| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SYMPOSIUM REPORT |
Department of Physiology and Biophysics, Cellular and Molecular Neurobiology Research Group, University of Calgary, Calgary T2N 4 N1, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
(Received 13 May 2003;
accepted after revision 5 June 2003;
first published online 18 June 2003)
Corresponding author G. W. Zamponi: Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada. Email: zamponi{at}ucalgary.ca
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
-conotoxin GVIA, and P- and Q-type channels differ in their current kinetics, but are both inhibited by the American funnel web spider toxin -agatoxin IVA, albeit with different affinities. R-type channels were originally defined based on their insensitivity to these blockers.
Molecular cloning has resulted in the identification of the molecular identities of native calcium current subtypes (for review, see Stea et al. 1995). Based on these studies, we now know that HVA calcium channels are heteromultimers comprised of a pore-forming 
1 subunit, plus ancillary ß, 2-
and 
subunits, whereas LVA calcium channels appear to contain only the 1 subunit (for review, see Catterall, 2000). To date, 10 different types of calcium channel 1 subunits have been identified and shown to represent the major types of native calcium channels. Cav1.1, Cav1.2, Cav1.3 and Cav1.4 calcium channel 1 subunits encode different types of L-type channel (Tanabe et al. 1987; Mikami et al. 1989; Williams et al. 1992; Koschak et al. 2003), different splice isoforms of Cav2.1 channels encode P- and Q-type channels (Bourinet et al. 1999), Cav2.2 and Cav2.3 encode N-type and R-type channels (Dubel et al. 1992; Niidome et al. 1992), respectively, and Cav3.1, Cav3.2 and Cav3.3 channels are members of the family of LVA (or T-type) calcium channels (Cribbs et al. 1998; Perez-Reyes et al. 1998; Lee et al. 1999a; McRory et al. 2001). The 1 subunit is comprised of four homologous repeats, each containing six transmembrane-spanning helices plus a re-entrant p-loop motif (see Fig. 1; Catterall, 2000). The four domains are linked through large cytoplasmic loops that are capable of interacting with a number of regulatory proteins, including the calcium channel ß subunit. Indeed, although the 1 subunits are capable of forming functional channels, their functional properties (including activation and inactivation kinetics, surface expression and second-messenger regulation) are modulated by the ancillary subunits. To date, four genes encoding ß subunits, four genes encoding 2- subunits and eight genes encoding different types of subunits have been identified, and their effects on 1 subunit function have been characterized in expression systems.
|
In response to a prolonged membrane depolarization, calcium channels, like many other types of ion channel, enter a non-conducting inactivated gating state. This prevents the breakdown of calcium gradients, ensures the temporal and spatial precision of calcium signals in response to membrane depolarization, and is an important mechanism by which the accumulation of excessive, cytotoxic levels of intracellular calcium is prevented (Choi, 1988; Orrenius et al. 1989; Orrenius & Nicotera, 1994). Specifically, the inactivation of calcium currents in nerve terminals appears to contribute to the short-term depression of neurosecretion (Branchaw et al. 1997; Forsythe et al. 1998). In neurones, the voltage-dependent inactivation of T-type calcium channels is a key determinant of pattern behaviour and pacemaker activity (Chemin et al. 2001, 2002). Moreover, many clinically active calcium channel blockers display an increased affinity for inactivated calcium channels (Sun & Triggle, 1995; Roullet et al. 1999; Jimenez et al. 2000). Finally, in P/Q-type calcium channels, inactivation behaviour is altered by naturally occurring point mutations linked to disorders such as familial hemiplegic migraine (Kraus et al. 1998, 2000; Wappl et al. 2002), thus underlining the importance of the inactivation process for CNS function. As a consequence, it is not surprising to note that voltage-gated calcium channels are capable of undergoing multiple types of inactivation processes. L-type channels (with the exception of Cav1.4 channels; McRory et al. 2004) undergo a pronounced speeding of inactivation kinetics in response to an increase in intracellular calcium concentrations (Peterson et al. 1999; Zuhlke et al. 1999). Although it was once believed that this calcium-dependent inactivation process is a unique feature of L-type channels, more recent patch-clamp experiments carried out in the presence of low concentrations of intracellular calcium buffers have revealed calcium-dependent inactivation in P/Q-type and other HVA calcium channels (Lee et al. 1999a; DeMaria et al. 2001; Soong et al. 2002; Liang et al. 2003). In contrast, T-type calcium channels do not appear to support calcium-dependent inactivation. The second means of inactivating calcium entry is through prolonged membrane depolarization. This voltage-dependent inactivation process has both fast and slow components, with fast inactivation occurring over several tens to hundreds of milliseconds, and slow inactivation requiring much more prolonged membrane depolarization (
1 min), and remains a poorly understood process (Sokolov et al. 2000; Shi & Soldatov, 2002). The ensuing sections will be concerned predominantly with fast, voltage-dependent inactivation of HVA calcium channels, with a particular focus on the underlying channel structural determinants.
