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NEUROSCIENCE

An intrusive chaperoneAnders S. Kristensen and Stephen F. Traynelis

Stargazin is best known for helping to ferry receptor proteins to the surfaceof neurons. The discovery that it has an unexpected additional role haswidespread implications for the way that neurons talk to each other.

leagues2, in contrast, become steep only whenthe grains flow, and are exponential for alljammed cases — irrespective of whether thesystem has experienced a shear stress. The twoexperiments probe somewhat different aspectsof the force network, but, even so, their resultsare not easily reconciled.

Yielding by shear is the main mechanismby which grains are made to flow. Indeed,Osbourne Reynolds suggested more than 100years ago a relation between packing densityand yielding: flowing grains dilate4. Thesenew experiments2,3 illustrate that force net-works also play a crucial role by signallingstresses, jamming and yielding — in otherwords, the state of the granular system. Theprecise connection between packing geome-try, force networks and jamming, however, isstill a puzzle7.

Recently, theoretical progress has beenmade by considering simplified systems with-out friction or shear such as packingsof deformable, frictionless particles. Oneof the most exciting findings is that thejamming–yielding transition in this system,which occurs when the confining pressure islowered to zero, has many properties of aphase transition such as that which occursbetween the solid and liquid states of matter.Near the critical point at which the transitionoccurs, the number of contacts reaches theminimal value allowed by mechanical stabil-ity, and the packing fraction approachesrandom close packing5 (Box 1): jamming,packing geometry and critical phenomena arethus connected. But what happens for systemsthat yield under shear? How do force net-works fit into this picture? Are these ideasrelevant to jamming and yielding of realisticfrictional granular media?

Studies relating jamming to the packing

Cognition relies on the fast transmission ofexcitatory signals between neurons. To achievethis, neurotransmitters such as glutamate arereleased from one neuron into the synapse(the junction between neurons) where they arepicked up by receptors on the opposing ‘post-synaptic’ cell. Glutamate receptors calledAMPARs form ion channels embedded in thecell membrane that, upon binding of gluta-mate, open rapidly to allow cations to floodinto the neuron — converting the chemicalsignal from the neurotransmitter into an elec-

trical pulse. In this issue, Tomita et al. (page1052)1 show that an accessory protein thathelps to shuttle AMPARs into the membranedoes double-duty to amplify the effectivenesswith which glutamate opens the channel.AMPARs are among the most intensivelystudied of the neurotransmitter ion channels,so this discovery of an ‘overlooked’ accessorysubunit is quite a surprise.

Tomita et al.1 describe a functional analysisof the membrane-spanning protein Stargazin,which until recently was known only as a

system cannot be distinguished from astationary — jammed — state. Corwin andcolleagues’ experiment show that thisassumption is incorrect — with the differencehidden in the force distributions.

What would happen if the rotating top discof Corwin and colleagues’ experiment weregradually stopped? The forces could simplyfreeze — but that would give yielded forces forjammed grains. The forces of the shearedgrains could relax to a jammed distribution —but this would imply the breakdown of rate-independence. One solution to this conun-drum could be the presence of additionalcharacteristics such as packing density4,5 oranisotropy6 of the contact and force networks,which might differ between jammed andyielded grains. To uncover what goes on, wethus need to look inside granular media.

Majmudar and Behringer3 have done justthat, investigating a granular material consist-ing of a layer of discs made of photoelasticplastic. The discs exhibit characteristic fringepatterns that encode the contact forces in thesystem, and, through the analysis of the result-ing images, the authors obtained the firstquantitative determination of force networks(Fig. 1b). They illustrate the power of thismethod by comparing a strongly jammed,uniformly compressed system with a weaklyjammed system under pure shear (compressedin one direction and expanded in the other).Even though both systems are jammed andtherefore static, the force networks of the twosystems are very different: the sheared systemexhibits strong anisotropies6, and ‘force-chains’ are much longer than is the case in acompressed system.

The tails of the force distributions estab-lished by Majmudar and Behringer3 hold asurprise: they change from steep for com-pressed, strongly jammed systems to expo-nential for sheared, weakly jammed systems.The tails determined by Corwin and col-

geometry for compressed frictional systemsmay start to bridge the gap between theoryand experiment. The packing-densities of fric-tional granular media under low pressure spana wide range from random close packing torandom loose packing5,8–10 (see Box 1). In theexperiments conducted by Majmudar andBehringer3, frictional forces are small (‘weaklymobilized’). But does this remain true forlower packing densities? Does random loosepacking correspond to a maximal mobiliza-tion of friction8? Do frictional grains approacha critical point at random loose packingsimilar to frictionless grains at random closepacking5,8?

