Calciumpermeable channels in plant cells - Wiley Online Library

MINIREVIEW

Calcium-permeable channels in plant cells Fabien Jammes1, Heng-Cheng Hu1, Florent Villiers1, Roxane Bouten1 and June M. Kwak1,2,3 1 Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, USA 2 Department of Plant Science and Landscape Architecture, University of Maryland, College Park, USA 3 Department of Plant Molecular Systems Biotechnology and Crop Biotech Institute, Kyung Hee University, Yongin, Korea

Keywords calcium; development; hormonal response; ion channel; signal transduction Correspondence Fabien Jammes & June M. Kwak, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA Fax: +1 301 314 1248 Tel: +1 301 405 9726 E-mail: [email protected]; [email protected] (Received 28 April 2011, revised 12 July 2011, accepted 4 August 2011) doi:10.1111/j.1742-4658.2011.08369.x

Calcium signal transduction is a central mechanism by which plants sense and respond to endogenous and environmental stimuli. Cytosolic Ca2+ elevation is achieved via two cellular pathways, Ca2+ influx through Ca2+ channels in the plasma membrane and Ca2+ release from intracellular Ca2+ stores. Because of the significance of Ca2+ channels in cellular signaling, interaction with the environment and developmental processes in plants, a great deal of effort has been invested in recent years with regard to these important membrane proteins. Because of limited space, in this review we focus on recent findings giving insight into both the molecular identity and physiological function of channels that have been suggested to be responsible for the elevation in cytosolic Ca2+ level, including cyclic nucleotide gated channels, glutamate receptor homologs, two-pore channels and mechanosensitive Ca2+-permeable channels. We provide an overview of the regulation of these Ca2+ channels and their physiological roles and discuss remaining questions.

Introduction The regulation of Ca2+ flux is a keystone of the integration of environmental signals and their translation into adaptive physiological responses. Critical information regarding the nature and intensity of the stimuli can be relayed by changes in the characteristics of the ‘Ca2+ signature’ which consists of differences in Ca2+ oscillation frequency, amplitude and localization [1–3]. The generation of stimulus-specific Ca2+ oscillations depends on the spatial and temporal control of Ca2+ fluxes, which relies on a process documented largely in animals, known as Ca2+-induced Ca2+ release [4]. One remarkable difference between animals and plants in this regard resides in the absence of the clear identification of plant channels able to bind signaling inter-

mediates that trigger Ca2+ release from internal stores, such as inositol-1,4,5-triphosphate [5], inositol hexakisphosphate [6], cyclic ADP-ribose [7] and nicotinic acid adenine dinucleotide phosphate [8]. Calcium channels in the plasma membrane, together with other transporters, play a role in shaping the Ca2+ signature by transporting Ca2+ into the cells. They are known to be activated by changes in membrane polarization in root hair cells, root epidermal cells, guard cells and mesophyll cells [9–16]. Calcium channels function in various cellular responses, including hormone responses [17], plant–pathogen interaction [18], development [19], symbiosis [20], salt stress [21], light signaling [22] and circadian rhythm [23]. Despite the central

Abbreviations ABA, abscisic acid; CNB domain, cyclic nucleotide binding domain; CNGC, cyclic nucleotide gated channel; HR, hypersensitive response; GLR, glutamate receptor homolog; iGluR, ionotropic glutamate receptors; MeJA, methyl jasmonate; MSCC, mechanosensitive calcium-permeable channel; MscS, small conductance mechanosensitive channel; MSL, MscS-like; SV channel, slow vacuolar channel; TPC, two-pore channel.

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role of Ca2+ channels in these crucial cellular responses, the identity and structure–function relationships of the proteins that underlie Ca2+ influx are not yet fully understood. Electrophysiological approaches have identified many classes of Ca2+ currents across the plasma membrane and some direct effectors of the Ca2+ influx [24], including mechanical stimulation [25], cyclic nucleotides [26], membrane potential [27] and amino acids [28,29]. The diversity of these effectors illustrates the plasticity of the Ca2+-dependent plant response. Several recent reviews have covered the complex cellular network and regulators of Ca2+ signals and channels in abiotic and biotic responses [2,30–32]. We focus here on the plant channels responsible for the modulation of intracellular Ca2+ concentration, their regulation and their physiological functions.

Cyclic nucleotide gated channels The cyclic nucleotides cAMP and cGMP are ubiquitous molecules that play key roles in the regulation of diverse cellular processes, gene expression and signal transduction [33,34]. Cyclic nucleotides are able to bind two functional domains in proteins, the GAF domain (cyclic GMP, adenylyl cyclase, FhlA) and the CNB domain (cyclic nucleotide binding) [35]. Photoreceptors and ethylene receptors contain GAF domains, but it has not been demonstrated whether or not they can bind directly to cyclic nucleotides. The CNB domain is mainly present in two groups of the cation-permeable channel family in plants, the cyclic nucleotide gated ion channels (CNGCs) and the Shaker-type potassium channels, for which the nucleotide binding capacity has not been shown [24,35]. Although they share a common membrane topology, CNGCs generally have a lower ion selectivity compared with the Shaker-type K+ channels, allowing a number of monovalent cations (mostly K+ and Na+) and some divalent cations such as Ca2+ to cross the plasma membrane.

