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Voltage-Gated Calcium Channels

William A. Catterall

Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280

Correspondence: [email protected]

Voltage-gated calcium (Ca2þ) channels are key transducers of membrane potential changesinto intracellular Ca2þ transients that initiate many physiological events. There are tenmembers of the voltage-gated Ca2þ channel family in mammals, and they serve distinctroles in cellular signal transduction. The CaV1 subfamily initiates contraction, secretion,regulation of gene expression, integration of synaptic input in neurons, and synaptic trans-mission at ribbon synapses in specialized sensory cells. The CaV2 subfamily is primarilyresponsible for initiation of synaptic transmission at fast synapses. The CaV3 subfamily isimportant for repetitive firing of action potentials in rhythmically firing cells such ascardiac myocytes and thalamic neurons. This article presents the molecular relationshipsand physiological functions of these Ca2þ channel proteins and provides information ontheir molecular, genetic, physiological, and pharmacological properties.

PHYSIOLOGICAL ROLES OFVOLTAGE-GATED Ca2þ CHANNELS

Ca2þ channels in many different cell typesactivate on membrane depolarization and

mediate Ca2þ influx in response to actionpotentials and subthreshold depolarizing sig-nals. Ca2þ entering the cell through voltage-gated Ca2þ channels serves as the secondmessenger of electrical signaling, initiatingmany different cellular events (Fig. 1). In car-diac and smooth muscle cells, activation ofCa2þ channels initiates contraction directly byincreasing cytosolic Ca2þ concentration andindirectly by activating calcium-dependentcalcium release by ryanodine-sensitive Ca2þ

release channels in the sarcoplasmic reticulum(Reuter 1979; Tsien 1983; Bers 2002). In skeletalmuscle cells, voltage-gated Ca2þ channels in thetransverse tubule membranes interact directly

with ryanodine-sensitive Ca2þ release channelsin the sarcoplasmic reticulum and activate themto initiate rapid contraction (Catterall 1991;Tanabe et al. 1993). The same Ca2þ channelsin the transverse tubules also mediate a slowCa2þ conductance that increases cytosolicconcentration and thereby regulates the forceof contraction in response to high-frequencytrains of nerve impulses (Catterall 1991). Inendocrine cells, voltage-gated Ca2þ channelsmediate Ca2þ entry that initiates secretion ofhormones (Yang and Berggren 2006). In neu-rons, voltage-gated Ca2þ channels initiate syn-aptic transmission (Tsien et al. 1988; Dunlapet al. 1995; Catterall and Few 2008). In manydifferent cell types, Ca2þ entering the cytosolvia voltage-gated Ca2þ channels regulates en-zyme activity, gene expression, and otherbiochemical processes (Flavell and Greenberg2008). Thus, voltage-gated Ca2þ channels are

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the key signal transducers of electrical excit-ability, converting the electrical signal of theaction potential in the cell surface membraneto an intracellular Ca2þ transient. Signal trans-duction in different cell types involves differ-ent molecular subtypes of voltage-gated Ca2þ

channels, which mediate voltage-gated Ca2þ

currents with different physiological, pharma-cological, and regulatory properties.

Ca2þ CURRENT TYPES DEFINED BYPHYSIOLOGICAL ANDPHARMACOLOGICAL PROPERTIES

Since the first recordings of Ca2þ currents incardiac myocytes (reviewed in Reuter 1979), ithas become apparent that there are multiple

types of Ca2þ currents as defined by physiolog-ical and pharmacological criteria (Tsien et al.1988; Bean 1989a; Llinas et al. 1992). In cardiac,smooth, and skeletal muscle, the major Ca2þ

currents are distinguished by high voltageof activation, large single channel conductance,slow voltage-dependent inactivation, markedup-regulation by cAMP-dependent proteinphosphorylation pathways, and specific inhi-bition by Ca2þ antagonist drugs includingdihydropyridines, phenylalkylamines, and ben-zothiazepines (Table 1) (Reuter 1979; Tsienet al. 1988). These Ca2þ currents have beendesignated L-type, as they have slow voltage-dependent inactivation and therefore are longlasting when Ba2þ is the current carrier and thereis no Ca2þ-dependent inactivation (Tsien et al.

Contraction SecretionSynaptic transmission

Gene transcription

Enzymeregulation

Proteinphosphorylation

Nucleus

β

γ

δ

α1

α2

Ca2+

Figure 1. Signal transduction by voltage-gated Ca2þ channels. Ca2þ entering cells initiates numerous intracel-lular events, including contraction, secretion, synaptic transmission, enzyme regulation, protein phosphoryla-tion/dephosphorylation, and gene transcription. (Inset) Subunit structure of voltage-gated Ca2þ channels.The five-subunit complex that forms high-voltage-activated Ca2þ channels is illustrated with a central pore-forming a1 subunit, a disulfide-linked glycoprotein dimer of a2 and d subunits, an intracellular b subunit,and a transmembrane glycoprotein g subunit (in some Ca2þ channel subtypes). As described in the text, thismodel is updated from the original description of the subunit structure of skeletal muscle Ca2þ channels.(Adapted from Takahashi et al. 1987).

W.A. Catterall

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1988). L-type Ca2þ currents are also recorded inendocrine cells where they initiate release of hor-mones (Yang and Berggren 2006) and in neuronswhere they are important in regulation of geneexpression, integration of synaptic input, andinitiation of neurotransmitter release at special-ized ribbon synapses in sensory cells (Tsienet al. 1988; Bean 1989a; Flavell and Greenberg2008). L-type Ca2þ currents are subject to regu-lation by second messenger–activated proteinphosphorylation in several cell types as discussedbelow.

Electrophysiological studies of Ca2þ cur-rents in starfish eggs (Hagiwara et al. 1975) firstrevealed Ca2þ currents with different propertiesfrom L-type, and these were subsequently char-acterized in detail in voltage-clamped dorsalroot ganglion neurons (Carbone and Lux1984; Fedulova et al. 1985; Nowycky et al.1985). In comparison to L-type, these novelCa2þ currents activated at much more negative

membrane potentials, inactivated rapidly, deac-tivated slowly, had small single channel con-ductance, and were insensitive to conventionalCa2þ antagonist drugs available at that time(Table 1). They were designated low-voltage-activated Ca2þ currents for their negative volt-age dependence (Carbone and Lux 1984) orT-type Ca2þ currents for their transient open-ings (Nowycky et al. 1985).

Whole-cell voltage clamp and single-channel recording from dissociated dorsal rootganglion neurons revealed an additional Ca2þ

current, N-type (Table 1) (Nowycky et al.1985). N-type Ca2þ currents were initiallydistinguished by their intermediate voltage de-pendence and rate of inactivation—more nega-tive and faster than L-type but more positiveand slower than T-type (Nowycky et al. 1985).They are insensitive to organic L-type Ca2þ

channel blockers but blocked by the cone snailpeptide v-conotoxin GVIA and related peptide

Table 1. Subunit composition and function of Ca2þ channel types

Ca2þ current

type

a1

Subunits

Specific

blocker Principal physiological functions Inherited diseases

L Cav1.1 DHPs Excitation-contraction coupling inskeletal muscle, regulation oftranscription

Hypokalemic periodicparalysis

Cav1.2 DHPs Excitation-contraction coupling incardiac and smooth muscle,endocrine secretion, neuronalCa2þ transients in cell bodies anddendrites, regulation of enzymeactivity, regulation of transcription

Timothy syndrome: cardiacarrhythmia withdevelopmentalabnormalites and autismspectrum disorders

Cav1.3 DHPs Endocrine secretion, cardiacpacemaking, neuronal Ca2þ

transients in cell bodies anddendrites, auditory transduction

Cav1.4 DHPs Visual transduction Stationary night blindnessN Cav2.1 v-CTx-GVIA Neurotransmitter release,

Dendritic Ca2þ transientsP/Q Cav2.2 v-Agatoxin Neurotransmitter release,

Dendritic Ca2þ transientsFamilial hemiplegic migraine,

cerebellar ataxiaR Cav2.3 SNX-482 Neurotransmitter release,

Dendritic Ca2þ transientsT Cav3.1 None Pacemaking and repetitive firing

Cav3.2 Pacemaking and repetitive firing Absence seizuresCav3.3

Abbreviations: DHP, dihydropyridine;v-CTx-GVIA,v-conotoxin GVIA from the cone snail Conus geographus; SNX-482, a

synthetic version of a peptide toxin from the tarantula Hysterocrates gigas.


