photoreceptors, hair cells, and electroreceptors.Ultrastructural studies show differences in the shapes of ribbonsin different cell types. For example, ribbons of rod and cone

Architecture of photoreceptor ribbon synapses 455

photoreceptors and bipolar cells are typically more plate-like,whereas ribbons in hair cells are often spherical in shape (tomDieck & Brandstätter, 2006). Synaptic ribbons in vertebrate photo-receptors are first expressed as similar precursor spheres (Regus-Leidig et al., 2009). Spherical ribbons are also found in photoreceptorsfrom the hagfish retina suggesting that this may represent the pri-mordial shape of the ribbon (Holmberg & Ohman, 1976). The mainprotein in the ribbon, ribeye, does not appear to be present ininvertebrates, but photoreceptors from Drosophila melanogasterhave T-bar structures that are sometimes compared to ribbons(Fouquet et al., 2009; Hamanaka & Meinertzhagen, 2010). Con-ventional vertebrate synapses also sometimes exhibit structures thatresemble ribbons, such as spherical structures at the frog neuro-muscular junction and punctate electron-dense projections at syn-apses between human hippocampal neurons (Zhai & Bellen, 2004).

Ribbons at synapses of vertebrate rod and cone photoreceptorsare typically 30–40 nm wide and project 200–400 nm vertically intothe cytoplasm (reviewed by Heidelberger et al., 2005; Sterling &Matthews, 2005; Schmitz, 2009). Cone ribbons have a baseextending 200–700 nm along the membrane, whereas rod ribbonsare 800–1500 nm long. Bipolar cell ribbons are normally smallerthan photoreceptor ribbons (Sterling &Matthews, 2005). Terminalsof mammalian rods typically contain one ribbon, whereas amphib-ian rods have multiple ribbons (Carter-Dawson & LaVail, 1979;Townes-Anderson et al., 1985; Migdale et al., 2003; Zampighi et al.,2011), but both mammalian and nonmammalian cones have largerterminals with a dozen or more ribbons. Vesicles tethered along thebottom one or two rows of the ribbon contact the plasma membraneand appear to form a readily releasable pool of vesicles that can fuserapidly following an increase in [Ca2+]i (Sterling &Matthews, 2005;Bartoletti et al., 2010). A single ribbon at a rod synapse tethers;25vesicles to the plasma membrane at the base of the ribbon witha total tethered pool of ;700 vesicles (Thoreson et al., 2004;Heidelberger et al., 2005), whereas cone ribbons have a readilyreleasable pool of ;20 vesicles and a total tethered pool of ;110vesicles (Innocenti & Heidelberger, 2008; Bartoletti et al., 2010).

Ribeye

Technological advances over the past 20 years have allowedscientists to characterize many of the key structural and functionaldomains of photoreceptor ribbons. The primary protein constituent ofthe ribbon is ribeye, which was first identified, characterized, andcloned by Schmitz et al. (2000). Ribeye is composed of a novelproline-rich A domain and a carboxyterminal B domain that is almostidentical in sequence to the nuclear repressor, CtBP2. Both proteinproducts are encoded by a single gene, but ribeye is expressed only atribbon synapses (Wan et al., 2005; Magupalli et al., 2008). Synapticribbons have been visualized by fluorescent and electron microscopyusing antibodies to ribeye (Schmitz et al., 2000), antibodies to CtBP2(tomDieck et al., 2005; Uthaiah &Hudspeth, 2010), and fluorescentlylabeled ribeye consensus peptides (Zenisek et al., 2004; Choi et al.,2008; LoGiudice et al., 2008; Zenisek, 2008).

The A domain of ribeye constitutes most of the internal scaffoldof the ribbon structure, while the B domain faces into thecytoplasm where it can interact with other ribbon-related proteins(Schmitz et al., 2000; Alpadi et al., 2008; Magupalli et al., 2008).The scaffold of the ribbon is constructed from homotypic andheterotypic interactions between A and B domains of adjacentribeye molecules. Heterotypic interactions between A and B domainsare inhibited by nicotinamide adenine dinucleotide [NAD(H)](Magupalli et al., 2008).

Ribbon-associated proteins

Although the backbone of a ribbon is constructed from interlinkingribeye peptides, a number of accessory cytomatrix proteins at thesynapse appear to help organize vesicle trafficking near the ribbon(Zanazzi & Matthews, 2009). Directly beneath the ribbon inphotoreceptor cells, but not most other ribbon synapses, isa trough-like electron-dense structure called the arciform density(Dowling & Boycott, 1966; Gray & Pease, 1971; Lasansky, 1973;Raviola & Gilula, 1975; Raviola & Raviola, 1982). The arciformdensity may help to anchor the ribbon to the plasma membrane andperhaps shape the diffusion of Ca2+ entering through Ca2+ channelsbeneath it, but the molecular constituents of the arciform densityhave not been identified.