Mechanisms of fast inactivation in sodium and potassium channels
More than two decades worth of research into the inactivation mechanisms of sodium and potassium channels (i.e. channels that are structurally homologous to the calcium channel 1 subunit) provide an excellent framework towards gaining insights into the mechanism of calcium channel inactivation. For example, certain types of potassium channels, such as Shaker B, inactivate through a ‘ball and chain’ mechanism (Armstrong et al. 1973) in which the amino terminus of the subunit contains a 20-amino-acid cluster (i.e. ‘ball’) of hydrophobic and polar domains that is tethered to the remainder of the subunit via a stretch of about 50 residues (i.e. ‘chain’, see Fig. 2A). Upon channel opening, the ball region enters the inner vestibule of the pore from the cytoplasmic end of the channel to occlude current flow, hence inactivating the channel. Deletion of this region dramatically slows voltage-dependent inactivation, and intracellular addition of synthetic N-terminal peptides to inactivation-deficient Shaker B mutants restores inactivation, consistent with open channel block (Hoshi et al. 1990; Zagotta et al. 1990; Demo & Yellen, 1991). Certain potassium channel ß subunit isoforms (e.g. Kvß1.1 and Kvß3) contain regions that resemble gating balls, and when coexpressed with certain types of non-inactivating Kv subunits such as Kv1.1 or Kv1.2, resulting in a rapidly inactivating phenotype channels (Heinemann et al. 1996; Robertson, 1997).
|
subunit acts as a ‘hinged lid’ to block the channel pore (West et al. 1992; Eaholtz et al. 1994; Kellenberger et al. 1997; see Fig. 2B). Cleavage of this region via proteolytic enzymes (Armstrong et al. 1973) or intracellular application of functional antibodies against this region removes inactivation (Vassilev et al. 1988, 1989). Indeed, site-directed mutagenesis of a cluster of three hydrophobic amino acid residues in the III–IV linker region (I1488, F1489, M1490; IFM) to glutamine abolishes fast inactivation (West et al. 1992). In analogy with experiments on potassium channels, intracellular application of a pentapeptide containing the IFM motif region partially restores inactivation in inactivation-deficient sodium channel mutants (Eaholtz et al. 1994). Also similar to potassium channels, coexpression of ancillary ß1 subunits modulates the inactivation kinetics of the subunit (McCormick et al. 1999). Taken together, these data indicate that there are many qualitative similarities in the mechanisms by which sodium and potassium channels undergo fast, voltage-dependent inactivation, including pore block by a cytoplasmic gating particle and regulation by ancillary subunits. As outlined in the ensuing sections, our current understanding of fast inactivation of calcium channels may in many ways resemble that of the families of sodium and potassium channels; however, the molecular details of calcium channel inactivation appear to be much more complex.
What are the determinants of 1 subunit structural inactivation in HVA channels?