Cite this article as Cold Spring Harb Perspect Biol 2011;3:a003947 3



toxins (Tsien et al. 1988; Olivera et al. 1994).This pharmacological profile has become theprimary method to distinguish N-type Ca2þ

currents, because the voltage dependence andkinetics of N-type Ca2þ currents in differentneurons vary considerably.

Analysis of the effects of other peptide tox-ins revealed three additional Ca2þ current types(Table 1). P-type Ca2þ currents, first recorded inPurkinje neurons (Llinas and Yarom 1981;Llinas et al. 1989), are distinguished by highsensitivity to the spider toxin v-agatoxin IVA(Mintz et al. 1992). Q-type Ca2þ currents, firstrecorded in cerebellar granule neurons (Randalland Tsien 1995), are blocked by v-agatoxin IVAwith lower affinity. R-type Ca2þ currents incerebellar granule neurons are resistant to mostsubtype-specific organic and peptide Ca2þ

channel blockers (Randall and Tsien 1995) andmay include multiple channel subtypes (Totteneet al. 1996). They can be blocked selectively insome cell types by the peptide SNX-482 derivedfrom the tarantula Hysterocrates gigas (New-comb et al. 1998). Although L-type and T-typeCa2þ currents are recorded in a wide range ofcell types, N-, P-, Q-, and R-type Ca2þ currentsare most prominent in neurons.

MOLECULAR PROPERTIES OF Ca2þ

CHANNELS

Subunit Structure

Ca2þ channels purified from skeletal muscletransverse tubules are complexes of a1, a2, b,g, and d subunits (Fig. 1) (Curtis and Catterall1984, 1986; Flockerzi et al. 1986; Hosey et al.1987; Leung et al. 1987; Striessnig et al. 1987;Takahashi et al. 1987). Analysis of the bio-chemical properties, glycosylation, and hydro-phobicity of these five subunits led to a modelcomprising a principal transmembrane a1subunit of 190 kDa in association with adisulfide-linked a2d dimer of 170 kDa, anintracellular phosphorylated b subunit of55 kDa, and a transmembrane g subunit of33 kDa (Fig. 1) (Takahashi et al. 1987).

The a1 subunit is a protein of about 2000amino acid residues in length with an aminoacid sequence and predicted transmembranestructure like the previously characterized,pore-forming a subunit of voltage-gatedsodium channels (Fig. 2) (Tanabe et al. 1987).The amino acid sequence is organized in fourrepeated domains (I–IV), which each containssix transmembrane segments (S1–S6) and a

+H3N+H3N

+H3N+H3N

+H3N

CO2–

CO2–

CO2–

CO2–

β

δ

γ α1 α2

domain: I II III IV

inside

1 2 3 4+

+5 6 1 2 3 4

+

+5 1 2 3 4

+

+5 1 2 3 4

+

+56 6 6

outside

Figure 2. Subunit structure of Ca2þ channels. The structures of Ca2þ channel subunits are illustrated astransmembrane folding models; predicted a helices are depicted as cylinders; the lengths of lines correlateapproximately to the lengths of the polypeptide segments represented; and the zigzag line on the d subunit illus-trates its glycophosphatidylinositol anchor.

W.A. Catterall




membrane-associated loop between transmem-brane segments S5 and S6. As expected frombiochemical analysis (Takahashi et al. 1987a),the intracellular b subunit has predicted a heli-ces but no transmembrane segments (Fig. 2)(Ruth et al. 1989), whereas theg subunit is a gly-coprotein with four transmembrane segments(Fig. 2) (Jay et al. 1990). The cloned a2 subunithas many glycosylation sites and several hydro-phobic sequences (Ellis et al. 1988), but biosyn-thesis studies indicate that it is an extracellular,extrinsic membrane glycoprotein, attached tothe membrane through disulfide linkage to thed subunit (Fig. 2) (Gurnett et al. 1996). The d

subunit is encoded by the 30 end of the codingsequence of the same gene as the a2 subunit,and the mature forms of these two subunitsare produced by posttranslational proteolyticprocessing and disulfide linkage (Fig. 2) (DeJongh et al. 1990). Although it was initi-ally assumed that the d subunit was anchored tothe membrane via a single membrane segment,recent work argues persuasively that furtherposttranslational processing actually cleavesthe predicted transmembrane segment andreplaces it with a glycophosphatidylinositolmembrane anchor (Fig. 2) (Davies et al. 2010).

Purification of cardiac Ca2þ channelslabeled by dihydropyridine Ca2þ antagonistsidentified subunits of the sizes of the a1, a2d,b, and g subunits of skeletal muscle Ca2þ chan-nels (Chang and Hosey 1988; Schneider andHofmann 1988; Kuniyasu et al. 1992), whereasimmunoprecipitation of Ca2þ channels fromneurons labeled by dihydropyridine Ca2þ

antagonists revealed a1, a2d, and b subunitsbut no g subunit (Ahlijanian et al. 1990).Purification and immunoprecipitation of N-type and P/Q-type Ca2þ channels labeled byv-conotoxin GVIA and v-agatoxin IVA, respec-tively, from brain membrane preparations alsorevealed a1, a2d, and b subunits but not g sub-units (McEnery et al. 1991; Martin-Moutotet al. 1995; Witcher et al. 1995a; Liu et al.1996). More recent experiments have unexpect-edly revealed a novel g subunit (stargazin),which is the target of the stargazer mutationin mice (Letts et al. 1998), and a related seriesof seven g subunits is expressed in brain and

other tissues (Klugbauer et al. 2000). Theseg-subunit-like proteins can modulate the volt-age dependence of CaV2.1 channels expressedin nonneuronal cells, so they may be associatedwith these Ca2þ channels in vivo. However, thestargazin-likeg subunits (also called transmem-brane AMPA receptor modulators [TARPs]) arethe primary modulators of glutamate receptorsin the postsynaptic membranes of brain neu-rons (Nicoll et al. 2006), and it remains to bedetermined whether they are also associatedwith voltage-gated Ca2þ channels in brain neu-rons in vivo.

