Journal of Receptors and Signal Transduction, 28:531–542, 2008Copyright C© Informa UK Ltd.ISSN: 1079-9893 print / 1532-4281 onlineDOI: 10.1080/10799890802602308

MINI REVIEW

Plant Adenylate Cyclases

Lidiya A. Lomovatskaya, Anatoliy S. Romanenko,and Nadejda V. FilinovaLaboratory of Phytoimmunology, Siberian Institute of Plant Physiology and Biochem-istry, Siberian Division of the Russian Academy of Sciences, Irkutsk, Russia

Adenylate cyclase (AC) (ATP diphosphate-lyase cyclizing; EC 4.6.1.1) is a key compo-nent of the adenylate cyclase signaling system and catalyzes the generation of cyclicadenosine monophosphate (cAMP) from ATP. This review summarizes data from theliterature and the authors’ laboratory on the investigation of plant transmembrane(tmAC) and soluble (sAC) adenylate cyclases, in comparison with some key character-istics of adenylate cyclases of animal cells. Plant sAC has been demonstrated to exhibitsimilarities with animal sAC with respect to certain characteristics. External factors,such as far-red and red light, temperature, exogenous phytohormones, as well as spe-cific triggering compounds of fungal and bacterial origin exert a significant influence onthe activity of plant tmAC and sAC.

Key Words: Plant transmembrane adenylate cyclase; Plant soluble adenylate cyclase;Red light; Phytohormones; Elicitors.

INTRODUCTION

Adenylate cyclase (AC) (ATP diphosphate-lyase cyclizing; EC 4.6.1.1) formspart of the adenylate cyclase signaling system and catalyzes the synthesisof cyclic adenosine monophosphate (cAMP) from ATP. Apart from AC, thissignaling system incorporates G protein-coupled receptors and G proteins(1,18,23,57,62,67), cAMP (4,7,44,45), cAMP phosphodiesterases, which convertthis second messenger into adenosine monophosphate (27,72), several proteinkinases, including protein kinase A, specific proteins of the AKAP (A kinase-anchoring proteins) family, and EPAC (exchange proteins activated) (11,15,55),as well as CREB (cAMP response element-binding protein) transcription fac-tors (29).

Address correspondence to Lidiya A. Lomovatskaya, Siberian Institute of Plant Physiol-ogy and Biochemistry, Siberian Division, Russian Academy of Sciences, ul. Lermontova32, Irkutsk, 664033 Russia. Fax: +3952-51-07-54. E-mail: LidaL@sifibr.irk.ru

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Animal and human adenylate cyclases have been known for over 50years, and their structures and functions have been reviewed in much detail(17,21,26,29,36,37,49,60). The existence of a plant adenylate cyclase signalingsystem has however long been doubted, and owing to this, data on plant adeny-late cyclases are scarce and often controversial (6,10,40,43,58).

Despite the fact that the AC enzymes perform the same function in alltypes of living organisms and use the same substrate, the different ACs vary intheir expression, structure, activity, and regulation (13–15,17,22,24,30,34,73).Based on their specific characteristics (e.g., similarities of amino acid se-quences within their catalytic domains), ACs from animal cells have been sub-divided into six classes (16). In contrast, plant ACs could not yet be catego-rized because of lack of detailed structural data such as complete nucleotidesequences.

Early on, the possibility of the presence of cAMP in plants, and thereforeof adenylate cyclase, has been discussed (4,6,12,45,58,64). Over the last 15–20years, thanks to the application of high-resolution nuclear magnetic resonancetechniques (45) and various types of chromatography, the presence of the ACsignaling system in plants was unambiguously established (3,7,39,40). Theseobservations were further strengthened by the discovery of different types ofprotein kinases and specific proteins linked to cAMP (6,32). Nevertheless, moststudies analyzing this signaling system in plants have been dedicated to theidentification of the actual concentrations of cAMP in different plant tissues(4,7,10,47), mainly in response to hormonal regulation of metabolic processes(25,30). There are much fewer publications focusing on the different compo-nents of the adenylate cyclase signaling system in plants such as AC or phos-phodiesterase (6,10,27,39,40,72).