When expressed in the absence of ancillary subunits, barium currents carried by various types of HVA calcium channel display pronounced voltage-dependent inactivation, suggesting that the primary structural determinants underlying the inactivation process reside in the 1 subunit itself. The first attempt at defining key structural determinants of calcium channel inactivation came from chimeric studies by Zhang et al. (1994). The authors created hybrid calcium channels between rat Cav2.1 and marine ray Cav2.3 and concluded, based on their electrophysiological characterization, that the domain IS6 segment was responsible for the difference in inactivation kinetics of these two calcium channel subtypes. Subsequently, a number of additional studies have implicated S6 segments in each of the remaining three transmembrane domains. Substituting the domain II or domain IIIS6 segments from rapidly inactivating Cav2.3 channels into slowly inactivating Cav1.2 channels is sufficient to induce a rapidly inactivating phenotype (Stotz et al. 2000). Familial hemiplegic migraine mutations in the IIS6 and IV S6 regions alter the inactivation kinetics of Cav2.1 calcium channels (Kraus et al. 1998, 2000). Artificial point mutations in the IIS6, IIIS6 and IVS6 regions (Hering et al. 1996, 1998; Berjukow et al. 2001; Stotz & Zamponi, 2001) also mediate dramatic increases in the inactivation of L-type calcium channels. For example, Berjukow et al. 2001) reported that substitution of a single methionine residue in the IVS6 region with glutamine increases inactivation rates by as much as 75-fold. Similarly, Stotz & Zamponi (2001) showed that replacement of a single phenylalanine residue in the IIS6 region dramatically speeds up the inactivation of rat Cav1.2 calcium channels. Taken together, these findings indicate that all four S6 segments in the calcium channel 1 subunit contribute to the inactivation process. Furthermore, Spaetgens & Zamponi (1999) observed that all four transmembrane domains contribute to determining the overall voltage-dependence of inactivation, supporting the notion that calcium channel inactivation may arise from a global structural change in the entire channel. We note that a global phenomenon of pore collapse has been proposed as a mechanism of C-type/slow inactivation of potassium and sodium channels (Hoshi et al. 1991; Lopez-Barneo et al. 1993; Lopez et al. 1994; Richmond et al. 1998; Vilin et al. 1999).
In contrast, a number of additional observations provide support for a classical hinged-lid-type mechanism of inactivation. One key feature of a hinged-lid/ball-and-chain mechanism is the involvement of cytoplasmic regions. The first striking evidence supporting the involvement of a cytoplasmic linker region came from observations with Cav2.1 calcium channel splice variants (Bourinet et al. 1999). Insertion of a single valine residue in the Cav2.1 I–II linker dramatically slows the rate of inactivation of this channel, effectively converting it from a Q-type to a P-type phenotype. Consistent with a key role of the I–II linker region in the inactivation process, substitution of the I–II linker of Cav2.3 into the Cav1.2 channel results in a significant increase in inactivation rates, whereas a partial substitution of this region has the opposite effect, virtually abolishing inactivation (Stotz & Zamponi, 2001). Furthermore, several other mutagenesis studies also support the involvement of the I–II linker in determining inactivation rates (Herlitze et al. 1997; Berrou et al. 2001). Finally, Cens et al. (1999) reported that overexpression of I–II linker peptides accelerates the inactivation kinetics of expressed Cav2.1 channels. Taken together, these findings raise the possibility that the domain I–II linker might perhaps act as a cytoplasmic gating particle. If so, how can this be reconciled with data implicating the S6 segments? One simple possibility is a mechanism in which the S6 segments may be involved in forming the docking site for the gating particle, similar to what has been proposed for sodium channels (McPhee et al. 1994). This will be discussed in greater detail below.