Structure of CNGCs In Arabidopsis, the CNGC family consists of 20 members, subdivided into five subfamily groups (I, II, III, IVa and IVb) [36]. Since the members of these subfamilies share homology with rice genes (16 members in the rice CNGC family), the separation into the different groups probably occurred prior to the monocot– dicot divergence [35].While possible redundancy might be expected to conserve a genetic buffering capacity, studies of mutated genes have proposed various numbers of physiological functions of plant CNGCs, from

pollen tube growth regulation to biotic and abiotic stress adaptation [26,37–40]. Based on structural similarities with their animal counterparts, the plant CNGCs are thought to be potentially composed of four subunits forming a central, non-selective pore gated by cyclic nucleotide ligands (for details see [39]). Each subunit consists of six transmembrane a-helices (S1–S6) with both N- and C-termini facing the cytosol (Fig. 1). The pore loop region, or P-loop, is located between the S5 and S6 domains and includes the pore helix and the selectivity filter. Inside the large C-terminal portion of the protein, the CNB domain overlaps a calmodulin binding region [41]. Interestingly, the position of the calmodulin binding site differs from that of most of the CNGCs in animals, where the calmodulin modulation occurs at the N-terminal part of the protein [42].

Ca2+ ⁄ CaM regulation of CNGCs In 1994, by using anti-calmodulin serum and the calmodulin inhibitors trifluoperazine and W7, Kurosaki et al. showed that the activation of a plasma membrane calmodulin contributed to the termination of the cAMP-dependent Ca2+ entry in cultured carrot cells [43]. In animals, the binding of Ca2+ ⁄ CaM to the N-terminal part of the olfactory and rod CNGCs disrupts the interaction between the N- and C-terminal regions within the molecule, causing inhibition of the channel activity [44–46]. The functionality of the CaM binding domain present in CNGCs has been shown in the tobacco NtCBP4 [47], the barley HvCBT1 [48] and the Arabidopsis channels AtCNGC1 [41], AtCNGC2 [41,49,50] and AtCNGC10 [51]. The consequences of the interaction between Ca2+ ⁄ CaM and the CaM binding domain have been demonstrated. The binding of CaM to AtCNGC2 controls a Ca2+-dependent feedback regulation by reducing the affinity of the cyclic nucleotides for the CNB domain [50]. In addition, by co-expressing a CaM and AtCNGC10 in a potassium transport mutant of Escherichia coli, Li et al. demonstrated that Ca2+ ⁄ CaM was able to significantly reduce the restored bacterial growth and that cGMP could revert the inhibition of the AtCNGC10-dependent potassium transport [51]. The expression of AtCNGC1 that lacks a portion of the calmodulin binding domain resulted in an increase in intracellular K+ concentration in the K+-uptake-deficient yeast mutant trk1 ⁄ trk2 [52]. It appears that the overlapping of the CaM binding sites with the CNB binding domain induces a direct inhibition of cyclic nucleotide binding in the presence of Ca2+ ⁄ CaM, a regulation similar to that of animal CNG channels.


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GLR L1

CNGC

N

Extracellular

MCA1**

L2

APRK

d EF han

C1* AtTP EF hand

C

N

N C

NBD D C CaMB

N

C

C

and EF h

Cytosol

Vacuole

Fig. 1. Subcellular localization and predicted transmembrane topology of Ca2+-permeable channels in plants. CNGC channels contain six transmembrane domains with the pore region (red line) located between the fifth and sixth domains. The cyclic nucleotide binding domain (CNBD) overlaps with the calmodulin binding region (CaMBD). GLRs are proposed to have three transmembrane domains, a pore-forming domain (red line) and two ligand binding domains L1 and L2 facing the extracellular space. The Arabidopsis two-pore channel (AtTPC1) has been predicted to have 12 transmembrane helices and two pores (red lines). A cytosolic loop contains two Ca2+ binding EF hands. The mechanosensitive channel MCA1 is predicted to have two transmembrane domains. The cytosolic N-terminal part contains an amino-terminal domain of rice putative protein kinases (ARPK) and a Ca2+ binding EF hand. *AtTPC1 has been localized in the Arabidopsis tonoplast, whereas other TCPs from different plant species have been localized to the plasma membrane in heterologous expression systems. **The prediction of the transmembrane topology of Mca1 is still preliminary, especially the orientation of the ARPK and the EF-hand domains. It is possible that other mechanosensitive channels might localize in different compartments in plant cells.