Three-Dimensional Structure of Ca2þ

Channels

The three-dimensional structure of Ca2þ chan-nels is not known at high resolution. Low-reso-lution structural models have been developedfrom image reconstruction analysis of CaV1.1channels purified from skeletal muscle mem-branes (Serysheva et al. 2002; Wang et al.2002; Wolf et al. 2003), and some of the struc-tural features have been associated with thea1,b, anda2d subunits (Fig. 3A). Further high-resolution structural analysis will be required toconfirm these initial structural models. Thethree-dimensional structure of the CaVb sub-units has been determined at high resolutionby X-ray crystallography (Fig. 3B) (Chen et al.2004; Van Petegem et al. 2004). These subunitscontain conserved SH3 and guanylate kinasedomains like the MAGUK family of scaffold-ing proteins. These two domains are arrayedside-by-side in the CaVb subunit (Fig. 3B).The CaVb subunits bind to a single site in thea1 subunits (the a interaction domain, AID)(Pragnell et al. 1994), which is located in thefirst half of the intracellular loop connectingdomains I and II. The AID forms an a helixthat is bound tightly to a groove in the guanylatekinase domain of the CaVb subunit. This tight,multipoint binding interaction likely sustainsthe association between Ca2þ channel a1 andb subunits throughout the lifetime of theCa2þ channel complex at the cell surface mem-brane. MAGUK proteins often bind more thanone protein partner, so CaVb subunits may





also interact with other intracellular proteins,and several potential binding partners are underactive investigation.

Functions of Ca2þ Channel Subunits

Expression of thea1 subunit is sufficient to pro-duce functional skeletal muscle Ca2þ channels,but with low expression level and abnormal

kinetics and voltage dependence of the Ca2þ

current (Perez-Reyes et al. 1989). Coexpressionof the a2d subunit and especially the b subunitenhanced the level of expression and conferredmore normal gating properties (Lacerda et al.1991; Singer et al. 1991). As for skeletal muscleCa2þ channels, coexpression of b subunits hasa large effect on the level of expression and thevoltage dependence and kinetics of gating of

α2

α1

δ γ

β

V2

V1

V3

SH3 NK

AID

C

N

A

B

Figure 3. Three-dimensional architecture of Ca2þ channels. (A) Illustration of the skeletal muscle CaV1.1 chan-nel based on cryo-electronmicroscopy. This drawing assumes pseudo-fourfold symmetry of thea1 subunit. Theview shows the extracellular side with the a2 subunit. The a1, g, and d subunits are embedded into the lipidmembrane (not shown), which separates the extracellular a2 subunit from the cytosol. a2 is anchored viathe disulfide-linked d subunit within the a1 subunit. The proposed model allows for a tight interaction betweena1 and d as well as a1 and g. (B) Structure of the CaVb subunit with the a interaction domain (AID). Coor-dinates are for the CaVb2a–CaV1.2 AID complex with SH3 (green) and NK (blue) domains are indicated.V1, V2, and V3 show the locations of the three variable domains that are absent from the structure. The AID(red) binds to a deep groove in the NK domain. AID residues tyrosine, tryptophan, and isoleucine are shownas CPK. The remaining residues are shown as lines.

W.A. Catterall




cardiac and neuronal Ca2þ channels (reviewedin Hofmann et al. 1994; Dolphin 2003). Ingeneral, the level of expression is increasedand the voltage dependence of activation andinactivation is shifted to more negative mem-brane potentials, and the rate of inactivation isincreased. However, these effects are differentfor the individual b subunit isoforms. Forexample, the b2a subunit slows channel in-activation in most subunit combinations.Coexpression of a2d subunits also increasesexpression and enhances function of Ca2þ

channels, but to a lesser extent and in a morechannel-specific way than do b subunits (Arik-kath and Campbell 2003; Davies et al. 2007). Ingeneral, g subunits have smaller effects.

Ca2þ Channel Diversity

The different types of Ca2þ currents are primar-ily defined by different a1 subunits, and ten dif-ferent ones have been characterized by cDNAcloning and functional expression in mamma-lian cells or Xenopus oocytes (Table 1). Thesesubunits can be divided into three structurallyand functionally related families (CaV1, CaV2,and CaV3) (Snutch and Reiner 1992; Ertelet al. 2000). L-type Ca2þ currents are mediatedby the CaV1 type of a1 subunits, which haveabout 75% amino acid sequence identityamong them. The CaV2 type Ca2þ channelsform a distinct subfamily with ,40% aminoacid sequence identity with CaV1 a1 subunitsbut .70% amino acid sequence identityamong themselves. Cloned CaV2.1 subunits(Mori et al. 1991; Starr et al. 1991) conduct P-or Q-type Ca2þ currents, which are inhibitedby v-agatoxin IVA. CaV2.2 subunits conductN-type Ca2þ currents blocked with high affinityby v-conotoxin GVIA (Dubel et al. 1992; Wil-liams et al. 1992). Cloned CaV2.3 subunitsform R-type Ca2þ channels, which are resistantto both organic Ca2þ antagonists specific forL-type Ca2þ currents and the peptide toxinsspecific for N-type or P/Q-type Ca2þ currents(Soong et al. 1994). T-type Ca2þ currents aremediated by the CaV3 Ca2þ channels (Perez-Reyes et al. 1998). These a1 subunits are onlydistantly related to the other known homologs,

with ,25% amino acid sequence identity.These results reveal a surprising structuraldichotomy between the T-type, low-voltage-activated Ca2þ channels and the high-voltage-activated Ca2þ channels. Evidently, these twolineages of Ca2þ channels diverged very earlyin evolution of multicellular organisms. Singlerepresentatives of the CaV1, CaV2, and CaV3subfamilies are present in invertebrate genomes,including the worm Caenorhabditis elegans andthe fruit fly Drosophila.

The diversity of Ca2þ channel structure andfunction is substantially enhanced by multiplebsubunits. Four b subunit genes have been iden-tified, and each is subject to alternative splicingto yield additional isoforms (reviewed in Hof-mann et al. 1994; Dolphin 2003). In Ca2þ chan-nel preparations isolated from brain, individualCa2þ channel a1 subunit types are associatedwith multiple types of b subunits, althoughthere is a different rank order in each case (Pich-ler et al. 1997; Witcher et al. 1995b). The differ-ent b subunit isoforms cause different shifts inthe kinetics and voltage dependence of gating,so association with different b subunits cansubstantially alter the physiological functionof an a1 subunit. Genes encoding four a2dsubunits have been described (Klugbauer et al.1999), and the a2d isoforms produced by thesedifferent genes have selective effects on thelevel of functional expression and the voltagedependence of different a1 subunits (Davieset al. 2007).

Molecular Basis for Ca2þ Channel Function

Intensive studies of the structure and functionof the related pore-forming subunits of Naþ,Ca2þ, and Kþ channels have led to identifica-tion of their principal functional domains(reviewed in Catterall 2000a,b; Yi and Jan2000; Bichet et al. 2003; Yu et al. 2005). Eachdomain of the principal subunits consists ofsix transmembrane a helices (S1–S6) and amembrane-associated loop between S5 and S6(Fig. 2). The S4 segments of each homologousdomain serve as the voltage sensors for activa-tion, moving outward and rotating under theinfluence of the electric field and initiating a





conformational change that opens the pore. TheS5 and S6 segments and the membrane-associ-ated pore loop between them form the porelining of the voltage-gated ion channels. Thenarrow external end of the pore is lined by thepore loop, which contains a pair of glutamateresidues in each domain that are required forCa2þ selectivity, a structural feature that isunique to Ca2þ channels (Heinemann et al.1992). Remarkably, substitutions that addonly three glutamate residues in the pore loopsbetween the S5 and S6 segments in domains II,III, and IV of sodium channels are sufficientto confer Ca2þ selectivity (Heinemann et al.1992; Sather and McCleskey 2003). The innerpore is lined by the S6 segments, which formthe receptor sites for the pore-blocking Ca2þ

antagonist drugs specific for L-type Ca2þ chan-nels (Hockerman et al. 1997a,b). All Ca2þ chan-nels share these general structural features, butthe amino acid residues that confer high affinityfor the organic Ca2þ antagonists used in ther-apy of cardiovascular diseases are present onlyin the CaV1 family of Ca2þ channels, whichconduct L-type Ca2þ currents.