The protein bassoon has received a great deal of attention asa ribbon coorganizer (Dick et al., 2003; tom Dieck et al., 2005;Frank et al., 2010; Regus-Leidig et al., 2010), although it is notlocalized exclusively to ribbon synapses (tom Dieck et al., 1998;Richter et al., 1999; Altrock et al., 2003; Hallermann et al., 2010).Bassoon is a large 420 KD protein that comigrates with ribeye inprecursor spheres during development (Regus-Leidig et al., 2009)and has been localized to the base of the synaptic ribbon (Brand-stätter et al., 1999; tom Dieck et al., 2005). Bassoon may function asa ribbon-anchoring protein, but it is not clear if it is directlyassociated with the arciform density (Zanazzi & Matthews, 2009).Bassoon knockout animals have detached ribbons, deformed Ca2+

channel clusters, and impaired vesicle attachment to the membranein both the retina (Dick et al., 2003; tom Dieck et al., 2005) andauditory hair cells (Khimich et al., 2005; Frank et al., 2010). In theretina, bassoon knockout mice exhibit diminished ERG b-waves. Inhair cells of bassoon knockout mice, fast synchronous release isinhibited more strongly than slower sustained release (Khimichet al., 2005), suggesting a role for nonribbon sites in maintainingtonic neurotransmission in these cells. At ribbon and nonribbonsynapses, bassoon mutants also show defects in vesicle replenish-ment, particularly for fast refilling (Frank et al., 2010; Hallermannet al., 2010). Bassoon and ribeye often colocalize with the proteinpiccolo (Cases-Langhoff et al., 1996), in both initial precursorspheres (Dresbach et al., 2006; Regus-Leidig et al., 2010) and fullyfunctional ribbon-associated active zones (Dick et al., 2001; tomDieck et al., 2005). Bassoon and piccolo share a similar structureand may share similar functions (Takao-Rikitsu et al., 2004;Mukherjee et al., 2010).

Cytomatrix at the active zone-associated structural protein(CAST) helps to organize the active zone at many synapses byinteracting with bassoon, piccolo, RIM1, and RIM2, as well asindirectly with Munc13 (Hida & Ohtsuka, 2010). CAST isconcentrated at the base of the ribbon along with RIM2, piccolo,and bassoon (Takao-Rikitsu et al., 2004; Deguchi-Tawarada et al.,2006). RIM proteins interact with many of the key proteins inrelease including synaptotagmin 1, SNAP-25, Rab3A, Munc13, andCaV channels (Matteoli et al., 1991; Geppert et al., 1997; Wanget al., 1997; von Kriegstein et al., 1999; Coppola et al., 2001; Schochet al., 2002; Deguchi-Tawarada et al., 2006; Gracheva et al., 2008;Kaeser et al., 2011).

RIM1 and RIM2 are differentially located with RIM1 foundalong the face of the ribbon and RIM2 clustered at the base of theribbon (tom Dieck et al., 2005). ELKS has a high degree ofhomology to CAST and shares similar binding partners includingbassoon and RIM1 (Inoue et al., 2006), but it is not concentrated astightly at the ribbon base (Deguchi-Tawarada et al., 2006). Thissuggests that RIM2 may interact with CAST near the base of the


ribbon, whereas interactions between RIM1 and ELKS maypredominate further away from the base. CAST, ELKS, bassoon,piccolo, and RIM all appear to interact with an N-terminal region ofMunc13. Interactions among these proteins may form an importantnode for organizing the synaptic active zone (Wang et al., 2009;Hida & Ohtsuka, 2010).

Interactions between RIM proteins and the C-terminal region ofCaV channel b subunits promote the clustering CaV channels closeto synaptic vesicles (Coppola et al., 2001; Kiyonaka et al., 2007;Gebhart et al., 2010; Han et al., 2011; Kaeser et al., 2011).Interactions between CaV channels and RIM proteins can also bepromoted by intermediary RIM-binding proteins (Hibino et al.,2002).

CaV b subunits possess SH3-HOOK-GK domains that canpotentially mediate multiple binding interactions with cytoskeletalelements, classifying them as membrane-associated guanylatekinase (MAGUK) proteins (Chen et al., 2004; Takahashi et al.,2004; Buraei & Yang, 2010). Although CaV channel b subunits areMAGUKs with homology to other scaffolding proteins like PSD-95,their interactions with other cytoskeletal proteins are limitedbecause the guanylate kinase domain is normally shielded byinteractions with the a1 pore-forming subunit and the SH3domain is shielded by other domains of the b subunit (Buraei &Yang, 2010).

In addition to potential cytoskeletal interactions with CaV bsubunits, the pore-forming a1 subunit of CaV1.3 channels hasa carboxyterminal sequence that recognizes class I PDZ domains(Zhang et al., 2005). CaV1.3 channels in photoreceptors can interactthrough this sequence with PDZ domains on the Usher proteinswhirlin (Kersten et al., 2010) and harmonin (Gregory et al., 2011).This recognition sequence may also facilitate interactions betweenCa2+ channels and other PDZ domain proteins (Nourry et al., 2003;Feng & Zhang, 2009).

Unc119 is located near the base of the ribbon where it playsa role in endocytosis (Karim et al., 2010) and interacts with bothribeye and the calcium-binding protein CaBP4 (Higashide et al.,1998; Alpadi et al., 2008; Haeseleer, 2008). CaBP4 can in turninteract with CaV1.4 or CaV1.3 channels (Haeseleer et al., 2004;Maeda et al., 2005; Yang et al., 2006), and these interactions mayfurther help to localize CaV channels near the base of the ribbon.

Endocytic proteins like dynamin, amphiphysin, and clathrin arealso expressed at ribbon synapses (Ullrich & Südhof, 1994: Sherry&Heidelberger, 2005). An amphiphysin splice variant has beenidentified in retinal ribbon synapses (Hosoya et al., 2004). Synapto-janin is a polyphosphoinositide phosphatase that plays a role inclathrin-mediated endocytosis (Song & Zinsmaier, 2003; Chang-Iletoet al., 2011). Synaptojanin antibodies label cone terminals moreprominently than rod terminals (Holzhausen et al., 2009), and loss ofsynaptojanin produces floating ribbons in cone terminals (Van Eppset al., 2004). Unlike cone synapses, rod synapses develop normallywithout synaptojanin suggesting different roles for this protein andthus perhaps different endocytic pathways in the two cell types(Holzhausen et al., 2009).