Cation transport and Ca2+ selectivity Expression of CNGCs in heterologous systems such as HEK293 cells or Xenopus oocytes coupled with electrophysiological analysis has contributed to unraveling the protein properties of some CGNCs. Complementation of various bacterial and yeast mutants deficient in K+ uptake, Na+ efflux or Ca2+ uptake by plant CNGCs has also provided clues regarding the ion selectivity of these channels with respect to monovalent and ⁄ or divalent cations. The structural modeling of plant CNGCs based on bacterial K+selective channels as well as structure–function studies of animal K+ and CNG channels define a triplet of amino acids in the P-loop region as the selectivity filter. In Arabidopsis, most CNGCs could be subdivided into one group harboring the GQN triplet 4264

(AtCNGC1, 3, 10–15, 17 and 18) and a second group bearing the GQG triplet (AtCNGC5 to 9) [53]. In contrast, AtCNGC19 and AtCNGC20 have AGN, AtCNGC16 has GQS, AtCNGC2 has AND, and AtCNGC4 contains the GN-L motif [53]. The CNG channels permeable to Ca2+ – AtCNGC1, 2, 10, 11, 12 and 18 (Table 1) – belong to the GQN group. However, it is clear that this triplet is not sufficient to facilitate the permeation of Ca2+ ions. In animals, the transmembrane segments S5 and S6 and the extracellular linkers flanking the pore region are the structural elements that account for the differences in Ca2+ permeation properties among the various channels [54]. In Arabidopsis, AtCNGC3 contributes to the K+ and Na+ uptake pathway and atcngc3 mutants showed no visible phenotype under a high concentration of Ca2+ (30–50 mm) [55]. AtCNGC4 and AtCNGC1 can



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Table 1. Putative Ca2+-permeable channels in plants. *Validated by RT-PCR and ⁄ or promoter analysis. The expression data available on www.genevestigator.com are not included. R, root; Rt, root tip; St, stem; P, petiole; L, leaf; H, hypocotyl; C, cotyledon, Fl, flower; Inf, inflorescence; S, seed; Sh, shoot; Sil, silique, Vsc, vascular tissue; GC, guard cell; Pol, pollen; nd, not determined. Family

Gene name

Expression pattern*

Other ion permeability

Physiological role

References

MSCCs

MCA1 At4g35920 MCA2 At2g17780 AtCNGC1 At5g53130 AtCNGC2 ⁄ DND1 At5g15410 AtCNGC10 At1g01340 AtCNGC11,12 At2g46440,450 AtCNGC18 At5g14870 AtGLR1.1 At3g04110 AtGLR1.2 At5g48400 AtGLR1.4 At3g07520 AtGLR2.1 At5g27110 AtGLR3.1 At2g17260 AtGLR3.2 At4g35290 AtGLR3.3 At1g42540 AtGLR3.4 At1g05200 AtGLR3.7 At2g32400 OsGLR3.1 Os04g49570 RsGLR nd AtTPC1 At4g03560

R, St, L, Fl, Sil

nd

Mechanosensing

130

R, St, L, H, C, Sh

nd

nd

132

nd

Na+, K+, Cs+, Pb2+, Sr2+

41,52,53,68,70

H, C, L, Inf

K+, Li+, Rb+, Cs+

Ca2+ homeostasis, heavy metal ions transport Defense, senescence

Rt, L

K+

51,56,64,65

nd

K+

Ca2+, K+ and Mg2+ homeostasis, response to salt Defense, cell death

Pol

nd

Pollen tube growth

19,62

R, St, P, L, S

Na+, K+

85,96,100,101

R, St, P, L, Fl, S

nd

ABA biosynthesis & signaling, carbon ⁄ nitrogen ratio sensing Pollen tube growth

R, St, P, L, Fl, S

Na+, K+

nd

96

R, St, P, L

nd

nd

85

R, St, P, L, Fl, S, GC

nd

104

R, St, P, L, Fl, S, Vsc

nd

Long-term Ca2+-programmed stomatal closure Calcium utilization ⁄ ion stress

81,85

R, St, P, L, Fl, S

nd

Root gravitropism

87,93,94,102

R, St, P, L, Fl, S

nd

Touch and cold responses

86,94

R, St, P, L, Fl, S

Na+, Ba+

Pollen tube growth

87,88

R, L

nd

Cell division and survival

83

nd

nd

Ca2+ influx and resistance to fungi

103

R, St, L, Fl, Sil

K+, Ba+, Mg2+, Na+, Ra+, Cs+

Guard cell signaling, defense, cation homeostasis

105,108,111, 114–116,121

CNGCs

GLRs

TPCs

transport Na+ and K+ [53], and AtCNGC1 is also permeable to Ca2+ in the Ca2+-uptake-deficient yeast mutant mid1cch1 [52]. AtCNGC10 is able to rescue the K+ channel mutants of E. coli, yeast and Arabidopsis, indicating its role in potassium transport [51]. It has recently been reported that antisense AtCNGC10 mutant lines contained significantly lower Mg2+ and Ca2+ contents in roots of seedlings and shoots of adult plants [56]. AtCNGC11, 12 and the chimeric AtCNGC11 ⁄ 12 can transport K+ in yeast [57]. The chimeric channel AtCNGC11 ⁄ 12 is also permeable to

41,49,50,53,59-61,71–74

57,58,65,76,77

88

Ca2+ in yeast [58]. A time- and concentration-dependent accumulation of Ca2+ in E. coli cells expressing AtCNGC18 has been observed by measuring the concentration of 14 different ions by atomic emission spectroscopy [19]. The pore selectivity filter of AtCNGC2, AND, is substantially different from the others, which probably results in the unique properties of AtCNGC2. Indeed, AtCNGC2 can transport monovalent cations, except Na+, with a selective permeability to K+ over Li+, Rb+ and Cs+ and is also permeable to Ca2+ [50,53,59–61].