Simple questions of the behaviour of sandand salt lead to deep riddles and complexphysics. Granular scientists, armed with mar-bles and plastic discs, are finding that some ofthese are now yielding to scrutiny. ■

Martin van Hecke is in the Kamerlingh OnnesLaboratory, Faculty of Mathematics and NaturalSciences, Leiden University, PO Box 9504, 2300 RA Leiden, The Netherlands.e-mail: mvhecke@physics.leidenuniv.nl

1. Liu, A. J. & Nagel, S. R. Nature 396, 21–22 (1998).2. Corwin, E. I., Jaeger, H. M. & Nagel, S. R. Nature 435,

1075–1078 (2005).3. Majmudar, T. S. & Behringer, R. P. Nature 435, 1079–1082

(2005). 4. Reynolds, O. Phil. Mag. 20, 467–481 (1885).5. O’Hern, C. S., Silbert, L. E., Liu, A. J. & Nagel, S. R. Phys. Rev. E

68, 011306 (2003).6. Snoeijer J. H., Vlugt, T. J. H., van Hecke, M. & van Saarloos,

W. Phys. Rev. Lett. 92, 054302 (2004).7. Daniels, K. E. & Behringer, R. P. Phys. Rev. Lett. 94, 168001

(2005).8. Makse, H. A., Johnson, D. L. & Schwartz, L. M. Phys. Rev.

Lett. 84, 4160–4163 (2000).9. Torto, S., Truskett, T. M. & Debenedetti, P. G. Phys. Rev. Lett.

84, 2064–2067 (2000).10. Onoda, G. Y. & Liniger, E. G. Phys. Rev. Lett. 64, 2727–2730

(1990).11. Donev, A. et al. Science 303, 990–993 (2004).

Box 1 Packing problemsWhen spherical grains in a container are shakendown, at the densest possible packing they fill avolume fraction of around 64%. This is ‘randomclose packing’ — a notoriously controversialconcept9, as regular periodic packings (similar tohow oranges are packed in your grocery store)reach higher densities of 74%. Allowing smallregular regions in disordered packings thus canincrease the density beyond random closepacking: ‘random’ and ‘close’ represent opposingtrends9. (Incidentally, non-spherical grains, suchas M&Ms, also pack more densely than 64%11).Even more elusive is random loose packing10,which can be achieved by immersing spheres ina neutrally buoyant fluid and letting them settlegently, creating very fragile packings at volumefractions around 55%. Packing and jamming arerelated: soft, frictionless spheres jam, in theabsence of shear, at a density precisely given byrandom close packing. Perhaps random loosepacking might be defined, similarly, as thedensity where frictional spheres jam. M.v.H.

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regulator that helped move AMPARs into thecell membrane. Their work shows thatStargazin can also control two key aspects ofreceptor function: the overall flux of ionsthrough the water-filled AMPAR pore, and theability of the receptor to function in the con-tinued presence of glutamate, such as mightoccur during rapid neuronal firing. This find-ing, which has been corroborated by otherrecent studies2,3, could have widespread impli-cations for the way that neurons in the brainnot only talk to each other, but how theyincrease or decrease their volume and changetheir pitch — features by which the brain mayencode memory.

This is not the first time that Stargazin hassurprised neuroscientists by having functionsother than those initially proposed for it.Stargazin was originally discovered as a neu-ronal protein expressed from a gene mutatedin the epileptic Stargazer mutant mouse4, andsequence analysis suggested it was a calcium-channel subunit. Then, it was the first integralmembrane protein discovered to interact withAMPARs5. Subsequently, Stargazin and itsfamily members were found to be necessarypartners for AMPARs, both during transportto the neuronal membrane and the subsequentpositioning of the receptors at synaptic sites.Highly coordinated spatiotemporal changes inthe synaptic content of AMPARs are a princi-pal mechanism by which the brain regulatessynaptic strength. This activity-dependentregulation of excitatory signalling strength isconsidered a prime candidate for the biologi-cal mechanism underlying memory. Stargazinassociates with AMPARs in an intracellularcompartment near the cell membrane to chap-erone their delivery to the neuronal surface,for example during changes in synapticstrength (Fig. 1).