CaV1 CHANNELS ANDEXCITATION-RESPONSE COUPLING

CaV1 channels serve to couple depolarization ofthe plasma membrane to a wide range of cellularresponses (Fig. 1). Three widely studied examplesare excitation-contraction coupling in muscle,excitation-transcription coupling in nerve andmuscle, and excitation-secretion coupling inendocrine cells and at specialized ribbon synapses.

CaV1 CHANNELS ANDEXCITATION-CONTRACTION COUPLING

Mechanisms of Excitation-ContractionCoupling

CaV1 channels initiate excitation-contractioncoupling in skeletal, cardiac, and smooth mus-cle. There are striking mechanistic differencesbetween excitation-contraction coupling inskeletal muscle and cardiac muscle. In skeletalmuscle, entry of external Ca2þ is not required

for initiation of contraction (Armstrong et al.1972). CaV1.1 channels in the transverse tu-bules are thought to interact directly withthe ryanodine-sensitive Ca2þ release channels(RyR1) of the sarcoplasmic reticulum (Numaet al. 1990), as observed in high-resolution elec-tron microscopy (Block et al. 1988), and thevoltage-driven conformational changes in theirvoltage-sensing domains are thought to directlyinduce activation of RyR1 (Numa et al. 1990).Reconstitution of excitation-contraction cou-pling in myocytes from mutant mice requiresboth CaV1.1 and RyR1 proteins and their rel-evant sites of protein–protein interaction(Tanabe et al. 1990; Nakai et al. 1998), and func-tional expression of the CaV1.1 channel in skel-etal muscle requires its RyR1 binding partner(Nakai et al. 1996).

In contrast to skeletal muscle, entry ofCa2þ is required for excitation-contractioncoupling in cardiac myocytes, and Ca2þ entryvia CaV1.2 channels triggers activation of theRyR2 and initiates Ca2þ-induced Ca2þ-release,activation of actomyosin, and contraction(Fabiato 1983; Bers 2002). Release of Ca2þ

from the sarcoplasmic reticulum via RyR2greatly amplifies the cellular Ca2þ transientand is required for effective initiation ofcontraction. All three steps in the cascade ofCa2þ transport processes—Ca2þ entry viaCaV1.2 channels, Ca2þ release via RyR, andCa2þ uptake into the sarcoplasmic reticulumby SERCA Ca2þ pumps—are tightly regulatedby second messenger signaling networks (Bers2002). The section below considers the regula-tion of CaV1 channels in excitation-contractioncoupling.

Regulation of Excitation-ContractionCoupling via CaV1 Channels

As part of the flight-or-flight response, the rateand force of contraction of both skeletal andcardiac muscle are increased through the activ-ity of the sympathetic nervous system. Release ofcatecholamines stimulates b-adrenergic recep-tors (b-ARs), which increases the force of skel-etal and cardiac muscle contraction and theheart rate (Reuter 1983; Tsien et al. 1986). In

W.A. Catterall




cardiac muscle, Ca2þ influx through Cav1.2channels is responsible for initiating excita-tion-contraction coupling, and increased Ca2þ

channel activity via the PKA pathway is primar-ily responsible for the increase in contractility.Cav1.2 channels are modulated by the b-adre-nergic receptor/cAMP signaling. Activation ofb-adrenergic receptors increases L-type Ca2þ

currents through PKA-mediated phosphoryla-tion of the Cav1.2 channel protein and/or asso-ciated proteins (Tsien 1973; Reuter and Scholz1977; Osterrieder et al. 1982; McDonald et al.1994).

The pore-forming a1 subunit and the aux-iliary b subunits of skeletal muscle CaV1.1channels (Curtis and Catterall 1985; Flockerziet al. 1986; Takahashi et al. 1987) and cardiacCaV1.2 channels (Hell et al. 1993b; De Jonghet al. 1996; Haase et al. 1996; Puri et al. 1997)are phosphorylated by PKA. These a1 sub-units are also truncated by proteolytic pro-cessing of the carboxy-terminal domain(Fig. 4) (De Jongh et al. 1989, 1991, 1996;Hulme et al. 2005). Voltage-dependent poten-tiation of Cav1.1 channels on the 50-msectime scale requires PKA phosphorylation(Sculptoreanu et al. 1993) as well as PKAanchoring via an A kinase anchoring protein(AKAP) (Johnson et al. 1994, 1997), suggestingclose association of PKA and Ca2þ channels. Anovel, plasma membrane–targeted AKAP(AKAP15) is associated with both Cav1.1 chan-nels (Gray et al. 1997, 1998) and CaV1.2 chan-nels (Hulme et al. 2003), and may mediatetheir regulation by PKA. This AKAP (alsoknown as AKAP18 [Fraser et al. 1998]) bindsto the carboxy-terminal domain of Cav1.1channels (Hulme et al. 2002) and CaV1.2 chan-nels (Hulme et al. 2003) via a novel modifiedleucine zipper interaction near the primary sitesof PKA phosphorylation. Block of this interac-tion by competing peptides prevents PKA regu-lation of Ca2þ currents in intact skeletal andcardiac myocytes (Hulme et al. 2002, 2003,2006b). These physiological results suggestthat a Ca2þ channel signaling complex contain-ing AKAP15 and PKA is formed in both skel-etal and cardiac muscle, and this conclusion issupported by specific colocalization of these

proteins in both skeletal and cardiac myocytesand specific coimmunoprecipitation of thiscomplex from both tissues (Hulme et al. 2002,2003, 2006a). Remarkably, block of kinaseanchoring is as effective as block of kinase activ-ity in preventing Cav1.1 and Cav1.2 channel reg-ulation, consistent with the conclusion thatPKA targeting via leucine zipper interactionsis absolutely required for regulation of Cav1channels in intact skeletal and cardiac myocytes.

Proteolytic Processing and Regulationvia the Carboxy-Terminal Domain

The distal carboxy-terminal domains of skeletalmuscle and cardiac Ca2þ channels are proteo-lytically processed in vivo (Fig. 4B) (De Jonghet al. 1991, 1996). Nevertheless, the most prom-inent in vitro PKA phosphorylation sites ofboth proteins are located beyond the site of pro-teolytic truncation (Rotman et al. 1992, 1995;De Jongh et al. 1996; Mitterdorfer et al. 1996),and interaction of AKAP15 and PKA with thedistal carboxy-terminal domain through aleucine zipper motif is required for regulationof cardiac Ca2þ channels in intact myocytes(Hulme et al. 2003). These results imply thatthe distal carboxy-terminal domain remainsassociated with the proteolytically processedcardiac CaV1.2 channel, and this is supportedby evidence that the distal carboxyl-terminuscan bind to the truncated CaV1.1 and CaV1.2channels in vitro (Gerhardstein et al. 2000;Gao et al. 2001; Hulme et al. 2005) and intransfected cells (Hulme et al. 2002; Hulmeet al. 2006b). Moreover, formation of thiscomplex dramatically inhibits cardiac Ca2þ

channel function in intact mammalian cells(Hulme et al. 2006b). Deletion of the distalcarboxy-terminal near the site of proteolyticprocessing increases Ca2þ channel activity(Wei et al. 1994; Hulme et al. 2006b). However,noncovalent association of the cleaved distalcarboxy-terminal reduces channel activitymore than 10-fold, to a level much below thatof channels with an intact carboxyl-terminus(Hulme et al. 2006b). Thus, proteolytic process-ing produces an autoinhibited Ca2þ channelcomplex containing noncovalently bound distal





carboxyl-terminus with AKAP15 and PKAassociated through a modified leucine zipperinteraction (Fig. 4B). This autoinhibited com-plex appears to be the primary substrate forregulation of cardiac Ca2þ channels by theb-adrenergic receptor/PKA pathway in vivo,

and PKA up-regulation results from phos-phorylation of a single site near the end of theproximal carboxy-terminal domain at the inter-face with the distal carboxy-terminal domain(Fig. 4B) (Hulme et al. 2006b; Emrick et al.2010; Fuller et al. 2010).