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Physiological roles of Ca2+-permeable CNGCs Pollen tube growth Pollen tubes grow very fast and release sperm cells in ovules by means of an efficient ion transport system. In a genome-wide study of Arabidopsis transporter genes expressed in the male gametophyte, Bock et al. identified three AtCNGCs (AtCNGC7, 8 and 16) as pollen ‘specific’ genes and AtCNGC18 as a gene ‘preferentially expressed’ in pollen [62]. A fusion of the AtCNGC18 promoter to the GUS reporter gene confirmed that AtCNGC18 is almost exclusively expressed in pollen [19]. In the same study, two independent atcngc18 T-DNA lines were found to have a male sterility phenotype. Although atcngc18 pollen was viable and germinated like wild-type pollen, the sterility, due to a growth defect in the transmitting tract of the pollen tube, prevents the tube from reaching the ovules. The permeability of AtCNGC18 to Ca2+ and its plasma membrane localization at the tip of the pollen tube raise the possibility that AtCNGC18 plays a role in the polarized Ca2+ gradient in the tip of growing pollen tubes [63]. Calcium homeostasis and transport of divalent heavy metal ions As the basis of ion homeostasis in plants relies on the fine-tuning of membrane transporter proteins, a disruption of the ionic balance can have drastic effects on plant growth and development. Studies with Arabidopsis plants expressing AtCNGC10 antisense transcripts showed altered growth, starch accumulation and response to salt stress in the transgenic plants [64,65]. Null mutations in CNGC2 result in Ca2+ hypersensitivity which, because of a probable defect in Ca2+-related sensing ⁄ signaling mechanisms, is likely to be responsible for the dwarf phenotype of the mutant [66]. Due to similar physicochemical properties with Ca2+ and the lack of discrimination of CNGCs, the channels have been shown to function as an entry to toxic heavy metals such as Ni2+, Sr2+and Pb2+. NtCBP4 is the close tobacco homolog of AtCNGC1 sharing 74% identity at the peptide level. Transgenic plants expressing NtCBP4 under the control of the CaMV 35S promoter show an increased tolerance to Ni2+ and a hypersensitivity to Pb2+ [67]. This observation correlates well with the enhanced tolerance to Pb2+ of atcngc1 T-DNA mutants or transgenic plants expressing a truncated, inactive version of NtCBP4 [68]. The increased tolerance of NtCBP4 overexpressing plants to Ni2+ appears coun4266

terintuitive. It has been proposed that NtCBP4 interacts with and suppresses the metal uptake activity of other transporters, including CNGCs. In addition, as previously shown in neuronal Ca2+ channels [69], the binding of Ni2+ to the channel could block NtCBP4 activity, implying that overexpression of NtCBP4 in transgenic plants would help the cell buffer the entry of Ni2+. In the study of Arabidopsis quantitative trait loci involved in cesium and strontium accumulation, Kanter et al. showed that the AtCNGC1, 3, 9, 11, 12 and 17 are among the candidate genes possibly involved in the natural variation of Sr2+ accumulation [70]. It would therefore be interesting to test whether AtCNGC9 and 17 are also permeable to Ca2+. Plant–pathogen interaction and cell death Calcium is a versatile second messenger orchestrating plant adaptation to environmental cues, including interactions with pathogens. The Arabidopsis AtCNGC2 channel was originally identified by the cloning of the gene responsible for the defense no death1 (dnd1) phenotype [71,72]. The dnd1 mutant exhibits higher levels of both salicylic acid and mRNAs encoding pathogenesisrelated genes and has an increased resistance to a wide spectrum of pathogens. Programmed cell death and hypersensitive response (HR) are impaired in the dnd1 mutants, however, providing evidence that resistance may be achieved without HR. The NO signal following pathogen elicitor recognition is important for the elevation of cytosolic Ca2+, which plays a role in HR [73]. The restoration of HR by NO for the atcngc2 ⁄ dnd1 mutant and the inability of the mutant to generate NO upon stimulation with the bacterial elicitor lipopolysaccharide strongly suggests that AtCNGC2 is one of the channels that links plasma membrane Ca2+ conductance to downstream NO generation in response to the pathogen elicitor [61]. In their model, Ali and co-workers propose that AtCNGC2 could be activated by the rise of cAMP in the cell following pathogen recognition, leading to an increase in cytosolic Ca2+ [61]. This rise in cytosolic Ca2+ may then have two consequences: (a) an increase of Ca2+ ⁄ CaM would result in a negative feedback regulation of AtCNGC2 (see above) and (b) Ca2+ ⁄ CaM would enhance the generation of NO participating in the HR. Interestingly, a recent study also showed that a plant defense signaling cascade could be initiated by an increase in AtCNGC2-dependent Ca2+ uptake after cGMP production [18]. The cGMP production could be regulated by an interaction between the plasma membrane receptor AtPepR1 and a member of the Danger-Associated Molecular Pattern family of plant peptides (AtPep) [18]. In axenic conditions, the