In addition to the domain I–II linker, several other cytoplasmic regions have been linked to the inactivation process. Data from Soldatov et al. (1998) and Sandoz et al. (2001) suggest that the C-terminal region may, in addition to being a key determinant of calcium-dependent inactivation, also regulate the voltage-dependent inactivation of calcium channels. In addition, truncation of the C-terminal region dramatically speeds the inactivation of Cav1.2 channels (Stotz & Zamponi, 2002). Stephens et al. (2000) suggested an additional involvement of the N-terminal region in determining inactivation rates. Geib et al. (2002) reported that the inactivation kinetics of Cav2.1 channels are slowed when an intramolecular interaction between the domain I–II and the domain III–IV linker regions are disrupted via mutagenesis. This effect, however, was only seen in the absence of the calcium channel ß subunit. Finally, deletion of part of the domain II–III linker region of human Cav2.2 channels through alternate splicing, while having little effect on inactivation kinetics, results in a depolarizing shift in the half-inactivation potential (Kaneko et al. 2002). Hence, voltage-dependent inactivation of HVA calcium channels involves both pore-lining transmembrane helices and all of the major intracellular domains of the 1 subunit.
Regulation of inactivation kinetics by extracellular metal ions and second messengers
A recent study by Beedle et al. (2002) has revealed that the inactivation kinetics of transiently expressed Cav2.1 and Cav1.2, but not other calcium channel subtypes, is regulated by extracellular application of trivalent metal ions. In the presence of nanomolar concentrations of yttrium, these channels underwent a pronounced speeding of the inactivation kinetics, an effect that was independent of the open channel blocking action of these ions. The effects were attenuated following manipulations that antagonize inactivation (i.e. coexpression of the rat ß2a subunit or structural modifications in the I–II linker region). The existence of an external regulation site that can bind multivalent ions is consistent with previous suggestions by Zamponi & Snutch (1996) and Zamponi et al. (1996), and indicates that extracellular regions of the channel may be coupled allosterically to the inactivation machinery.
An observation from the Findlay laboratory showing that ß-adrenergic modulation regulates voltage-dependent inactivation of native cardiac L-type calcium channels (Findlay, 2002a,b,c) is perhaps more easily explained in the context of prior structure versus function data. The author showed that ß-adrenergic receptor activation slowed down voltage-dependent inactivation, but that this effect was abolished by carbachol. There are a number of phosphorylation sites in the C-terminal region of the channel, perhaps providing a structural explanation for these observations, considering that C-terminal truncations alter voltage-dependent inactivation of the channels. Site-directed mutagenesis of putative protein kinase A (PKA) sites would be required in future experiments to elucidate the underlying molecular determinants. Nonetheless, these data show that intracellular messenger pathways can dynamically regulate the inactivation characteristics of L-type calcium channels.
Determinants of LVA calcium channel inactivation
Compared with HVA calcium channels, the molecular determinants that underlie the inactivation of LVA calcium channels have been well characterized. In perhaps the most detailed study to emerge to date, Staes et al. (2001) reported that the C-terminus region of the Cav3.1 channel is important for inactivation, whereas the III–IV linker and N-terminal regions (i.e. the structures involved in sodium and potassium channel inactivation, respectively) do not appear to play a major role. The authors did not, however, examine a putative role for the I–II linker. In contrast, Marksteiner et al. (2001) implicated the domain IIIS6 region as an important inactivation determinant of Cav3.1 channels, thus suggesting some overlap in the mechanism of LVA and HVA calcium channel inactivation. More detailed structure–functional analysis will be required to substantiate such as possibility.
Ancillary subunits regulate calcium channel inactivation
It is now well established that ancillary ß subunits are important regulators of voltage-dependent inactivation of HVA calcium channels (Lacerda et al. 1991; Varadi et al. 1991), which is consistent with the observation that the primary ß subunit interaction site is located in the domain I–II linker region of the 1 subunit (Pragnell et al. 1994). As a general rule of thumb, coexpression of HVA channels with ß1b or ß3 subunits accelerates inactivation, whereas ß4 subunits result in inactivation kinetics that are as slow as those seen with the 1 subunit alone. The rat and human ß2a subunits dramatically slow inactivation kinetics (Isom et al. 1994) due to palmitoylation of two cysteine residues in the N-terminus region of this subunit and subsequent tethering of this region to the plasma membrane (Olcese et al. 1994; Qin et al. 1996, 1998; Hurley et al. 2000; Restituito et al. 2000; Feng et al. 2001). Additional interactions between the N-terminus of the calcium channel 1 subunit and second variable region of ß2a subunit also affect inactivation characteristics (Qin et al. 1996; Stephens et al. 2000). Inactivation of the 1 subunit is also modulated, although to a lesser degree, by 2- and subunits. Coexpression of different 2- subunits with Cav1.2 and Cav2.3 calcium channels alters the kinetics and the voltage-dependence of inactivation (Klugbauer et al. 1999). The effects of the subunit are more subtle, resulting in an enhancement of a slowly inactivating current component seen with Cav2.1 calcium channels (Rousset et al. 2001). Neither their interaction sites with the calcium channel 1 subunit nor the molecular mechanisms by which these two ancillary subunits regulate inactivation kinetics are understood.