Exocytotic proteins

There is evidence that release from ribbon synapses of inner haircells does not involve neuronal SNARE proteins (Nouvian et al.,2011). However, photoreceptor ribbon synapses, like those of mostother neurons, appear to employ SNARE proteins during vesiclefusion: synaptobrevin (VAMP1 and 2), SNAP-25, and syntaxin(Ullrich & Südhof, 1994; Brandstätter et al., 1996a,b; Greenlee

et al., 1996, 2001; von Kriegstein et al., 1999; Bergmann et al.,2000; Morgans, 2000; Sherry et al., 2001, 2006; Heidelberger et al.,2003). The v-SNARE, synaptobrevin, is located exclusively onsynaptic vesicles. Immunoelectron micrographs suggest that thet-SNARE, SNAP-25, may be present not only on the plasmamembrane but also on vesicles along the ribbon (Brändstatteret al., 1996b; Morgans et al., 1996; Morgans & Brändstatter,2000). It is possible that vesicular SNAP-25 may promote vesiclepriming or compound fusion prior to synaptic release. Ribbonsynapses also possess Munc18 proteins, which assist in assemblingthe SNARE complex and priming vesicles (Ullrich & Südhof,1994). One difference between photoreceptors and most otherneurons is the reliance on syntaxin 3 rather than the syntaxin 1isoform used at many synapses (Morgans et al., 1996; Curtis et al.,2008). Additionally, retinal ribbon synapses use complexins 3 and 4rather than complexins 1 and 2 used at most other terminals (Reimet al., 2005; Zanazzi &Matthews, 2010). In complexin 3/4 knockoutmice, ;25% of the synaptic terminals exhibit free floatingspherical ribbons perhaps as a result of altered synaptic activity(Reim et al., 2005).

The identity of the calcium sensor molecules that regulateexocytosis from photoreceptors is unclear. Experiments on non-mammalian rods and cones show that the sensor exhibits anunusually high affinity for Ca2+ with a threshold of 400 nM andlow cooperativity of approximately two Ca2+ ions (Rieke &Schwartz, 1996; Thoreson et al., 2004; Sheng et al., 2007; Duncanet al., 2010). This is quite different from release at synapses emp-loying synaptotagmin 1, which show a cooperativity of fiveCa2+ ions and a requirement for much higher Ca2+ levels (Heidel-berger et al., 1994; Bollmann et al., 2000; Schneggenburger &Neher, 2000; Beutner et al., 2001). Kreft et al. (2003) found thatsalamander rod terminals could be labeled with an antibody tosynaptotagmin 1, but other synaptotagmin 1 antibodies do not labelterminals of photoreceptors in salamander or goldfish (Berntson &Morgans, 2003; Heidelberger et al., 2003; Fox & Sanes, 2007). Bycontrast with these results in lower vertebrates, antibodies tosynaptotagmin 1 consistently label photoreceptor ribbon synapsesin the OPL of mammalian and chick retina (Greenlee et al., 1996;Bergmann et al., 2000; Berntson & Morgans, 2003; Heidelbergeret al., 2003; von Kriegstein & Schmitz, 2003; Lazzell et al., 2004;Fox & Sanes, 2007; Wahlin et al., 2008). Antibodies for synapto-tagmin 2 do not label photoreceptor terminals in chick, mouse,salamander, or goldfish, although there is evidence for labeling ofterminals in ray retina (Fox & Sanes, 2007). In hair cells, it has beenproposed that otoferlin or synaptotagmin 4 might be the calciumsensor (Roux et al., 2006; Johnson et al., 2010). Otoferlin is absentfrom photoreceptor ribbon synapses (Uthaiah & Hudspeth, 2010);the distribution of synaptotagmin 4 in the retina has not beenexamined.

Cytoskeletal components

Ribeye and ribbon-associated proteins interact extensively with theintracellular cytoskeleton. Much of the early work elucidatingcytoskeletal networks in photoreceptors was performed usingspecies whose rods and cones show photosensitive contractilemotion (Burnside, 1986; Nagle et al., 1986) or regenerativeproperties that require cytoskeletal-dependent trafficking (Mandellet al., 1993; Vecino & Avila, 2001; Hasegawa et al., 2007). Thesestudies focused more on changes in cellular morphology than onspecific molecular interactions, but they offered insight into thesubcellular organization of the cytoskeleton and generally agreed


that there are moderate levels of actin within the synaptic terminalsof both rod and cone photoreceptors (Nagle et al., 1986; Schmitz &Drenckhahn, 1993; Schmitz et al., 1993; Katsumata et al., 2009).Actin and microtubule networks in photoreceptors help to stabilizeactive zone components and to aid in cargo trafficking to andfrom the synapse (Schmitz & Drenckhahn, 1997; Zanazzi &Matthews, 2009).