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dnd1 mutant also showed an increase in leaf senescence, correlating with a reduced leaf accumulation of Ca2+ and a lower level of NO, indicating the role of AtCNGC2 in a Ca2+-regulated repression of senescence through NO production [74]. The mutant cpr22 (constitutive expresser of PR gene 22) exhibits spontaneous lesion formation even in the absence of pathogen, a higher salicylic acid level and an increased resistance to downy mildew [75]. The spontaneous lesions harbor some characteristics of programmed cell death, including condensed cytoplasm, invaginations of the plasma membrane, condensed chromatin, and DNA fragmentation. Interestingly, this phenotype can be avoided by treating the tissue with Gd3+, an inhibitor of Ca2+ channels. It turns out that cpr22 is a semi-dominant mutation due to a homologous recombination event between AtCNGC11 and 12, inside the third membrane region, creating a new chimeric AtCGNC gene, AtCNGC11 ⁄ 12 [57].This chimeric protein forms a functional channel and also provides a unique opportunity to study the structure–function relationship within the CNGC family [76,77]. Taken altogether, these studies suggest that CNGCs participate in Ca2+ influx required for programmed cell death or HR-like lesions.

Glutamate receptor homologs (GLRs)

different species suggests that they function in diverse cellular processes in plants. Due to their structural similarities and from the results from previous studies GLR proteins have been proposed to function as ligand-gated Ca2+-permeable channels [28,82,86] although the direct proof of the proteins’ function has not been established. Expression patterns of GLRs Understanding where a gene is expressed could provide clues to help identify the roles of the proteins. In this context, comprehensive RT-PCR analyses of all 20 AtGLR genes were conducted in two studies [85,87], which showed that AtGLRs are in general ubiquitously expressed (Table 1). The high expression levels of GLRs in roots suggest a possible role for these proteins in ion transport and uptake [85]. Promoter-reporter analyses show that GLR1.1 is ubiquitously expressed, GLR2.1 strongly in roots and GLR3.1 in guard cells, flowers, siliques, roots and vascular tissues [85]. GLR3.2 is mainly expressed in vasculature [81] while GLR3.4 is expressed in roots, vascular bundle, mesophyll cells and guard cells and upregulated by mechanical and cold stress [86]. GLR1.2 and GLR3.7 are expressed in pollen tubes [88]. The overlapping expression patterns of AtGLRs suggest that they may interact with each other and share common physiological functions in vivo.

Structure of GLRs In animals, most ionotropic glutamate receptors (iGluRs) are ligand-gated non-selective cation channels that are permeable to Ca2+ and play important roles in excitatory neurotransmission and other cellular processes [78,79]. Based on primary and secondary sequence similarities, a number of glutamate receptor homologs (GLRs) have been identified in several species of higher plants in both dicotyledons and monocotyledons [80–83]. Similar to their animal homologs, GLR proteins are predicted to have three transmembrane domains: a pore-forming domain, and two putative ligand binding motifs (Fig. 1) [80]. Phylogenetic analyses suggest that GLRs may have evolved from the insertion of an inward K+-selective ion channel into an amino acid binding protein, and then further evolved into distinct forms when animals and plants diverged [84,85]. Plant GLR proteins belong to a large multigene family. In the Arabidopsis genome, the GLR family consists of 20 homologs and is subdivided into three clades [82]. Thirteen and 61 GLRs are encoded in the rice genome and the poplar genome, respectively [24]. The large number of GLR proteins encoded in

Electrophysiological properties of GLRs In animal systems, iGluR genes are classified based upon their ligand specificities as well as their electrophysiological properties [89,90].The prokaryotic GluR0 gene, an ancestor of plant GLRs and animal iGluRs, has been reported to encode a functional ion channel [91], suggesting that plant GLRs might have similar functions. The presence of glutamate-activated ion currents in Arabidopsis was previously shown [29]. A large and rapid depolarization was observed in electrophysiological measurements when glutamate was added to Arabidopsis roots. In addition, using transgenic plants expressing the Ca2+-sensitive luminescent protein aequorin, it was shown that glutamate and glycine induce an increase in cytosolic Ca2+ in roots [28,29]. Furthermore, glutamate-dependent activation of instantaneous Na+ and Ca2+ currents was found in a patch clamp study on root protoplasts [92]. In Arabidopsis mesophyll cells, a strong membrane depolarization and Ca2+ transients were induced upon exogenous glutamate application, and the desensitization of ionic response to glutamate appeared to be required for the