Transmembrane Form of AC (tmAC)It is assumed that structure and function of adenylate cyclases in plants is

similar to animal adenylate cyclases. This assumption is based on the findingthat many regulators of AC activity in animal cells produce a similar effecton plant tmAC (10,40,43,48,49,68). The structure of animal cell adenylate cy-clases is characterized by a number of specialized domains associated witheach other in the following N- to C-terminal order: The N-terminal domainexposed to the cytosol; C1, a (hydrophobic) transmembrane domain consist-ing of six α-helices; C1, a large cytoplasmic domain; M2, the second trans-membrane domain with a glycosyl residue; and C2, the second cytoplasmicdomain, which is homologous to C1 and placed at the C-terminus. DomainsC1 and C2 with molecular masses of 25 kDa each interact with each otherbased on the principle of “head-to-tail,” forming a catalytic domain contain-ing binding sites for ATP, the AC-activator forskolin, as well as for the α-subunit of Gs(stimulating) and Gi(inhibiting) GTP-binding proteins (57,62).

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This peculiarity of functional construct is the basis for distinct regulations,specific for each tmAC isoform (26,36,49,57). The molecular weight of animaltmACs ranges from 180 to 200 kDa (26). Nine animal tmAC isoforms areknown to date, and they differ in organ specificity and regulation by G pro-teins and calcium ions (13,14,17,18,23,60,62,73). There are no literature datawith respect to AC isoenzymes in plants, but the same agents (Mn2+, Mg2+,Ca2+) regulating animal cell ACs are known to produce different and often re-verse effects on the activity of plant tmAC (6,10,34,43,68,74). These findingsindirectly confirm the likely presence of several tmAC isoforms in plants.

The earliest data on plant tmAC activity were acquired at the ultrastruc-tural level with a catalytic cytochemistry method. The identification of an ACreaction product— inorganic phosphate (pi), formed as a result of cAMP syn-thesis from ATP—is based on Pi precipitation by heavy metals (lead or ceriumsalts) (64). However, this method is not sufficiently reliable, because on theone hand, Pi may be a reaction product of many enzymes (e.g., ATPase orRNAase). On the other hand, the enzyme activity may be suppressed by afixer or heavy metals salts. Nevertheless, this method demonstrated adenylatecyclase activity in plants at the inner and outer sides of the plasma membraneand in chloroplast membranes, but it did not identify AC activity in other cellorganelles such as mitochondria, endoplasmic reticulum, or lysosomes (64).Other authors (3), using adenylate imidodiphosphate as a substrate, showedtmAC localized on the plasma membrane and on vacuolar and plastid mem-branes in cells of Bryum argenteum seedlings, but they did not find tmACon the membranes of other cell organelles. Witters and colleagues (70), us-ing adenylate imidodiphosphate as a substrate and gold-labeled antibodies tocAMP, identified the product of adenylate cyclase activity in stroma and theintermembrane space of isolated tobacco chloroplasts. At the same time bio-chemical methods allowed identification of AC activity in mitochondria andvacuolar membranes fractions (64). Our investigations conducted at the ultra-structural level using primary antibodies to cAMP revealed cAMP formation inalmost all organelles of potato cells (41). This finding was partially confirmedby biochemical methods. Both “soluble” and trans-membrane forms of AC werefound to be present in nuclei and chloroplasts isolated from potato cells (39).

In accordance to literature data, the optimum of plant tmAC has a widerange: one form of tmAC was found with the optimum activity at pH 4.8–5.2(66), whereas other isoforms have an optimum activity at alkaline (pH 8.8)(63). Our experimental data show that in plasma membranes of potato roots,stems, and leaves, tmAC has an optimum activity at pH 7.4 (40). For functionalactivity, plant tmAC requires magnesium ions, because it is known for tmAC ofanimal cells and microorganisms. Forskolin and NaF also have a stimulatingeffect on plant tmAC (10,25,32).