Interactions between actin and various binding partners help tosculpt pre- and postsynaptic structure (Doussau & Augustine,2000; Hotulainen & Hoogenraad, 2010). For example, actininteracts with dystrophin and closely related spectrin proteins,all of which are found in photoreceptor terminals (Lazarides et al.,1984; Isayama et al., 1991; Spencer et al., 1991; Schmitz et al.,1993; Ueda et al., 1995, 1998; Drenckhahn et al., 1996; Blanket al., 1997, 1999; Morgans, 2000; Jastrow et al., 2006; Uthaiah andHudspeth, 2010). One of the more common binding partners foractin in most presynaptic terminals is synapsin, but synapsin isabsent from photoreceptor terminals (Mandell et al., 1990; Koontz& Hendrickson, 1993). Its absence at ribbon synapses is thought toexplain the high mobility of synaptic vesicles at ribbon synapses(Holt et al., 2004; Rea et al., 2004). The network of actin fibers canexhibit tremendous plasticity as shown in hair cells where the entireactin cytoskeleton turns over every 48 h (Schneider et al., 2002). Theregulation of actin varies among different retinal cell types but ofteninvolves Ca2+-dependent and CaV-associated processes (Fukudaet al., 1981; Johnson & Byerly, 1993; Job & Lagnado, 1998;Schubert & Akopian, 2004, 2006; Oertner & Matus, 2005; Cristo-fanilli et al., 2007; Mizuno et al., 2010). At photoreceptor synapses,single particle tracking studies show that individual CaV channelsdiffuse more freely after the disruption of actin with cytochalasin,raising the possibility that an actin network helps to maintain thespatial position of photoreceptor synaptic proteins (Mercer et al.,2011a).

In addition to actin, the other two primary cytoskeletal proteins,intermediate filaments and microtubules, are present in photo-receptors (Gray, 1976; Nagle et al., 1986). Intermediate filamentsare present in the axon and perinuclear region, whereas microtubulesare found throughout the cell (Nagle et al., 1986). At many synapses,microtubules play an important role in vesicle delivery (Elluruet al., 1995; Lin-Jones et al., 2003; Gonzalez-Bellido et al., 2009)and, consistent with such a possibility, they can sometimes beobserved close to the ribbon and ribbon-associated vesicles (Gray,1976; Nagle et al., 1986; Zanazzi & Matthews, 2009).

Deficits in cytoskeletal and cytomatrix proteins can causeneurological defects including Usher syndrome (Williams, 2008),which is the most common form of deaf-blindness. Clinically, thereare three subtypes of Usher syndrome, caused by at least 12identified gene loci (Kremer et al., 2006; Maerker et al., 2008;Friedman et al., 2011; Richardson et al., 2011). Seven USH1 locihave been identified to date and are responsible for the most severeform of deaf-blindness syndrome (Ahmed et al., 2003; Yan & Liu,2010). These gene regions encode for various cytomatrix moleculesincluding the scaffold proteins harmonin (USH1C) and “scaffoldprotein containing ankyrin repeats/SAM domain” (USH1G), themotor protein myosin VIIa (USH1B), and the cell–cell adhesionmolecules cadherin 23 (USH1D) and protocadherin 15 (USH1F)(Reiners et al., 2003, 2005a, 2006; Adato et al., 2005; El-Amraoui &Petit, 2005). Three USH2 loci encode for the scaffold proteinsusherin (USH2A) and whirlin (USH2D) as well as very largeG-protein-coupled receptor 1b (USH2C) (Reiners et al., 2005b;Yang et al., 2010). The downstream product of the lone USH3 geneis the synaptic protein clarin-1 (Adato et al., 2002; Isosomppi et al.,

2009). Many of the Usher proteins interact with one another, as wellas with the actin cytoskeleton (Boëda et al., 2002; Inoue et al., 2006;Rzadzinska et al., 2004) and cell–cell adhesion molecules (Küssel-Andermann et al., 2000; Reiners et al., 2006). In hair cell stereociliaand the connecting cilium in photoreceptors, these protein networksappear to be important for intracellular protein trafficking andstructural organization. In addition to being found in cilia, whirlin,myosin VIIa, harmonin, cadherin 23, protocadherin 15, and clarin-1are also present in photoreceptor terminals where they likely helporganize the structure of the ribbon synapse (El-Amraoui et al.,1996; Reiners et al., 2003, 2005a; Williams et al., 2009; Zallocchiet al., 2009).

Lipid rafts

Along with cytoskeletal interactions, the distribution of lipidswithin the plasma membrane is a major mechanism for segregatingand compartmentalizing membrane proteins (Lenne et al., 2006).Using electron microscopy and a cholesterol-binding antibiotic,filipin, Cooper and McLaughlin (1984) found that photoreceptorsdisplay a high concentration of cholesterol in lipid rafts at margins ofthe ribbon-style active zone. Consistent with the presence of lipidrafts in photoreceptor terminals, Mercer et al. (2011a) foundthat labeling of lipid raft ganglioside GM1 glycoproteins withfluorescein isothiocyanate-conjugated toxin B stained the OPL.Cholesterol-containing lipid rafts were absent from nonribbon loca-tions in presynaptic terminals and were not observed in the post-synaptic dendrites of horizontal and bipolar cells (Cooper &McLaughlin, 1984). P-/Q-type CaV channels and a2d CaV channelaccessory subunits have been shown to localize preferentially to lipidrafts (Taverna et al., 2004; Davies et al., 2006), suggesting thatmembrane cholesterol may assist in clustering ion channels close tovesicle release machinery (Lang et al., 2001; Gil et al., 2004; Salaünet al., 2005; Taverna et al., 2007; Linetti et al., 2010). Consistent withsuch a possibility at photoreceptor synapses, depleting membranecholesterol from photoreceptors expanded the synaptic confinementarea for CaV channels (Mercer et al., 2011a). These results alsosupport the hypothesis that lipid rafts act as diffusion barriers to limitthe lateral mobility of membrane proteins (Renner et al., 2009).