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recovery of reactivation [86]. Both stimulus-induced cytosolic Ca2+ concentrations and membrane potential responses were significantly reduced in two GLR3.3 knockout mutants [93]. Based on the responses in cytosolic Ca2+ and membrane potential, six amino acids (Glu, Gly, Ala, Ser, Asp and Cys) and the tripeptide glutathione have been proposed to function in GLRdependent responses [93]. Individual GLRs may exhibit different ligand specificity as the six amino acids were not equally active in eliciting the response [94]. Recently, a rare amino acid stereoisomer, d-Ser, was reported to cause GLR activity in pollen tube, describing a similar activation mechanism of ligand-gated ion channels in plants and animals [88,95]. As with their structural homologs in animal cells, plant GLRs are likely to transport cations. Expression of AtGLR3.7 in Xenopus oocytes resulted in Ba2+, Ca2+ and Na+ conductance [87]. Furthermore, using a domain swapping approach and heterologous expression in Xenopus oocytes, an analysis of chimeric proteins that contain the ion pore domains of each of 17 Arabidopsis GLR proteins in rat GluR1 or GluR6 receptors has suggested that AtGLR1.1 and AtGLR1.4 have functional Na+-, K+- and Ca2+-permeable pore domains and that currents through the AtGLR1.1 pore resemble the glutamate-activated currents observed in plants [96].These data suggest that GLRs might be non-selective cation channels. Physiological roles for GLRs Several lines of evidence indicate that GLRs function in plant growth, development and adaptation to stresses. Using a pharmacological approach, putative functions of GLRs have been suggested. An animal iGluR antagonist, 6,7-dinitroquinoxaline-2,3-dione, was found to impair light-induced inhibition of hypocotyl growth and reduce light-dependent formation of chlorophyll [80]. In addition, an iGluR agonist, S(+)-beta-methylalpha, beta-diaminopropionic acid, was shown to increase Arabidopsis hypocotyl elongation and inhibit cotyledon opening under light [97]. Interestingly, kanamycin, an inhibitor of N-methyl-d-aspartate type iGluR, appears to act as an agonist of AtGLRs and rescues the de-etiolated 3 (det3) mutant phenotype [98]. Moreover, animal iGluR antagonists inhibit Ca2+ influx and NO production induced by the pathogen elicitor cryptogein, suggesting a role for GLRs in plant defense signaling [99]. In addition, genetic approaches have been used to point out that GLRs participate in a broad range of cellular processes. Transgenic seeds expressing antisense transcripts of AtGLR1.1 barely germinated in the presence of sucrose, which was restored upon exogenous 4268

application of nitrate, suggesting that AtGLR1.1 functions in coordinating carbon and nitrogen balancing [100]. The antisense GLR1.1 transgenic plants also exhibited phenotypes comparable with those associated with abscisic acid (ABA) hypersensitivity such as reduced stomatal aperture sizes and downregulation of the type 2C protein phosphatases ABI1 and ABI2, two negative regulators of ABA signaling [101]. In rice, an OsGLR3.1 null mutant displayed a phenotype that is related to root meristematic activity and to the programmed cell death process, suggesting a role for OsGLR3.1 in the maintenance of cell division and growth [83]. atglr3.3 null mutants present an impaired gravitropic response causing roots to bend more slowly [102]. GLRs appear to play a role in Ca2+ homeostasis and signaling. Constitutive overexpression of GLR3.2 in Arabidopsis led to Ca2+ deficiency symptoms even though Ca2+ accumulation in these plants was not affected [81]. Moreover, AtGLR3.2 overexpressing plants are hypersensitive to sodium and potassium ionic stresses [81]. Overexpression of a radish GLR cDNA in Arabidopsis resulted in a greater glutamateinduced Ca2+ influx in root cells [103]. Ectopic expression of AtGLR3.1 in Arabidopsis causes an impairment in Ca2+ oscillation-induced stomatal closure, suggesting a role for AtGLR3.1 in Ca2+ signaling in guard cells [104]. Furthermore, a very recent report indicates that GLR1.2 and GLR3.7 are involved in pollen tube growth and morphogenesis [88]. Taken together, these studies imply that GLRs are widely involved in diverse plant signaling and cellular processes.

Two-pore channels Structure and properties of TPC1 The two-pore channel 1 (TPC1) gene in Arabidopsis encodes Ca2+-induced Ca2+-release channels found in plant tonoplasts. TPC1 is a member of a family of voltage-gated cation channels consisting of two homologous domains each with six transmembrane helices and one pore domain (Fig. 1). The cytoplasmic loop contains two Ca2+ binding domains, EF hands, suggesting Ca2+-dependent regulation of the protein [27]. TPC1 was initially thought to be localized in the plasma membrane, but has now been identified as the slow vacuolar (SV) channel in Arabidopsis [105,106]. The SV channel is the most abundant tonoplast channel and seems to be ubiquitous among terrestrial plants including ferns and liverworts [27]. TPC1 was initially characterized as K+ selective but it has been reported that, in addition to K+ and Ca2+, the