We are not aware of any publications on structural characteristics, such asamino acid or nucleotide sequences of plant tmACs. This may be explained by

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the fact that studies of plant tmAC began much later than the investigationson AC in animals and humans.

“Soluble” Form of AC (sAC)Literature data on “soluble” AC are even more controversial. Animal sAC

has been studied in much detail in the last 10 years, mainly with extracts fromrat testicles (9,38,51,75). Unlike tmAC, the activity of sAC depended on thebivalent cation Mn2+, and sAC was insensitive to the regulation by G proteinsand forskolin. sAC exhibited lower affinity (approximately 10 times) to ATP(Km ∼ 1 mM) compared to tmAC (Km ∼1 µM). In addition, sAC in animalcells proved quite responsive to changes of concentrations of intracellular bi-carbonate (9,71,75). Ubiquitous presence of carbonate anhydrases in animalorganisms indicates that intracellular concentrations of bicarbonate (and sACactivity) may reflect changes in and/or CO2 (5). Because CO2 is a final prod-uct of energy-forming processes, sAC may function as an intracellular sensorof metabolic activity (75). Analysis of full-length cDNA of animal cells showedthat the predicted protein should have a size of 187 kDa, whereas the catalyti-cally active form of the purified enzyme has a molecular weight of only 48 kDa,suggesting a proteolytic mechanism of sAC activation (29,71). sAC was shownto contain two catalytic domains and a C-terminal auto-inhibiting domain thatreduces Vmax without change of affinity to the substrate (38). A distinctive fea-ture of sAC is the presence of a coordinated P-loop (i.e., a nucleotide-bindingmotif for binding ATP or GTP) (71). Furthermore, the C-terminal part of sACcontains an amino acid sequence with a high content of leucine, a potentialleucine zipper or domain of spiral-spiral interaction of unknown designation(29). It is assumed that this region is a necessary domain for protein-proteininteraction, apparently to attach sAC to the cytoskeleton (76,77). According toZipin et al. (76), sAC in animal cells is specifically bound to various intracel-lular compartments and structures: mitochondria, centrioles, mitotic spindle,middle plates, and nucleus. The shortened form of sAC has two domains (re-gions of amino acid residues no. 145–200 and 257–318), colocalized with thecatalytic domains, without which the enzyme in the nucleus cannot function(29). The presence of sAC within organelles, and of EPAC in the perinuclearspace and in mitochondria (55), as well as AKAPs in the nuclear matrix, mem-brane, and in mitochondria (11), may suggest the possibility of the existence ofthe entire adenylate cyclase signaling cascade in intracellular compartments.sAC in animal cells is likely to be present in the nucleus only in functionallyactive (i.e., shortened form) (76).

In 1988 Carricarte et al. (10) isolated a fraction of “soluble” AC from alfalfaroots and partially studied its properties. AC activity measured in the presenceof MgATP as a substrate was stimulated by Ca2+ ions and calmodulin. GTP,guanosine 5′-[βγ-imido]-triphosphate, forskolin, fluoride, and cholera toxin

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Plant Adenylate Cyclases 535

(well-known modulators of animal tmAC) did not activate this enzyme. Theauthors established certain molecular characteristics of alfalfa sAC: sedimen-tation coefficient 4.1 S; Stockes’ radius 4.4 nm. Ishikava and colleagues (25)identified the protein in tobacco plant cells, which in their view was named“soluble” AC. The enzyme studied contained a leucine-enriched sequence andshowed significant homology with an analogous enzyme from yeast Schizosac-charomyces pombe, based on the analysis of the respective genes encodingadenylate cyclase (and named axi141). Also, according to the data of these au-thors, a 1.4-kb DNA fragment from the Arabidopsis database has a 57% iden-tity with axi 141, and it is its homolog (25). However, Roelofs and Van Haastertexpress a contrary opinion (56), after analyzing the relevant database and per-forming a comparative study of genomes of many pro- and eukaryotes; theyconcluded that arabidopsis, and apparently plants in general, have no sAC. Toa certain extent this assumption may be explained by the finding of Mutinhoet al. (44) that AC genes in plants may be camouflaged under a wide range oflarge gene families, in particular R genes, which amount to 200–300 in ara-bidopsis and to about 1500 in rice. Protein transcripts of R genes may directlyactivate multiple signal pathways in plants. Resistance responses of the latterto pathogenic fungi and bacteria may occur within a few minutes, accompaniedby a rapid transient increase in cAMP (44). The finding that the novel signalingprotein PSiP isolated from pollen of Agapanthus umbellatus contains a P-loopand leucine-rich repeats, led the authors to conclude (44) that PSiP has thecompetence for producing cAMP and therefore may be considered an sAC.