Summary of protein interactions within the photoreceptorribbon synapse

Fig. 2 illustrates the coassembly of proteins at the photoreceptorribbon synapse. Interactions among ribeye A domains form thebackbone of the ribbon (Schmitz et al., 2000; Magupalli et al.,2008), whereas ribeye B domains on the outer face of the ribbonappear to link it to scaffold proteins at the base such as bassoon,piccolo, and Unc119 (Alpadi et al., 2008). Bassoon and piccolo alsointeract with CAST and the homologous protein ELKS (Takao-Rikitsu et al., 2004; Tokoro et al., 2007). The protein “hub” formedby CAST, bassoon, piccolo, RIM, and Munc13 proteins helps tocluster a number of proteins near the ribbon (Ohara-Imaizumi et al.,2005; Inoue et al., 2006; Wang et al., 2009; Hida & Ohtsuka, 2010).Contacts between SNARE proteins and Munc13 may help tolocalize SNARE complexes beneath the ribbon (Betz et al., 1997;Guan et al., 2008; Deng et al., 2011), while interactions betweenRIM andMunc13 with Rab3a may link this ribbon complex directlyto vesicles (Dulubova et al., 2005). CaV channels can associate withthe ribbon by virtue of interactions with RIM proteins, CaBP4, andUnc119 (Hibino et al., 2002; Kiyonaka et al., 2007; Han et al., 2011;Kaeser et al., 2011). Many other proteins are found at photoreceptor


ribbon synapses (Uthaiah and Hudspeth, 2010), and thus,interactions with other synaptic, scaffolding, and motor proteins(Muresan et al., 1999; tom Dieck et al., 2005; Katsumata et al.,2009) are also likely to help organize CaV channels, synapticvesicles, and fusion machinery at the ribbon synapse.

The ECM

In addition to interactions with intracellular proteins and intra-membrane proteins, active zone-associated proteins can interactwith the ECM in the synaptic cleft. A number of different synapticcleft proteins are important for positioning presynaptic release sitesacross from postsynaptic receptors (Specht & Triller, 2008; Feng &Zhang, 2009; Lajoie et al., 2009). We review ECM proteins, bothretina specific (e.g., pikachurin, retinoschisin, and nyctalopin) andotherwise, that have been shown to help organize photoreceptorsynapses and their postsynaptic contacts in the OPL.

Alterations in the proteins dystrophin and dystroglycan causemuscular dystrophy and can produce visual deficits (Straub &Campbell, 1997; Waite et al., 2009). Both dystrophin and dystro-glycan are expressed at the synapses of rod and cone photoreceptors(Schmitz et al., 1993; Ueda et al., 1995; Drenckhahn et al., 1996;Blank et al., 1997, 1999; Ueda et al., 1998; Morgans, 2000; Jastrowet al., 2006). Futhermore, mutations in dystrophin and dystroglycancan cause reductions in the ERG b-wave (Cibis et al., 1993;Fitzgerald et al., 1994; Pillers et al., 1999). A retina-specific formof dystrophin, Dp260, is localized to photoreceptor synapses(D’Souza et al., 1995), and reductions in this protein causea selective loss of dystroglycan from the OPL (Kameya et al.,1997). Dystroglycan precursor proteins are cleaved into twosubunits: b-dystroglycan and a-dystroglycan. a-dystroglycan isa heavily glycosylated extracellular protein that interacts withmultiple ECM partners including b-dystroglycan, pikachurin,fibulin, and laminin (Ibraghimov-Beskrovnaya et al., 1992; Talts

Fig. 2. Protein–protein interactions at the photoreceptor ribbon synapse. The synaptic ribbon anchors to bassoon and piccolo at theterminals of rods and cones. The vertical ribbon is complexed at the base through CAST to a hub including RIM2, Rab3a, and Munc13.This synaptic node may help to position primed vesicles close to CaV channels and the fusion machinery (e.g., syntaxin, SNAP-25). CaVchannels also appear to interact with the actin cytoskeleton and, by virtue of interactions with CaBP4, RIM, and Unc119, may coupledirectly to the ribbon itself. Kif3a and a complex of ELKS and RIM1 appear to be located at more distant sites up the vertical face ofthe ribbon. In Figs. 2 and 3, solid lines show direct interactions and dashed lines show putative interactions, for which direct interactionshave not yet been definitively established.


et al., 1999; Sato et al., 2008). In addition to binding to a-dystroglycanoutside the cell, b-dystroglycan spans the plasma membrane andbinds to dystrophin inside the cell. Dystrophin in turn interacts withthe actin cytoskeleton. Disruption of b-dystroglycan causes changesin K+ channel clustering in Müller cells but does not appear to alterdystrophin localization in the outer retina or cause changes in retinallamination patterns (Satz et al., 2009). By contrast, as discussedbelow, impaired interactions between a-dystroglycan and pikachurinproduce significant outer retinal defects.

The ECM protein pikachurin interacts with glycosylated a-dystroglycan at photoreceptor terminals (Sato et al., 2008; Kanagawaet al., 2010; Hu et al., 2011). The presence of pikachurin is criticalfor establishing contacts between rods and bipolar cells (Sato et al.,2008). Pikachurin knockout mice yield viable offspring but showmorphological defects in OPL organization (Kanagawa et al., 2010)and blunted ERG responses (Sato et al., 2008). Hypoglycosylationof a-dystroglycan can impede dystroglycan–pikachurin interac-tions, causing defects in the OPL similar to those observed inpikachurin knockout mice (Kanagawa et al., 2010; Hu et al., 2011).Although a postsynaptic protein partner for pikachurin has not beenidentified, these data suggest that pikachurin provides an interme-diary tether between the terminal of a photoreceptor and dendrite ofa bipolar cell.