1 2

+H3N

GβγnCaS/CaM

CaMKII

PKC

SNARES+H3N CO2

–

RIM

3 5 6 1

718

I

A

B

III IVOutside

Outside

Inside

Mg2+

Inside

CO2–

II

Domain: I III IVII

2 3+4+

5 6 1 2 3+4+

5 6 1 2 3+4+

5 6+4+

1 2 3 5 6+4+

1 2 3 5 6+4+

1 2 3 5 6+4+

1 2 3 5 6+4+

P

β

β

C

B

D

IM

+H3NEF-Hand

IQ+H3NCa2+/CaM

cAMP

COOH

PCRDDCRD

ABD

P++

PKA

AKAP 15–––

Figure 4. Ca2þ channel signaling complexes. (A) The presynaptic Ca2þ channel signaling complex. A presynapticCa2þ channel a1 subunit is illustrated as a transmembrane folding diagram as in Figure 2. Sites of interaction ofSNARE proteins (the synprint site), Gbg subunits, protein kinase C (PKC), CaMKII, and CaM and CaS proteinsare illustrated. IM, IQ-like motif; CBD, CaM binding domain. (B) The cardiac Ca2þ channel signaling complex.The carboxy-terminal domain of the cardiac Ca2þ channels is shown in expanded presentation to illustrate theregulatory interactions clearly. ABD, AKAP15 binding domain; DCRD, distal carboxy-terminal regulatorydomain; PCRD, proximal carboxy-terminal regulatory domain; scissors, site of proteolytic processing. TheDCRD binds to the PCRD through a modified leucine zipper interaction.

W.A. Catterall




Ca2þ Binding Proteins

In addition to their regulation by the PKA/AKAP15 signaling complex, cardiac Ca2þ

channels have calmodulin bound to theircarboxy-terminal domain through an IQ motif(Fig. 4B), and Ca2þ binding to calmodulincauses Ca2þ-dependent inactivation (Petersonet al. 1999; Qin et al. 1999; Zuhlke et al. 1999).Activation of CaV1.2 channels in the presenceof Ba2þ as the permeant ion results in inwardBa2þ currents that activate rapidly and inacti-vate slowly via a voltage-dependent inactivationprocess. In contrast, in the presence of Ca2þ asthe permeant ion, Ca2þ currents are rapidlyinactivated via Ca2þ/calmodulin-dependentinactivation. The Ca2þ-dependent inactivationprocess is crucial for limiting Ca2þ entry duringlong cardiac action potentials. In light of theseresults, it is evident that both the cAMP andCa2þ second messenger pathways regulateCaV1.2 channels locally, dependent on associ-ated regulatory proteins in Ca2þ channel signal-ing complexes.

CaV1 CHANNELS IN EXCITATION-TRANSCRIPTION COUPLING

Ca2þ entering neurons through L-type Ca2þ

currents conducted by CaV1 channels has aprivileged role in regulation of gene transcrip-tion, compared to similar amounts of Ca2þ

entering via other voltage-gated or ligand-gatedion channels (Flavell and Greenberg 2008). Thisunique access of CaV1 channels to regulation oftranscription might arise from preferentiallocalization, which could provide Ca2þ in thevicinity of transcriptional regulators, preferen-tial interaction with binding partners, whichcould be activated by local Ca2þ entry and carrythe regulatory signal to the nucleus, or nucleartargeting of a subunit or domain of the CaV1channel itself, which would serve to regulatetranscription directly. It is likely that all threeof these mechanisms are involved based onrecent experiments.

CaV1 channels are localized in higher den-sity in the cell bodies and proximal dendritesof neurons compared to CaV2 and CaV3

channels, which are more prevalent in nerveterminals and dendrites, respectively (Westen-broek et al. 1990; Hell et al. 1993a). This prefer-ential localization would favor Ca2þ entrythrough these channels in control of transcrip-tion in the nucleus. However, this effect seemsinsufficient to fully account for the dominanceof this Ca2þ entry pathway.

Studies with selective Ca2þ buffers indicatethat only a local increase in Ca2þ is requiredfor up-regulation of transcription in neurons(Wheeler et al. 2008). These findings suggestthat specifically bound Ca2þ-dependent reg-ulatory proteins may respond to local Ca2þ

entering via CaV1 channels and regulate tran-scription. Calmodulin is a resident Ca2þ-dependent regulator of CaV1 channels (Pittet al. 2001), and calmodulin binding to theproximal carboxy-terminal domain of CaV1.2channels is required for regulation of transcrip-tion in neurons (Bito et al. 1996; Dolmetschet al. 2001). Thus, calmodulin itself might serveas a regulator by binding local Ca2þ, changingconformation to the active form, and movingto the nucleus (Bito et al. 1996; Deisserothet al. 1998). However, there are large pools offree and Ca2þ-bound calmodulin throughoutthe cell, so additional mechanisms must beengaged to specifically move Ca2þ/calmodulincomplexes from the CaV1 channels to thenucleus in the context of this mode of regula-tion. Calcineurin bound to the distal carboxy-terminal domain of CaV1 channels also is apotential transcriptional regulator throughdephosphorylation of regulatory proteins (Oli-veria et al. 2007). In cultured hippocampalneurons, dephosphorylation of the nuclear fac-tor of activated T cells (NFAT) by calcineurinbound to CaV1.2 channels induces its dissocia-tion, movement to the nucleus, and regulationof transcription (Oliveria et al. 2007). Thispathway appears to have all of the necessaryelements for selective regulation of gene tran-scription by Ca2þ entering neurons via CaV1.2channels and has the precedent that it is a cru-cial element in gene regulation in lymphocytesby a similar mechanism.

The distal carboxy-terminal domain of theCaV1 channel itself has also been proposed as





a transcriptional regulator (Gomez-Ospina et al.2006). The large carboxy-terminal domain ofCaV1.1 and CaV1.2 channels is proteolyticallyprocessed in vivo near its center (De Jonghet al. 1991, 1996), leaving a noncovalently asso-ciated distal carboxy-terminal domain of morethan 300 residues intact to regulate channelactivity (Fig. 4B) (Hulme et al. 2006b). Inneurons, this proteolytic cleavage process isregulated by Ca2þ and blocked by calpaininhibitors (Hell et al. 1996). The distal carboxy-terminal domain can be detected in the nucleiof a subset of neurons in the developing brainand in neurons in cell culture (Gomez-Ospinaet al. 2006), opening the possibility of directeffects on transcription in the nucleus. Indeed,the distal carboxy-terminal domain can regu-late the transcription of a substantial set of othergenes in neurons (Gomez-Ospina et al. 2006),as well as the transcription of the gene encodingthe CaV1.2 channel itself in cardiac myocytes(Schroder et al. 2009). This regulatory mecha-nism also has all of the necessary elements togive selective regulation of gene expression byCaV1.2 channels, but it remains unknown howthe parallel effects of the distal carboxyl-terminus on regulation of channel activity ver-sus migration to the nucleus and regulation oftranscription are controlled. At least in neurons,it seems that only a small fraction of the distalcarboxy-terminal is located in the nucleus(Gomez-Ospina et al. 2006), so it may be thatmost of the proteolytically processed distalcarboxy-terminal domain remains associatedwith CaV1.2 channels as an autoinhibitory reg-ulator of channel activity while a small fractiondissociates and moves to the nucleus to regulatetranscription.