Stargazin seems to remain in complex withAMPAR after delivery6,7, indicating that mostneuronal AMPARs are always in associationwith Stargazin or other family members. Inthis study, Tomita et al.1 explore the potentialcontributions of Stargazin to AMPAR func-tion once the receptor reaches the synapticmembrane (Fig. 1). They found that increasesin the density of AMPARs at the cell surfacecould not entirely account for increases in thecell’s functional responses to glutamate in thepresence of Stargazin. An analysis of the kinet-ics of AMPAR function showed that the pres-ence of Stargazin reduces the amount of timethe receptor spends in the ‘desensitized’ state.In this state, glutamate remains tightly boundto the receptor, but the ion-conducting porerarely opens. Moreover, the functional stepswhere the receptor closes its channel andglutamate unbinds also slowed in the presenceof Stargazin (see also ref. 2).

These effects imply that Stargazin alters theease with which the pore opens (referred to asgating) after glutamate binding (Fig. 1). Gatingis defined as the conformational changes inthe glutamate-bound receptor as energygained from the interaction of glutamate withits binding site is used to open the ion channel.Recordings of currents from single channelsindeed showed that in the presence ofStargazin, glutamate-bound AMPAR morefrequently opens into high-conducting con-formations — indicative of increased gatingefficiency. Stargazin in native AMPARs shouldtherefore enhance the efficiency with whichglutamate released from nerve terminals candepolarize a postsynaptic neuron. This predic-tion was confirmed through experimentationwith a mutated version of Stargazin that wasunable to regulate AMPAR function but couldfacilitate AMPAR trafficking.

This new role for Stargazin raises obviousquestions about previous kinetic and struc-tural studies that used experimental systemslacking Stargazin or its siblings. In addition, ithas become even more important to deter-mine whether results obtained with recombi-nant receptors (produced from introductionof cloned DNA into cells) accurately reflectwhat happens with native neuronal receptors.There are also several complex questions thatneed to be answered about the accessory func-tion of Stargazin. What factors control the sizeand nature of the AMPAR ion-conductingpore, and how does Stargazin regulate thesefactors? Can Stargazin’s actions on permeationand gating themselves be regulated? Stargazinand other members of its family have discreteexpression patterns in different regions of thecentral nervous system. Does such hetero-geneity contribute to regional or developmen-tal difference in AMPAR roles?

As always, much remains to be done toanswer these and other questions. But for themoment, the uncovering of Stargazin’s abilityto regulate AMPAR function itself reminds usto expect surprises from even the best-studiedsystems. Who knows how many more crucialfunctions hide among proteins we think weunderstand? ■

Anders S. Kristensen and Stephen F. Traynelis arein the Department of Pharmacology, EmoryUniversity School of Medicine, Atlanta, Georgia 30322, USA.

1. Tomita, S. et al. Nature 435, 1052–1058 (2005).2. Priel, A. et al. J. Neurosci. 25, 2682–2686 (2005).3. Yamazaki, M. et al. Neurosci. Res. 50, 369–374 (2004).4. Letts, V. A. et al. Nature Genet. 19, 340–347 (1998).5. Chen, L. et al. Nature 408, 936–943 (2000).6. Nakagawa, T., Cheng, Y., Ramm, E., Sheng, M. & Walz, T.

Nature 433, 545–549 (2005).7. Vandenberghe, W., Nicoll, R. A. & Bredt, D. S. Proc. Natl

Acad. Sci. USA 102, 485–490 (2005).

Figure 1 |Dual roles for Stargazin. a, Neuronal communication takes place at specialized junctions (synapses) formed between nerve terminals oftransmitting (presynaptic) and receiving (postsynaptic) neurons. In excitatory synapses, glutamate is released from presynaptic membranes and binds to agroup of glutamate receptors referred to as AMPARs. This leads to opening of ion channels and influx of cations, causing a brief electrical pulse. Stargazinengages AMPARs shortly after synthesis in the cell and influences transport of the receptors into the cell membrane. b, A model of AMPAR functionwhereby Stargazin controls receptor ‘gating’. Following binding of glutamate, receptors can either undergo a conformational change into an open-channelstate or a desensitized, closed state. Tomita et al.1 suggest that Stargazin increases the rate by which AMPARs enter the open state, leading to enhanced ionflux during glutamate stimulation.

Glutamate

Desensitized

AMPAR

Stargazin

+OpenAMPAR AMPAR + Stargazina b +

Postsynapticneuron

Presynapticneuron

+

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