Laminin isoforms have been implicated in the functionalorganization of the OPL and photoreceptor outer segment layer(Libby et al., 1999; Biehlmaier et al., 2007). Laminin interacts withmultiple ECM proteins including a-dystroglycan and retinoschisin(Claudepierre et al., 2005; Steiner-Champliaud et al., 2006). Sevenlaminin subtypes have been described in the retina (Libby et al.,2000), and mutations of at least two laminin subtypes result infloating ribbons (Biehlmaier et al., 2007).

Retinoschisin is a secreted retina-specific OPL matrix protein,and mutations cause the retinopathy X-linked retinoschisis (Gray-son et al., 2000; Tantri et al., 2004; Vijayasarathy et al., 2008). Thisprotein is a large disulfide-linked ECM organizing protein, witha critical adhesion site called the discoidin domain. Defects in thediscoidin domain of retinoschisin disrupt trafficking and secretion(Wu & Molday, 2003) and are thought to contribute to develop-mentally dependent changes in retina morphology and subsequentretinal dysfunction (Weber et al., 2002; Takada et al., 2004, 2008).The discoidin domain of retinoschisin can interact with a number ofbinding partners: anionic phospholipids (Vijayasarathy et al., 2007;Kotova et al., 2010), galactose (Dyka et al., 2008), Na+/K+-ATPase(Molday et al., 2007; Shi et al., 2009; Friedrich et al., 2011),photoreceptor CaV channels (Shi et al., 2009), laminin, alphacrystallin, and the binding partner for peanut agglutinin (Steiner-Champliaud et al., 2006). Like pikachurin, a postsynaptic bindingpartner for retinoschisin has not been identified, but retinoschisin isnevertheless essential for proper development and function of theretina (Park et al., 2009; Sergeev et al., 2010).

The retina-specific ECM protein nyctalopin, derived from theNYX gene, has been implicated in a form of CSNB (Bech-Hansenet al., 2000; Pusch et al., 2000) and the mouse “no b-wave” (NYXnob)mutant (Gregg et al., 2003, 2007). Analysis of ERGs in CSNBpatients and NYXnob mutant mice indicates a failure of transmissionfrom photoreceptors to ON bipolar cells (Khan et al., 2005;Bahadori et al., 2006; Leroy et al., 2009). This is similar to effectsof postsynaptic mutations in the glutamate receptor, mGluR6, or thetransduction channel, TRPM1, at the ON bipolar synapse (McCall& Gregg, 2008; Shen et al., 2009; van Genderen et al., 2009; Koikeet al., 2010; Morgans et al., 2010). Nyctalopin appears to targetTRPM1 to the tips of ON bipolar cell dendrites, which may explain

the similarity in ERG phenotypes when nyctalopin or TRPM1 aremutated (Cao et al., 2011; Pearring et al., 2011). Like mGluR6 andTRPM1 knockout animals, nyctalopin knockout animals shownormal morphology in the OPL (Ball et al., 2003). This contrastswith mutations of presynaptic proteins (e.g., CaV channels, bassoon,or ribeye) that lead to disorganization of the OPL, including thesprouting of ectopic synapses (McCall & Gregg, 2008). The rela-tively normal OPL structure of NYX mutants is consistent with thehypothesis that nyctalopin is more important for maintaining thedendritic organization of ON bipolar cells, whereas the disorgani-zation of the OPL that accompanies mutations in pikachurin orretinoschisin suggests that these proteins are more important forpresynaptic organization.

Crumbs (Crb), a transmembrane ECM protein, acts as a scaffoldand is a critical element in the apical–basal development of photo-receptors (reviewed in Gosens et al., 2008). Three CRB proteinshave been identified in humans and mice. Deletion or missensemutations of Crumbs genes can lead to Leber’s congenital amau-rosis and retinitis pigmentosa type 12 (den Hollander et al., 1999;Lotery et al., 2001; Meuleman et al., 2004; van den Hurk et al.,2005) indicating a pivotal role in the normal assembly and functionof the retina. Gain-of-function mutations also suggest that properexpression of CRB during development is required to produce thenormal laminar structure of the outer retina (Fan et al., 2003). TheCRB protein assembly links photoreceptors to surrounding Müllerglia at the outer limiting membrane, just beyond the outer nuclearlayer (Mehalow et al., 2003; Van de Pavert et al., 2004). CRB1,CRB2, and CRB3 bind directly to protein 4.1 (EBP41)-L5 andMPP5 family to maintain neural–glial connectivity at adherensjunctions in the outer limiting membrane (Knust & Bossinger, 2002;Meuleman et al., 2004; van de Pavert et al., 2004). At photoreceptorsynapses, there is evidence for CRB2, CRB3, MPP4, MPP5, andVeli3 expression but not CRB1 expression (van de Pavert et al.,2004; Kantardzhieva et al., 2005, 2006; Stöhr et al., 2005; Aartsenet al., 2006). Among other functions, these proteins are thought toregulate the synaptic localization of PMCA proteins in rods (Yanget al., 2007).

Despite its name, PSD-95 is not limited to postsynapticlocations but can also be found presynaptically in terminals ofphotoreceptors (Koulen et al., 1998). PSD-95 contains PDZdomains that can interact with interact with a number of proteins(Nourry et al., 2003; Feng and Zhang, 2009). In photoreceptorterminals, PSD-95 has been shown to interact with Crumbs-relatedproteins (Aartsen et al., 2006), PMCA (Aartsen et al., 2009), and theputative calcium-activated chloride channel, TMEM16B (Stöhret al., 2009). PMCA and calcium-activated chloride channels arenot clustered tightly near the synaptic ribbon but distributedmore diffusely throughout photoreceptor terminals (Morganset al., 1998; Mercer et al., 2011b). PSD-95 may thus be moreimportant for organizing proteins in surrounding parts of thesynaptic terminal, whereas other proteins discussed earlier (e.g.,RIM and Munc13) may be more important for organizing proteinsnear the ribbon.