CaV1 CHANNELS INEXCITATION-SECRETION COUPLING

Ca2þ entry via CaV1 channels initiates secretionof hormones from endocrine cells (Artalejoet al. 1994; Yang and Berggren 2006) and releaseof neurotransmitters at specialized ribbon syn-apses in sensory-transduction neurons (Table 1)(Kollmar et al. 1997; Barnes and Kelly 2002).The relative role of individual CaV1 channel

subtypes in secretion, as well as the contributionof CaV2 channels, differs among cell types andspecies. In the pancreas, the requirement forL-type Ca2þ currents for insulin secretion isgreater in mouse than in human b cells (Elias-son et al. 2008; Braun et al. 2009). In adrenalchromaffin cells, L-type Ca2þ currents con-ducted by CaV1.2 and CaV1.3 channels triggersecretion of catecholamines, and their activityis strongly regulated by second messenger sig-naling pathways, including cAMP (Marcantoniet al. 2007).

Neurotransmitter release at specialized rib-bon synapses is continuous, similar to hormonesecretion in some physiological circumstances,and CaV1 channels are specifically required forthis mode of synaptic transmission. In photore-ceptors, CaV1.4 channels are primarily respon-sible for Ca2þ entry that triggers exocytosis ofneurotransmitters (Table 1) (Barnes and Kelly2002). Mutations in the CaV1.4 channel inhumans lead to stationary night blindness(Bech-Hansen et al. 1998; Striessnig et al.2010). In auditory hair cells, CaV1.3 channelsconduct the L-type Ca2þ currents that triggerneurotransmitter release (Kollmar et al. 1997).Deletion of the gene encoding CaV1.3 channelscauses deafness in mice (Platzer et al. 2000). Thedistal carboxy-terminal domain plays an auto-regulatory role in both CaV1.3 and CaV1.4channels (Singh et al. 2006, 2008), but it isnot known whether it is subject to proteolyticprocessing in vivo. CaV1.3 channels are regu-lated by multiple interacting proteins (Cuiet al. 2007; Jenkins et al. 2010), which may beimportant in tuning their activity to fit the spe-cific requirements of hair cells transmittingauditory information at different frequencies.

CaV2 CHANNELS IN SYNAPTICTRANSMISSION

Presynaptic Ca2þ channels conduct P/Q-, N-,and R-type Ca2þ currents, which initiate syn-aptic transmission (Table 1). The efficiency ofneurotransmitter release depends on the thirdor fourth power of the entering Ca2þ. This steepdependence of neurotransmission on Ca2þ

entry makes the presynaptic Ca2þ channel an

W.A. Catterall




exceptionally sensitive and important target ofregulation. In the nervous system, CaV2.1 chan-nels conducting P/Q-type Ca2þ currents andCaV2.2 channels conducting N-type Ca2þ cur-rents are the predominant pathways for Ca2þ

entry initiating fast release of classical neuro-transmitters like glutamate, acetylcholine, andGABA. Extensive studies indicate that they arecontrolled by many different protein interac-tions with their intracellular domains, whichserve as a platform for Ca2þ-dependent signaltransduction (Fig. 4A).

SNARE Proteins

Ca2þ entry through voltage-gated Ca2þ chan-nels initiates exocytosis by triggering the fusionof secretory vesicle membranes with the plasmamembrane through actions on the SNARE pro-tein complex of syntaxin, SNAP-25, and VAMP/synaptobrevin (reviewed in Bajjalieh and Schel-ler 1995; Sudhof 1995, 2004). The function ofthe SNARE protein complex is regulated byinteractions with numerous proteins, includingthe synaptic vesicle Ca2þ-binding protein syn-aptotagmin. Presynaptic CaV2.1 and CaV2.2channels interact directly with the SNARE pro-teins through a specific synaptic protein interac-tion (synprint) site in the large intracellularloop connecting domains II and III (Fig. 4A)(Sheng et al. 1994; Rettig et al. 1996). This inter-action is regulated by Ca2þ and protein phos-phorylation (Sheng et al. 1996; Yokoyama et al.1997, 2005). Synaptotagmin also binds to thesynprint site of CaV2 channels (Charvin et al.1997; Sheng et al. 1997; Wiser et al. 1997). Injec-tion into presynaptic neurons of peptides thatblock SNARE protein interactions with CaV2channels inhibits synaptic transmission, consis-tent with the conclusion that interaction withSNARE proteins is required to position dockedsynaptic vesicles near Ca2þ channels for fastexocytosis (Mochida et al. 1996; Rettig et al.1997). These results define a second functionalactivity of the presynaptic Ca2þ channel–target-ing docked synaptic vesicles to a source of Ca2þ

for effective transmitter release.In addition to this functional role of inter-

action between Ca2þ channels and SNARE

proteins in the anterograde process of synaptictransmission, these interactions also have retro-grade regulatory effects on Ca2þ channel func-tion. Coexpression of the plasma membraneSNARE proteins syntaxin or SNAP-25 withCaV2.1 or CaV2.2 channels reduces the level ofchannel expression and inhibits Ca2þ channelactivity by shifting the voltage dependence ofsteady-state inactivation during long depolariz-ing prepulses toward more negative membranepotentials (Bezprozvanny et al. 1995; Wiseret al. 1996; Zhong et al. 1999). The inhibitoryeffects of syntaxin are relieved by coexpressionof SNAP-25 and synaptotagmin to form a com-plete SNARE complex (Wiser et al. 1997; Tobiet al. 1999; Zhong et al. 1999), which has theeffect of enhancing activation of CaV2 channelswith nearby docked synaptic vesicles that haveformed complete SNARE complexes and areready for release. These processes fine-tune theefficiency of neurotransmitter release at frogneuromuscular junctions, where peptide andcDNA reagents can be used to modify synapticfunction in vivo (Keith et al. 2007).

G Protein Modulation

N-type and P/Q-type Ca2þ currents are regu-lated through multiple G protein coupled path-ways (Hille 1994; Jones et al. 1997; Ikeda andDunlap 1999). Although there are several G pro-tein signaling pathways that regulate these chan-nels, one common pathway that has been beststudied at both cellular and molecular levels isvoltage dependent and membrane delimited(i.e., a pathway without soluble intracellularmessengers whose effects can be reversed bystrong depolarization). Inhibition of Ca2þ

channel activity is typically caused by a positiveshift in the voltage dependence and a slowing ofchannel activation (Bean 1989b). These effectsare relieved by strong depolarization resultingin facilitation of Ca2þ currents (Marchettiet al. 1986; Bean 1989b). Synaptic transmissionis inhibited by neurotransmitters through thismechanism. G-protein a subunits are thoughtto confer specificity in receptor coupling, butGbg subunits are responsible for modulationof Ca2þ channels. Cotransfection of cells with





the Ca2þ channel a1 and b subunits plus Gbg

causes a shift in the voltage dependence ofCa2þ channel activation to more positivemembrane potentials and reduces the steepnessof voltage-dependent activation, effects thatclosely mimic the actions of neurotransmit-ters and guanyl nucleotides on N-type and P/Q-type Ca2þ channels in neurons and neuroen-docrine cells (Herlitze et al. 1996). In contrast,transfection with a range of Ga subunits doesnot have this effect. This voltage shift can bereversed by strong positive prepulses resultingin voltage-dependent facilitation of the Ca2þ

current in the presence of Gbg, again closelymimicking the effects of neurotransmittersand guanyl nucleotides on Ca2þ channels. Sim-ilarly, injection or expression of Gbg subunitsin sympathetic ganglion neurons induces facili-tation and occludes modulation of N-typechannels by norepinephrine, but Ga subunitsdo not (Herlitze et al. 1996; Ikeda 1996). Theseresults point to the Gbg subunits as the primaryregulators of presynaptic Ca2þ channels via thisvoltage-dependent pathway through direct pro-tein–protein interactions (Fig. 4A).