A molecular model of HVA calcium channel inactivation
How can all of the observations described in the previous sections be reconciled into one all-encompassing model of inactivation? Structure versus function studies have consistently implicated the S6 segments as well as intracellular regions (see Fig. 3). Of the latter, structural alterations in the I–II linker appear to mediate the greatest effects. Together with the observation that overexpression of I–II linker peptides results in increased inactivation of Cav2.1 channels, a role for this region as a putative hinged-lid gating particle is an attractive possibility. Within the confines of such a model, the S6 segments (which probably line the inner vestibule of the pore) could form part of the docking site for the inactivation gate. Consistent with this idea, there is a ring of highly conserved residues at the innermost part of the four S6 regions, which when mutated in individual S6 segments, results in the slowing of inactivation (Shi & Soldatov, 2002). Moreover, mutations in multiple S6 segments produce additive effects. It is also interesting to note that mutations in the domain IIS6 region, which speed the rate of inactivation, do not affect the rate of recovery from inactivation (Stotz & Zamponi, 2001), which indicates that these mutations selectively affect the rate of entry into the inactivated conformation, but not its stability. Based on these findings, Stotz & Zamponi (2001) proposed that in response to membrane depolarization, the S6 segments might undergo a slight conformational change that allows the domain I–II linker gating particle to dock at the cytoplasmic ends of the S6 segments (Fig. 4). Mutations in the S6 regions that speed the rate of inactivation would then simply promote the conformational switch without affecting the stability of the interaction with the I–II linker. Application of trivalent metal ions such as yttrium (Beedle et al. 2002) may perhaps also promote such a putative conformational change in the S6 segments.
|
|
In summary, the model presented in Fig. 4 can accommodate virtually all of the structure–function data reported in the literature to date. Although this model will need to be rigorously tested, we suggest that the basic mechanism of calcium channel inactivation is qualitatively similar to that seen with other types of voltage-dependent ion channels, thus underlining the fundamental importance of the inactivation process in the physiology of excitable cells.
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Armstrong CM, Bezanilla F & Rojas E (1973). Destruction of sodium conductance inactivation in squid axons perfused with pronase. J General Physiol 62, 375–391.
Atwood HL & Karunanithi S (2002). Diversification of synaptic strength: presynaptic elements. Nat Rev Neurosci 3, 497–516.[Medline]
Beedle AM, Hamid J & Zamponi GW (2002). Inhibition of transiently expressed low- and high-voltage-activated calcium channels by trivalent metal cations. J Membr Biol 187, 225–238.[CrossRef][Medline]
Berjukow S, Marksteiner R, Sokolov S, Weiss RG, Margreiter E & Hering S (2001). Amino acids in segment IVS6 and beta–subunit interaction support distinct conformational changes during Ca(v)2.1 inactivation. J Biol Chem 276, 17076–17082.
Berrou L, Bernatchez G & Parent L (2001). Molecular determinants of inactivation within the I–II linker of alpha1E (CaV2.3) calcium channels. Biophys J 80, 215–228.
Borodinsky LN, O'Leary D, Neale JH, Vicini S, Coso OA & Fiszman ML (2003). GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA(A) receptor activation, calcium influx and CaMKII and erk1/2 pathways. J Neurochem 84, 411–420.
Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J & Snutch TP (1999). Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci 2, 407–415.[CrossRef][Medline]
Branchaw JL, Banks MI & Jackson MB (1997). Ca2+- and voltage-dependent inactivation of Ca2+ channels in nerve terminals of the neurohypophysis. J Neurosci 17, 5772–5781.
Catterall WA (2000). Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16, 521–555.[CrossRef][Medline]
Cens T, Restituito S, Galas S & Charnet P (1999). Voltage and calcium use the same molecular determinants to inactivate calcium channels. J Biol Chem 274, 5483–5490.
Chemin J, Monteil A, Dubel S, Nargeot J & Lory P (2001). The alpha1 T-type calcium channel exhibits faster gating properties when overexpressed in neuroblastoma/glioma NG 108–15 cells. Eur J Neurosci 14, 1678–1686.[CrossRef][Medline]
Chemin J, Monteil A, Perez-Reyes E, Bourinet E, Nargeot J & Lory P (2002). Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I) to neuronal excitability. J Physiol 540, 3–14.
Choi DW (1988). Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11, 465–469.[CrossRef][Medline]
Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M & Perez-Reyes E (1998). Cloning and characterization of 1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res 83, 103–109.
DeMaria CD, Soong TW, Alseikhan BA, Alvania RS & Yue DT (2001). Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels. Nature 411, 484–489.[CrossRef][Medline]
Demo SD & Yellen G (1991). The inactivation gate of the Shaker potassium channel behaves like an open-channel blocker. Neuron 7, 743–753.[CrossRef][Medline]
Dolmetsch RE, Pajvani U, Fife K, Spotts JM & Greenberg ME (2001). Signaling to the nucleus by an 1-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294, 333–339.
Dubel SJ, Starr TV, Hell J, Ahlijanian MK, Enyeart JJ, Catterall WA & Snutch TP (1992). Molecular cloning of the alpha-1 subunit of an omega-conotoxin-sensitive calcium channel. Proc Natl Acad Sci U S A 89, 5058–5062.
Eaholtz G, Scheuer T & Catterall WA (1994). Restoration of inactivation and block of open sodium channels by an inactivation gate peptide. Neuron 12, 1041–1048.[CrossRef][Medline]
Feng ZP, Arnot MI, Doering CJ & Zamponi GW (2001). Calcium channel beta subunits differentially regulate the inhibition of N-type channels by individual Gbeta isoforms. J Biol Chem 276, 45051–45058.
Findlay I (2002a). Beta-adrenergic and muscarinic agonists modulate inactivation of 1-type Ca2+ channel currents in guinea-pig ventricular myocytes. J Physiol 545, 375–388.
Findlay I (2002b). Beta-adrenergic stimulation modulates Ca2+- and voltage-dependent inactivation of 1-type Ca2+ channel currents in guinea-pig ventricular myocytes. J Physiol 541, 741–751.
Findlay I (2002c). Voltage-dependent inactivation of 1-type Ca2+ currents in guinea-pig ventricular myocytes. J Physiol 545, 389–397.
Forsythe ID, Tsujimoto T, Barnes-Davies M, Cuttle MF & Takahashi T (1998). Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse. Neuron 20, 797–807.[CrossRef][Medline]
Fox AP, Nowycky MC & Tsien RW (1987). Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones. J Physiol 394, 149–172.
Geib S, Sandoz G, Cornet V, Mabrouk K, Fund-Saunier O, Bichet D, Villaz M, Hoshi T, Sabatier JM & De Waard M (2002). The interaction between the I–II loop and the III–IV loop of Cav2.1 contributes to voltage-dependent inactivation in a beta -dependent manner. J Biol Chem 277, 10003–10013.
Heinemann SH, Rettig J, Graack HR & Pongs O (1996). Functional characterization of Kv channel b-subunits for rat brain. J Physiol 493, 623–633.
Hering S, Aczel S, Grabner M, Doring F, Berjukow S, Mitterdorfer J, Sinnegger MJ, Striessnig J, Degtiar VE, Wang Z & Glossmann H (1996). Transfer of high sensitivity for benzothiazepines from 1-type to class A (BI) calcium channels. J Biol Chem 271, 24471–24475.