Yamagata and Sanes (2010) showed evidence for a transsynapticscaffold in photoreceptors involving MAGI proteins. Like PSD-95,MAGI proteins contain multiple PDZ domains (Nourry et al., 2003).MAGI proteins in the presynaptic terminals of photoreceptorsappear to be linked across the synaptic cleft by extracellularSidekick-2 proteins and cadherins to MAGI proteins in postsynapticdendrites (Yamagata et al., 2002; Yamagata & Sanes, 2010).Sidekick-2 may be retina specific since homologous transsynapticscaffold proteins have not yet been described at other synapses.


Summary of protein interactions with the ECM at thephotoreceptor ribbon synapse

Fig. 3 summarizes various extracellular protein–protein interactionsacross the OPL. As described above, PSD-95 in photoreceptorterminals can link to PMCA (Aartsen et al., 2009), TMEM16Bcalcium-activated chloride channels (Stöhr et al., 2009), and theCrumbs complex (Yang et al., 2007). Whereas RIM and Munc13proteins appear to be particularly important for organizing activezone proteins close to the ribbon (Fig. 2), PSD-95 may be moreimportant for organizing proteins in neighboring nonribbon regionsof the terminal. By virtue of its interactions with laminin, CaVchannels, and Na+/K+ ATPases, retinoschisin may be an importantnode for organizing ECM proteins (Molday et al., 2007; Shi et al.,2009; Friedrich et al., 2011). Laminin and pikachurin can alsointeract with the dystroglycan/dystrophin complex (Claudepierreet al., 2005; Kanagawa et al., 2010). Other links among ECMproteins remain to be discovered, such as binding partners fornyctalopin and Crumbs complex proteins.

Dynamic changes in ribbon proteins

The need to maintain efficient and reliable neuron-to-neuroncommunication would appear to dictate a relatively fixed arrange-ment of calcium channels, vesicle release sites, and postsynapticreceptors at many synapses, including photoreceptor synapses. Themany interactions among cytoskeletal, intramembrane, ribbon-associated, and ECM proteins described above also suggest a staticand heavily reinforced structure. However, despite these expect-ations, there is evidence for a surprising degree of structuralplasticity at photoreceptor ribbon synapses, some of whichoperates on a very rapid time scale.

As mentioned above, mutations in a number of differentpresynaptic proteins can cause neurodegenerative changes thatare accompanied by changes in ribbon structure. For example,mutations in CaV1.4, bassoon, complexin, synaptojanin, andlaminin can produce floating ribbons (Dick et al., 2003; Reimet al., 2005; tom Dieck et al., 2005; Chang et al., 2006; Biehlmaieret al., 2007). Mutations in tubby-like protein 1 (TULP1), which

Fig. 3. Structural organization and protein interactions across the OPL. There appear to be at least two major nodes of protein–proteininteractions in the ECM within the OPL. The Sidekick-2 transsynaptic scaffold attaches MAGI proteins in apposed cells, with putativelateral presynaptic interactions to PSD-95. PSD-95 also appears to anchor the Cl(Ca) channel TMEM16B and PMCA extrusion pump atnonribbon sites in the terminal. The second hub of scaffolding interactions occurs between a transmembrane dystroglycan complex and theretina-specific ECM proteins pikachurin and retinoschisin. These complexes are linked through synaptic laminin and cytoplasmic actin,while also attaching to the extracellular face of transmembrane CaV channels and the Na+/K+-ATPase.


underlies a form of autosomal recessive retinitis pigmentosa, alsocauses changes in the structure of photoreceptor ribbons (Grossmanet al., 2009). TULP1 appears to play a role in intracellular membranetrafficking but its role in synaptic function is unclear. Additionally,mutations in cysteine string protein alpha, a chaperone protein thatprevents SNAP-25 degradation and SNARE complex formation(Sharma et al., 2011), cause photoreceptor degeneration accompa-nied by floating ribbons and the appearance of electron-denseaggregates (Schmitz et al., 2006). In addition to changes in ribbonstructure, mutations in presynaptic CaV channel subunits (a1F, b2a,a2d4), and the calcium channel-associated protein CaBP4 can alsopromote the extension of dendritic processes from bipolar andhorizontal cells into the outer nuclear layer and formation of ectopicsynapses (Haeseleer et al., 2004; McCall & Gregg, 2008).

More surprising than the ability of mutations and neurodegen-erative changes to induce long-term structural changes, ribbons inrods and cones can alter their structure reversibly on a diurnal basis(Abe & Yamamoto, 1984; Vollrath & Spiwoks-Becker, 1996; Adlyet al., 1999; Balkema et al., 2001; Spiwoks-Becker et al., 2004).At night, rod ribbons form plate-like structures, but in daytime,ribbons become much shorter and are associated with adjacentelectron-dense spherical bodies. In the transition between these twoforms during crepuscular conditions, the ribbons often assumea club-like appearance (Abe & Yamamoto, 1984; Vollrath &Spiwoks-Becker, 1996; Adly et al., 1999). It has recently beenreported that these differences are much more pronounced in C57Bl/6J mice than Balb/cJ mice (Fuchs et al., 2011). Diurnal changes inribbon shape appear to be driven by light, not circadian rhythms(Spiwoks-Becker et al., 2004). Diurnal structural changes have alsobeen observed in ribbons from pineal photoreceptors (Kurumado &Mori, 1977; Kikuchi et al., 2000) and retinal bipolar cells (Hullet al., 2006). The finding that heterotypic interactions between Aand B domains of ribeye are inhibited by NAD(H) has led to theproposal that metabolically driven changes in NAD(H) levels mightregulate diurnal changes in ribbon structure (Magupalli et al.,2008).