Our own studies showed (41) that nuclei and chloroplasts of potato cells—along with tmAC—also contain forms of sAC. This enzyme was activated bymanganese and bicarbonate ions (which is a characteristic of sAC), and it didnot respond to sodium fluoride (an activator of tmAC). With immunocytologi-cal studies we identified sAC in cell walls, the cytosol, mitochondria, vacuoles,and chloroplasts of potato plant cells (unpublished data). In addition, prelimi-nary data based on immunoprecipitation and immunoblotting experiments inpotato cells showed that different forms of sAC could be identified, displayingmolecular masses of 225 kDa, 193 kDa, 92 kDa , 68 kDa, and also 60 kDa (thelatter as a minor band) (42).

Regulation of Plant tmAC and sAC Activity by External FactorsBecause plant ACs appear to be part of a complex signaling system, the

activity of ACs is considerably affected by environmental factors of both bioticand abiotic nature. There are data that low temperature (32,48,72), exogenousphytohormones, biogenic inductors (25,30,45), light (20,33,47,52,53), as wellas viruses and fungal and bacterial metabolites exert a highly significant in-fluence on the concentration of endogenous cAMP (12,28,39,41,64,78), whichimplicitly confirms that the activity of AC can be modulated. Phedenko et al.

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(52,53) and Gazumov et al. (20) proved the activation of AC in plants, in thatthey identified light-induced tmAC (52,53) and sAC (20). AC localized in mem-brane fractions (tmAC) showed seasonal changes of activity with respect to itsresponse to red and far-red light, whereas fractions containing sAC, which isalso sensitive to both red and far-red light, did not change depending on theseason (20). Phedenko et al. (52,53) also showed that tmAC in plants is ac-tivated by light absorbed by phytochrome with a wavelength of 660 nm. Theinfluence of red light was neutralized by far-red light (λ = 730 nm), which ischaracteristic of processes controlled by phytochrome. In unicellular algae Eu-glena gracillis, photo-activated AC was identified, which is believed to be aphotoreceptor for step-up photophobic responses (46). Treatment of potato rootcells with extracellular polysaccharides of potato bacterial ring root resultedin a modulation of the activities of tmAC and sAC of nuclei and chloroplasts.Both forms of the enzyme isolated from these organelles of cells from a re-sistant cultivar increased their activity, and those extracted from a sensitivecultivar decreased the activity significantly (39).

Different Pathways of cAMP Signaling?Despite the fact that there is an abundance of data on the functioning of

animal cell adenylate cyclases and relatively fewer studies on plant ACs, theissue of coordination of tmAC and sAC function has not yet been resolved forboth sources of AC. In other words, there is still no clarity with respect to thedifferent intermediate stages of transfer of intracellular signal to sAC and therole of tmAC in this process (76).

The analysis of literature data and of our own results shows that both inplant and animal cells, the AC signaling system may consist of two intercon-nected signal pathways consisting of tmAC and sAC (29,76). A hypotheticalscheme of the mechanisms of this dual pathway is presented in Figure 1. Anincrease of the local concentration of cAMP resulting from the activation oftmAC in the plasma membrane of plant cells provokes the stimulation of atransitory signal directed both to the cell genome and the outside the cell (29).Ion channels specifically activated by cAMP also form part of the signalingmechanism (35,61). Change of concentration of K+ and Ca2+ ions affects thevalue of cell membrane potential (8,34,64,65,68,73,74), which may rapidly, inless than a minute, spread from top to the bottom of the plant (54), activatingtmAC in its remote areas (40).