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channel is also permeable to Ba2+, and Mg2+, Na+, Ra+ and Cs+ in various species (Table 1) [107]. Further work in Arabidopsis has revealed that TPC1 co-localizes with the K+-selective channel TPK1 in the vacuolar membrane [108]. In addition, while early studies suggested anion permeability [109], more recent work has determined that anion (Cl)) permeability of the SV channel is extremely low, the negative membrane potential probably contributing to this property [110]. The TPC1 channel is activated by increased cytosolic Ca2+ concentration and by an increased membrane potential at the tonoplast [105,111]. Function of TPC1 It has been shown that a knockout mutant, tpc1, lacks the functional SV channel activity and is defective both in ABA-induced germination repression and in the stomatal response to extracellular Ca2+ [105]. A recent study calls into question whether TPC1 contributes to cytosolic Ca2+ homeostasis as results indicate that ABA- and CO2-induced stomatal closure and ABA-, K+- and Ca2+-dependent root growth phenotypes were no different in tpc1 compared with wild-type plants [108]. Furthermore, the loss of TPC1 expression did not change the activity of the hyperpolarization activated Ca2+-permeable channels in the plasma membrane [108]. ABA and methyl jasmonate (MeJA) are known to elicit production of reactive oxygen species and NO, cytosolic Ca2+ concentration oscillations and S-type anion channel currents leading to stomatal closure (for reviews see [112,113]). AtTPC1 has been suggested to function in priming of the plasma membrane S-type anion channels as S-type anion currents were activated in tpc1 guard cells treated with ABA or MeJA, but not in those treated with Ca2+ [114]. A genetic screen isolated fou2 (fatty acid oxygenation upregulated 2) that has a gain of function mutation in AtTPC1 [115]. The fou2 mutant displays increased tolerance to inhibitory luminal calcium and phenotypes related to altered jasmonate biosynthesis, including enhanced resistance to a fungus [115,116]. In contrast to the localization of AtTPC1 in Arabidopsis, studies using rice, tobacco and wheat TPC1s indicate that the protein localizes to the plasma membrane in BY-2 and onion epidermal cells [117,118]. The discrepancy could be due to the fact that the genes were expressed in a heterologous system, or that they may not be true homologs of AtTPC1. Additional methods are required to verify the protein localization and function in different plant species. Ca2+ transport activity was suggested for AtTPC1 and its homologs in tobacco (NtTPC1a and NtTPC1b), rice (OsTPC1) and wheat

(TaTPC1), after heterologous expression in yeast [111,118–120]. CCH1 is a yeast homolog of a subunit of the voltage-dependent Ca2+ channel found in animal cells. A knockout mutant (cch1) which is defective in Ca2+ uptake and growth rate was used to examine the function of TPC1 from the various plant species. In these studies, the plant TPC genes rescued the yeast mutants defective in CCH1, restoring normal Ca2+ uptakes and growth rates [111,118–120]. Various additional results have been reported in the pursuit of a more complete understanding of TPCs. NtTPC1s have been characterized as a pathway for Ca2+ entry across the plasma membrane in tobacco cells in response to cold shock, sucrose, H2O2, salicylic acid, as well as elicitors [119]. OsTPC1 has been proposed to represent a key regulator of elicitor-induced defense responses [120], whereas TaTPC1 appears to function in response to abiotic stresses [118]. As well as defining the role of TPCs in various plant species, work has been undertaken comparing the function of TPCs in different cell types of the same plant. Recently, it was found that the activity of the SV channel encoded by TPC1 is larger in guard cells than in mesophyll cells, probably due to more TPC1 transcripts produced in guard cells [121]. In addition, the SV channels in guard cells were found to be more sensitive to cytosolic Ca2+ concentrations than are the same channels in mesophyll cells, explaining the stomatal phenotype in the tpc1 mutant [121]. The role of the SV channel TPC1 in vacuolar Ca2+ release is still under investigation and, because the channel is relatively non-selective among monovalent and divalent cations, the observed phenotypes may be derived from TPC1’s function in general cation homeostasis, turgor regulation, as well as the various aspects of Ca2+ signaling. The balance between the dual functions of cation homeostasis and Ca2+ release could depend on the combination of a wide variety of factors governing the activation of the channel. Mechanosensitive Ca2+-permeable channels (MSCCs) A plant’s ability to sense, and to adapt to, a variety of mechanical stimuli such as wind, obstacles in the soil or even prey in the case of the venus flytrap, has long been known [25,122]. It had been suspected that Ca2+ mediates the signaling processes that occur in response to physical contact, and experimental proof of this assumption arose with the monitoring of cytosolic Ca2+ changes after mechanical stimulation of aequorin-expressing tobacco seedlings [123]. A few years later, Ding and Pickard reported [124] the existence


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of mechanosensitive Ca2+-selective cation channels (MSCCs) in epidermal cells, highlighting cytosolic Ca2+ elevation as an important component of the channels’ activity. It was shown that, by patch clamping onion cells, Ca2+ channel activity in the plasma membrane is dependent on the negative pressure applied to the membrane, suggesting a link between Ca2+ and mechanical stimuli [124]. Biochemical characterization of these MSCCs provides evidence that numerous effectors are able to modulate the mechanosensitivity. Gd3+, La3+, and very low temperature inhibit the channels, whereas ethyl-TV-phenylcarbamate, low temperature, pH rise, and membrane hyperpolarization sensitize the channels [124]. The preponderant role of Ca2+ in touch-sensing events was reassessed via physiological [125] or molecular [126] approaches, where 12 calmodulin-like proteins have been shown to be upregulated upon mechanical stimulation. While previously identified in bacteria, in which they are proposed to be involved in cell response to change in osmotic pressure (MscS, [127]), molecular constituents of a mechano-dependent ion flux had not been cloned in Arabidopsis until 10 members of a so-called MSL (MscS-like) family were identified based on sequence homology with their bacterial counterpart [128]. These proteins were found to be associated with a mechanosensitive activity revealed by complementation experiments in bacteria (MSL3, [128]) and by electrophysiology using protoplasts (MSL9 and 10, [129]). It has also been suggested that MSL proteins control plastid shape (MSL2 and 3, [128]) and, at least in part, root mechanosensitivity (MSL9 and 10, [129]). These channels, however, are thought to be Cl) permeable rather than Ca2+ permeable [129]. Furthermore the partial phenotype of msl9 ⁄ msl10 double and msl4 ⁄ msl5 ⁄ msl6 ⁄ msl9 ⁄ msl10 quintuple mutants, which do not show clear mechano-insensitivity at the whole plant level, implies the presence of other mechanosensing elements, including MSCCs [129]. An Arabidopsis cDNA library screening for complementation of the lethal mid1 yeast mutation led to the isolation of MCA1 (mid1-complementing activity 1), potentially a mechanosensitive Ca2+ channel [130]. MID1 is a stretch-activated Ca2+ channel in Saccharomyces cerevisiae [131]. Widely expressed in nearly all parts of the plant, MCA1 localizes to the plasma membrane (Fig. 1) and its overexpression leads to an increase in Ca2+ levels in roots, indicating that this protein is a Ca2+ transporter [130]. The higher cytosolic Ca2+ was abolished by the non-specific Ca2+ channel blocker Ga3+ but not by verapamil, a specific voltage-gated Ca2+ channel blocker [130], which sug4270