Possible sites of G protein bg subunit inter-action with Ca2þ channels have been extensivelyinvestigated by construction and analysis ofchannel chimeras, by G protein binding experi-ments, and by site-directed mutagenesis andexpression (Fig. 4A). Evidence from G proteinbinding and site-directed mutagenesis experi-ments points to the intracellular loop betweendomains I and II (LI-II) as a crucial site of G pro-tein regulation, and peptides from this region ofCaV2.2 prevent inhibition of channel activity byGbg, presumably by binding to Gbg and com-petitively inhibiting its access to Ca2þ channels(De Waard et al. 1997; Herlitze et al. 1997; Zam-poni et al. 1997). This region of the channelbinds Gbg in vitro as well as in vivo in the yeasttwo-hybrid assay (De Waard et al. 1997; Zam-poni et al. 1997; Garcia et al. 1998). Increas-ing evidence also points to segments in theamino- and carboxy-terminal domains of Ca2þ

channels that are also required for G protein reg-ulation (Zhang et al. 1996; Page et al. 1997, 1998;Qin et al. 1997; Canti et al. 1999; Li et al. 2004).As the amino- and carboxy-terminal domains

are likely to interact with each other in thefolded channel protein, a second site of interac-tion for G proteins may be formed at theirintersection.

Ca2þ Binding Proteins

Ca2þ-dependent facilitation and inactivationof presynaptic Ca2þ channels was observed inpatch clamp recordings of presynaptic nerveterminals in the rat neurohypophysis (Bran-chaw et al. 1997) and the calyx of Held synapsein the rat brainstem (Forsythe et al. 1998b).During tetanic stimulation at this synapse,Cav2.1 channel currents show both Ca2þ-dependent facilitation and inactivation (Borstand Sakmann 1998; Cuttle et al. 1998; Forsytheet al. 1998a), which results in facilitation anddepression of excitatory postsynaptic responses(Borst and Sakmann 1998; Cuttle et al. 1998;Forsythe et al. 1998b). Ca2þ-dependent facilita-tion and inactivation are also observed forcloned and expressed Cav2.1 channels expressedin mammalian cells (Lee et al. 1999, 2000). Anovel CaM-binding site was identified by yeasttwo-hybrid screening in the carboxy-terminaldomain of the pore-forming a12.1 subunit ofCav2.1 channels (Lee et al. 1999). This CaM-binding domain (CBD) (Fig. 4A) is located onthe carboxy-terminal side of the sequence ina12.1 that corresponds to the IQ-domain thatis required for CaM modulation of cardiacCav1.2 channels (Peterson et al. 1999; Qinet al. 1999; Zuhlke et al. 1999). The modifiedIQ domain of a12.1 begins with the aminoacid sequence IM instead of IQ and has otherchanges that would be predicted to substantiallyreduce its affinity for CaM. CaM binding to theCBD is Ca2þ-dependent. Both Ca2þ-dependentfacilitation and inactivation are blocked bycoexpression of a CaM inhibitor peptide (Leeet al. 1999), suggesting that Ca2þ-dependentmodulation of Cav2.1 channels in neurons iscaused by two sequential interactions withCaM or a related Ca2þ-binding protein.

The mechanism for Ca2þ-dependent fa-cilitation and inactivation of Cav2.1 channelsinvolves CaM binding to two adjacent sub-sites—the CBD and the upstream IQ-like motif

W.A. Catterall




(Lee et al. 2003). The IQ-like motif is requiredfor facilitation, whereas the CBD is requiredfor inactivation. In addition, the two lobes ofCaM are also differentially involved in thesetwo processes. Mutation of the two EF handsin the carboxy-terminal lobe primarily preventsfacilitation, whereas mutation of the EF handsin the amino-terminal lobe primarily preventsinactivation (DeMaria et al. 2001; Ericksonet al. 2001; Lee et al. 2003). FRET studies indi-cate that apo-calmodulin can bind to Cav2.1channels in intact cells and binding is enhancedby Ca2þ binding to calmodulin (Erickson et al.2001). Altogether, these results support a modelin which the two lobes of CaM interact differ-entially with the modified IQ domain and theCBD to effect bi-directional regulation, withthe high-affinity carboxy-terminal lobe pri-marily controlling facilitation through inter-actions with the IQ-like domain and thelower-affinity amino-terminal lobe primarilycontrolling inactivation through interactionswith the CBD. This biphasic regulation ofCaV2.1 channels causes synaptic facilitationand depression in transfected sympathetic gan-glion neuron synapses in which neurotransmis-sion is initiated by transfected CaV2.1 channels(Mochida et al. 2008).

CaM is the most well-characterized memberof a superfamily of Ca2þ sensor (CaS) proteins,many of which differ from CaM in havingneuron-specific localization, amino-terminalmyristoylation, and amino acid substitutionsthat prevent Ca2þ binding to one or two ofthe EF hands (Haeseleer and Palczewski 2002).The CaS protein CaBP1 binds to the CBD, butnot the IQ-like domain, ofa12.1 and its bindingis Ca2þ-independent (Lee et al. 2002). CaBP1causes a strong enhancement of the rate ofinactivation, a positive shift in the voltage-dependence of activation, and a loss of Ca2þ-dependent facilitation of Cav2.1 channels,which would combine to reduce the activity ofthese channels. Because it coimmunoprecipi-tates and colocalizes with Cav2.1 channels inthe brain (Lee et al. 2002), CaBP1 may be animportant determinant of Cav2.1 channelfunction in neurons and may contribute to thediversity of function of these channels in the

nervous system. Visinin-like protein 2 (VILIP-2) is a neuronal Ca2þ-binding protein that isdistantly related to CaBP-1 (Haeseleer andPalczewski 2002). Consistent with these struc-tural differences, VILIP-2 has opposite effectson CaV2.1 channels than CaBP-1 (Lautermilchet al. 2005). Coexpression of VILIP-2 causesslowed inactivation and enhanced facilitation,but its binding and effects are Ca2þ-independ-ent like CaBP-1. VILIP-2 may serve as a positivemodulator of synaptic transmission, pro-longing Ca2þ channel opening, and enhancingfacilitation. Differential expression of CaBP1and VILIP-2 at synapses would lead to oppositemodulation of synaptic transmission in re-sponse to trains of action potentials and oppos-ing input–output functions at the synapse.