Ribbons are also capable of dynamic movements on very shorttime scales. Bipolar cell ribbons labeled with fluorescently conju-gated ribeye-binding peptide can exhibit both small (Zenisek et al.,2004; Mercer et al., 2011a) and occasional large rapid excursionsthrough the cell (Zenisek et al., 2004).

Diurnal changes in postsynaptic processes have been described.However, these appear to occur only in fish retina where exposureto light stimulates the tips of horizontal cell dendrites (known asspinules) to extend into the cone pedicle and darkness causes themto retract (reviewed by Wagner & Djamgoz, 1993).

The possibility of rapid changes in the arrangement of pre-synaptic proteins has been investigated by visualizing the move-ments of individual CaV channels labeled with brightly fluorescentquantum dots (Mercer et al., 2011a). Streptavidin-coated quantumdots, bound through a biotinylated secondary antibody, wereattached to the extracellular domain of the a2d4 accessory subunitof L-type CaV channels in photoreceptors. Even though CaVchannels interact with multiple proteins, single particle trackingexperiments show that individual CaV channels are continuously inmotion within the plasma membrane of photoreceptors (Merceret al., 2011a). Movements of CaV channels are confined to a smallregion near the ribbon that roughly matches the size of the activezone, consistent with evidence that CaV channels cluster beneaththe ribbon in photoreceptors and hair cells (Raviola & Gilula,1975; tom Dieck et al., 2005; Frank et al., 2010). Some of the CaVchannel movement may reflect movement of the overlying ribbon

but ribbon movements are much smaller than CaV channel move-ments (Mercer et al., 2011a).

Depolarization-evoked fusion of vesicles at the base of theribbon can abruptly increase CaV channel movements, propellingthem away from the center of the confinement domain (Mercer et al.,2011a). The lipid constituents of vesicle membranes do not appearto differ from plasma membrane lipids (Takamori et al., 2006),suggesting that this increased channel movement is probably notdue to changes in local lipid composition but more likely due toa brief expansion of the active zone membrane. Channels reboundtowards the center of the confinement domain soon after thetermination of exocytosis with a time course similar to that ofendocytotic membrane retrieval. Thus, changes in the rate of vesiclefusion may cause the synaptic membrane to inflate and deflate like aballoon. These results are consistent with the suggestion that thefusion of synaptic vesicles may disorganize the arrangement ofnearby exocytotic proteins and thereby contribute to postsynapticdepression (Neher & Sakaba, 2008; Hosoi et al., 2009; Kim & vonGersdorff, 2009). Disorganization of the synapse by altered mem-brane fusion and retrieval may also explain the presence ofmalformed ribbons produced by mutations of proteins involved inexocytosis and endocytosis.

Disruption of the actin cytoskeleton or depletion of cholesterolfrom cholesterol-rich lipid rafts at the base of the ribbon expand thesize of the CaV channel confinement domain, allowing channels tomove further away from the ribbon (Mercer et al., 2011a). Ca2+

channels are normally confined to a region within 50–100 nm ofrelease sites (Mercer et al., 2011b). Increasing that distance wouldbe expected to reduce the probability that an individual channelopening could induce vesicle fusion and thereby diminish thecoupling efficiency between channel opening and vesicle fusion.Changes in postsynaptic receptor mobility can produce changes insynaptic strength (Heine et al., 2008; Petrini et al., 2009; Rust et al.,2010). For example, increasing the lateral mobility of AMPAreceptors in the hippocampus promotes recovery from desensitiza-tion by speeding the return of undesensitized receptors to thesynapse (Heine et al., 2008). Turnover of actin promoted by n-cofilinenhances AMPA receptor mobility and impairs both long-termpotentiation and long-term depression (Rust et al., 2010). By analogy,we hypothesize that changes in CaV channel mobility caused bychanges in endocytotic activity, actin, cholesterol-rich lipid rafts, orother partner proteins might also be a mechanism for regulatingrelease presynaptically.

Conclusion

This review summarizes many of the different cytoskeletal,cytosolic, membrane, and ECM proteins that participate in assem-bling the synapse during development and maintaining the positionof proteins in locations needed for efficient and reliable trans-mission. Photoreceptors share many intracellular and ECM pro-teins with other central nervous system synapses, but there are alsoa number of unique architectural elements (e.g., synaptic ribbon).A handful of proteins appear to form particularly important nodesfor organizing proteins both in and around the active zone (e.g.,RIM, Munc13, and PSD-95). Despite the many interactions amongmany different proteins, the synaptic terminals of photoreceptorsare surprisingly dynamic. For example, ribbons can reversiblyassemble and disassemble on a diurnal basis. On shorter timescales, CaV channels move continuously within the membrane andthe ability of vesicle fusion to perturb these movements suggests that


fusion can alter the arrangements of these and perhaps otherpresynaptic proteins.

In recent years, investigators have made great progress inidentifying many of the key synaptic, cytoskeletal, and ECMproteins that regulate the anatomy and physiology of conventionaland ribbon synapses. The more difficult task of understanding thecomplex functional and structural interrelationships linking thesemany proteins has only begun, and future studies are likely toreveal an even more complex and dynamic web of interactions.

Acknowledgments

This work was supported by Research to Prevent Blindness, NIH grantEY10542 (W.B.T.), and a University of Nebraska Medical Center GraduateStudent Fellowship (A.J.M.).

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the dynamic architecture of photoreceptor ribbon synapses

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