gests that MCA1 could actually be a member of the MSCC protein family. In order to evaluate MCA1’s involvement in mechano-dependent cytosolic Ca2+ elevation, Nakagawa and colleagues used MCA1 overexpression plants, mca1-null and wild-type seedlings, which express the Ca2+ indicator protein aequorin [130]. The plants were challenged with either trinitrophenol, an activator of mechanosensitive channels in E. coli, or hypo-osmotic stress to monitor variation in cytosolic Ca2+ upon membrane stretching [130]. Higher cytosolic [Ca2+] elevation, upon stimulation in MCA1ox compared with mca1-null and wild-type plants, suggested MCA1 as the MSCC characterized at the molecular level in Arabidopsis [130]. Consistent with these findings, MCA1ox also exhibited a higher level of the TCH3 transcript, which encodes one of the touch-induced calmodulin-like proteins [126], linking MCS1 to the regulation of touch-induced genes. In addition, the inability of mca1-null seedlings to penetrate 1.6% agar-containing medium suggests a defect in the plant’s ability to sense and adapt to environmental changes from a mechanical viewpoint. Interestingly, the noticeable similarity in TNP- and hypo-osmolarity-induced cytosolic Ca2+ changes between mca1-null and wild-type plants suggests the existence of additional MSCCs with overlapping functions. MCA2, which shares over 72% identity and ! 90% similarity with MCA1, was therefore tested for its role in mechanosensitive Ca2+ flux [132]. While MCA2 is able to complement mid1 and induce an increase in cytosolic Ca2+ when overexpressed in plants, no clear in planta function of MCA2 in mechanosensing processes was found [25]. Additional MSCCs remain to be identified.

Conclusion Ca2+ channels play pivotal roles in many cellular processes, but their function and regulatory mechanisms at the molecular level remain largely elusive. Given the fact that Ca2+ channels in plants belong to large gene families, it is plausible to presume a high level of functional redundancy. Thus, the generation of multiple knockout mutants and ⁄ or simultaneous knockdown by the use of artificial microRNAs [133] will be required to address the functional redundancy issue and provide further insights into the functions of Ca2+ channels in planta. In addition, identification of interacting partners and the subunit composition of Ca2+ channel proteins in vivo using a systematic approach [134] would help to understand the regulatory mechanism, gene expression and cellular signaling networks that involve Ca2+ channels. Comparison of



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different regulatory mechanisms between monocots and dicots would provide answers to some of the contrasting results. The recent findings regarding the various Ca2+ channels described in this review, and the identification of new components of the plant Ca2+ network bear witness to this dynamic research field. A recent study showing that two purified proteins from the maize annexin family, ANN33 and ANN35, are permeable to both K+ and Ca2+ [135,136], supports the previous observation that Caspicum annuum annexin 24 can promote Ca2+ influx [137]. These results suggest that the annexin family could act as Ca2+ channels. By expressing a member of the rice high affinity K+ transporter family (OsHKT2;4) in Xenopus oocytes, Lan et al. showed its permeability to a broad range of monovalent and divalent species, Ca2+ being the most permeable cation [138]. However, recent competition experiments showed that OsHKT2;4 has a stronger selectivity for K+ than Ca2+ and Mg2+ [139]. Due to the absence of clear phenotypes in OsHKT2;4 disruptive mutants [138,139], the function of plant HKTs in Ca2+ signaling remains unclear. As well as their relative selectivity for K+, some outward-rectifying K+ channels can also conduct other cations including Ca2+ (for reviews see [140,141]). The contribution of these channels to Ca2+ homeostasis and signaling, which may depend on ionic conditions and cell types, is reviewed in detail in Dreyer and Uozumi [142] and would be an interesting area of research. Multidisciplinary approaches including functional genomics and computational modeling combined with Ca2+ imaging techniques [143] would help to put the puzzles together in the Ca2+ signaling network and thus shed light on the cellular processes regulated by cytosolic Ca2+ and Ca2+ channels.

Acknowledgements We thank other members in the laboratory for reading the manuscript. The work in the authors’ laboratory was supported by NRI grants from the USDA National Institute of Food and Agriculture (200735100-18377, 2004-35100-14909) and grants from NSF (MCB-0614203, IOS-1025837) to J.M.K.

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