CaV3 CHANNELS AND FREQUENCYMODULATION

Molecular Properties of CaV3 Channels

Ca2þ channels of the CaV3 subfamily conductT-type Ca2þ currents (Catterall et al. 2005).These Ca2þ currents are activated at compara-tively negative membrane potentials, in thesame range as Naþ currents in most cells, andthey have fast voltage-dependent inactivationcompared to other Ca2þ currents (Nowyckyet al. 1985). These Ca2þ currents are thereforewell-suited for rhythmic firing of action poten-tials. They are also well-suited for generation oflarge Ca2þ transients because they are activatedat negative membrane potentials where thedriving force for Ca2þ entry is large. A familyof three CaV3 channel a1 subunits have beencharacterized by cDNA cloning and sequencing(Catterall et al. 2005). Remarkably, these Ca2þ

channel subunits have the same molecularorganization as CaV1 and CaV2 channels butare only �25% identical in amino acidsequence (Catterall et al. 2005). This is a similarlevel of amino acid sequence identity as Ca2þ

channels have with Naþ channels, indicatingthat these subfamilies of Ca2þ channels sepa-rated from each other at the same point of evo-lution as Naþ channels separated from Ca2þ

channels. Although CaV3 channels are similar





in structure to CaV1 and CaV2 channels, there isno clear evidence at present that they interactwith the same set of auxiliary subunits. In fact,the prevailing view is that the a1 subunits func-tion independently of other subunits. Thiswould be unique among the families of Naþ

and Ca2þ channels.

Functional Roles of CaV3 Channels

As expected from their functional properties,CaV3 channels are important in repetitively fir-ing tissues. In the sino-atrial node of the heart,they conduct an important component of thepacemaker current that generates the heartbeat(Mangoni et al. 2006). In the relay neurons ofthe thalamus, they are crucial for generationof the rhythmic bursts of action potentialsthat drive sleep spindles and control sleep (Leeet al. 2004). Moreover, mutations in CaV3channels cause absence epilepsy, in which theaffected individuals transiently enter a sleep-likestate that interrupts their normal activities (Kimet al. 2001; Song et al. 2004). In the adrenalcortex, they are important in regulation of syn-thesis and secretion of aldosterone (Welsby et al.2003).

Regulation of CaV3 Channels

In neurons, dopamine and other neurotrans-mitters inhibit T-type Ca2þ currents via a path-way that is specific for the Gb2 subunit (Wolfeet al. 2003). As for CaV2 channels, G protein bg

subunits bind directly to CaV3 channels andregulate them (DePuy et al. 2006). The site ofinteraction is in the intracellular loop connect-ing domains II and III (DePuy et al. 2006). Inaddition, in adrenal glomerulosa cells, angio-tensin II regulates aldosterone secretion via en-hanced activation of CaV3.2 channels (Welsbyet al. 2003). This regulation is mediated by asignaling complex of CaMKII bound to theintracellular loop connecting domains II andIII (Yao et al. 2006). Phosphorylation of a singleserine residue in this intracellular loop nega-tively shifts the voltage dependence of activationand thereby substantially increases Ca2þ currentat negative membrane potentials (Yao et al.

2006). It is unknown at this stage whether bind-ing of CaMKII is required for physiological reg-ulation or whether binding of the kinase per sehas any regulatory effect.

THE EFFECTOR CHECKPOINT MODEL OFCa2þ CHANNEL REGULATION

In closing this article on Ca2þ signaling viavoltage-gated Ca2þ channels, it is interestingto introduce an emerging theme that unitesseveral aspects of the localized regulation ofthese proteins. Ca2þ channel signaling com-plexes are formed when the effectors and regu-lators of the Ca2þ signal bind to the intracellulardomains of Ca2þ channels to effectively receiveand respond to the local Ca2þ signal. In fourcases, binding of the effectors of the Ca2þ signalhas been shown to enhance the activity of theCaV1 and CaV2 channels. First, in skeletalmuscle, interactions of the plasma membraneCaV1.1 channel with the ryanodine-sensitiveCa2þ release channel in the sarcoplasmic reticu-lum, which serves as the effector of excita-tion-contraction coupling, greatly increase thefunctional activity of the CaV1.1 channels(Nakai et al. 1996a). Second, as described above,interaction with individual plasma membraneSNARE proteins inhibits the activity of CaV2channels, but formation of complete SNAREcomplex containing synaptotagmin, the effec-tor of exocytosis, relieves this inhibition andenhances Ca2þ channel activity (Bezprozvannyet al. 1995; Wiser et al. 1996, 1997; Zhonget al. 1999). Third, binding of Ca2þ/CaM-dependent protein kinase II, an effector ofCa2þ-dependent regulatory events, to a site inthe carboxy-terminal domain of CaV2.1 chan-nels substantially increases their activity (Jianget al. 2008). Finally, binding of RIM, a regulatorof SNARE protein function, to the CaVb sub-units substantially increases CaV2 channelactivity (Kiyonaka et al. 2007). The commonthread in all of these diverse examples of Ca2þ

channel regulation by interacting proteins isthat binding of an effector ready to respond tothe Ca2þ signal enhances the activity of theCa2þ channel. Thus, this mechanism providesa functional checkpoint of the fitness of a

W.A. Catterall




Ca2þ channel to carry out its physiological role,and enhances its activity if it passes this check-point criterion. This “effector checkpoint”mechanism would serve to focus Ca2þ entryon the CaV channels that are ready to use theresulting Ca2þ signal to initiate a physiologicalintracellular signaling process. It seems likelythat further studies will reveal more examplesof this form of regulation and that it may be aunifying theme in the regulation of Ca2þ signal-ing by CaV channels.

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11, 20112011; doi: 10.1101/cshperspect.a003947 originally published online JulyCold Spring Harb Perspect Biol

William A. Catterall Voltage-Gated Calcium Channels

Subject Collection Calcium Signaling

DiseaseCalcium-Handling Defects and Neurodegenerative

StutzmannSean Schrank, Nikki Barrington and Grace E.

Store-Operated CRAC Channels Microdomains from2+Signaling through Ca

Pradeep Barak and Anant B. Parekh

Health and Disease Homeostasis and Signaling in2+Lysosomal Ca

Emyr Lloyd-Evans and Helen Waller-Evans/Calmodulin-Dependent Protein Kinase II (CaMKII)

2+Structural Insights into the Regulation of Ca

John KuriyanMoitrayee Bhattacharyya, Deepti Karandur and

Signaling in Exocrine Cells2+CaMalini Ahuja, Woo Young Chung, Wei-Yin Lin, et al. to Structure and Back Again

Store-Operated Calcium Channels: From Function

Richard S. Lewis

Transcription-Dependent Metabolic PlasticitySynapse-to-Nucleus Communication: Focus on Functional Consequences of Calcium-Dependent

Bas-OrthAnna M. Hagenston, Hilmar Bading and Carlos

Channels2+Receptors and Other Organellar Ca3Bcl-2-Protein Family as Modulators of IP

al.Hristina Ivanova, Tim Vervliet, Giovanni Monaco, et

Old Enzyme: CalcineurinIdentifying New Substrates and Functions for an

Jagoree Roy and Martha S. Cyert

Calcium Signaling in Cardiomyocyte Function

et al.Guillaume Gilbert, Kateryna Demydenko, Eef Dries,

Entry2+Junction: A Hub for Agonist Regulation of Ca

Plasma Membrane−The Endoplasmic Reticulum

Hwei Ling Ong and Indu Suresh Ambudkar

and Disease Transport Systems in Health2+Primary Active Ca

Jialin Chen, Aljona Sitsel, Veronick Benoy, et al.

PrimerFundamentals of Cellular Calcium Signaling: A

Martin D. Bootman and Geert BultynckModulators

Signal2+ Buffers Are Inherently Ca2+Cytosolic Ca

Beat Schwaller

Development and Cellular DifferentiationRole of Two-Pore Channels in Embryonic

MillerSarah E. Webb, Jeffrey J. Kelu and Andrew L.

Reticular NetworkOrganellar Calcium Handling in the Cellular

Wen-An Wang, Luis B. Agellon and Marek Michalak

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