The regulation of activity of the different forms of AC (tmAC and sAC)localized in cell organelles apparently is indirectly dependent on the activityof tmAC localized on the plasma membrane. A local increase of cAMP levelsin the zone of the plasma membrane by induction of the respective signal-ing mechanisms facilitates the exit of calcium ions from intracellular depots,such as mitochondria, vacuoles, and endoplasmic reticulum (8) (Fig. 1). As

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Plant Adenylate Cyclases 537

Figure 1: Scheme demonstrating the participation of plant tmAC and sAC in thetransmission of intra- and intercellular signaling. Biotic factors (elicitors, phytohormones) andabiotic factors (light, temperature) activate tmAC via stimulation of receptors and Gproteins. Ca2+ influx—through nucleotide-activated calcium channels (CNG)—apparentlyleads to an activation of nuclear and chloroplast tmAC and sAC. The latter may be alsostimulated by manganese and bicarbonate ions, which are always present in plant cells.cAMP may also diffuse to the outside of the cell, participating in the transfer of intracellularsignals to the environment. Abbreviations: NDIC, nucleotide-dependent ion channels; PKA,protein kinase A; sAC, soluble adenylate cyclase; SWR, cell wall receptors; PMR, plasmamembrane receptors; SS, intercellular signaling system; tmAC, transmembrane adenylatecyclase; PDE, phosphodiesterase; TF, cAMP-dependent transmission factors (CREBs, cAMPresponse element-binding proteins); G, G proteins.

reported for animal AC (13,68), calcium ions may act as modulators of planttmAC and sAC activities (10). This assumption is proved by literature dataand the fact that bicarbonate (an activator of animal sAC) also activates sACfrom nuclei and chloroplasts of potato leaf cells (39). This is of particular inter-est because CO2 as precursor of bicarbonate is always present in plant cells,and its partial pressure depends on ambient factors (e.g., temperature), andin chloroplasts bicarbonate is an important intermediate product of photosyn-thesis (5). In addition, there are data showing that in diatomic algae the level

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of cytosolic cAMP increased with the level of growth and of CO2 in the envi-ronment and that the carboanhydrase gene was repressed in chloroplasts viapromoter ptca 1 (22).

CONCLUSION

A phylogenetic connection of ACs of many pro- and eukaryotic organisms,quite distant from each other in terms of evolution, has been unequivocallydemonstrated. The mechanism of two-ion catalysis (Mg2+ or Mn2+) of tmACwas found to be fully inherent to animals, bacteria, and protozoa (59). An au-toinhibiting domain in sAC was found in yeast (24) and higher animals (29).Two different segments of the catalytically active part of animal sAC are quitesimilar to the catalytic segment of AC from cyanobacteria and mixobacteria(9). As reviewed by Barkovsky and Achinovich (2), the homology between fourhuman tmAC subfamilies and the respective orthologues in Drosophila provesthat evolutionary precursors of these forms of tmAC existed already in earlystages of formation of biochemical systems of multicellular invertebrates (i.e.,about 1 billion years ago).

There are two publications on plants reporting a similarity in nucleotidesequence of AC from lily pollen with sAC of fungi (44) and AC from tobaccoleaf cells with sAC of yeast (25). Because the general principles of signalingsystems in microorganisms, plants, and animals are relatively similar thanksto universality of DNA as a major information carrier a significant homologymay also be discovered in the structure of sAC of all organisms.

The identification of common principles of functioning of individual com-ponents of signaling systems, in our case plant tmAC and sAC, will allow toresolve a number of fundamental and applied issues. For example, novel ex-perimental data on tmAC and sAC will not only provide a better understand-ing of the evolutionary links between lower and higher organisms it will alsoenrich our knowledge on the mechanisms of plant protective responses underthe influence of unfavorable external factors.

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