Hering S, Berjukow S, Aczel S & Timin EN (1998). Ca2+ channel block and inactivation: common molecular determinants. Trends Pharmacol Sci 19, 439–443.[CrossRef][Medline]
Herlitze S, Hockerman GH, Scheuer T & Catterall WA (1997). Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel alpha1A subunit. Proc Natl Acad Sci USA 94, 1512–1516.
Hoshi T, Zagotta WN & Aldrich RW (1990). Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250, 533–553.
Hoshi T, Zagotta WN & Aldrich RW (1991). Two types of inactivation in Shaker potassium channels: effects of alterations in the carboxyl terminal. Neuron 7, 547–556.[CrossRef][Medline]
Hurley JH, Cahill AL, Currie KP & Fox AP (2000). The role of dynamic palmitoylation in Ca2+ channel inactivation. Proc Natl Acad Sci USA 97, 9293–9298.
Isom LL, De Jongh KS & Catterall WA (1994). Auxiliary subunits of voltage-gated ion channels. Neuron 12, 1183–1194.[CrossRef][Medline]
Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP & Nargeot J (2000). Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology 39, 1–10.[CrossRef][Medline]
Kaneko S, Cooper CB, Nishioka N, Yamasaki H, Suzuki A, Jarvis SE, Akaike A, Satoh M & Zamponi GW (2002). Identification and characterization of novel human Ca(V)2.2 (alpha 1B) calcium channel variants lacking the synaptic protein interaction site. J Neurosci 22, 82–92.
Kellenberger S, West JW, Catterall WA & Scheuer T (1997). Molecular analysis of potential hinge residues in the inactivation gate of brain type IIA Na+ channels. J General Physiol 109, 607–617.
Klockner U & Isenberg G (1985). Calcium currents of cesium loaded isolated smooth muscle cells (urinary bladder of the guinea pig). Pflugers Arch 405, 340–348.[CrossRef][Medline]
Klugbauer N, Lacinova L, Marais E, Hobom M & Hofmann F (1999). Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci 19, 684–691.
Koschak A, Hoda JC, Reimer D, Walter D, Heinzle T, Grabner M & Striessnig J (2003). Cav1.41 subunits form slowly inactivating BayK8644-sensitive 1-type Ca2+ channels (LTCCs). Biophys Abstract 1602–plat.
Kraus RL, Sinnegger MJ, Glossmann H, Hering S & Striessnig J (1998). Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics. J Biol Chem 273, 5586–5590.
Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S, Carrera P & Striessnig J (2000). Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics. J Biol Chem 275, 9239–9243.
Kurjak M, Sennefelder A, Aigner M, Schusdziarra V & Allescher HD (2002). Characterizing voltage-dependent Ca(2+) channels coupled to VIP release and NO synthesis in enteric synaptosomes. Am J Physiol Gastrointest Liver Physiol 283, G1027–1034.
Lacerda AE, Kim HS, Ruth P, Perez-Reyes E, Flockerzi V, Hofmann F, Birnbaumer L & Brown AM (1991). Normalization of current kinetics by interaction between the 1 and ß subunits of the skeletal muscle dihydropyridine-sensitive Ca2+ channel. Nature 352, 527–530.[CrossRef][Medline]
Lee A, Wong ST, Gallagher D, Li B, Storm DR, Scheuer T & Catterall WA (1999a). Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 399, 155–159.[CrossRef][Medline]
Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klöckner U, Schneider T & Perez-Reyes E (1999b). Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci 19, 1912–1921.
Liang H, DeMaria CD, Erickson MG, Mori M, Alseikhan BA & Yue DT (2003). Unified mechanisms of Ca2+ regulation across the Ca2+ channel family. Neuron 39, 951–960.[CrossRef][Medline]
Lilienbaum A & Israel A (2003). From calcium to NF-kappa B signaling pathways in neurons. Mol Cell Biol 23, 2680–2698.
Llinas R, Sugimori M, Lin JW & Cherksey B (1989). Blocking and isolation of a calcium channel from neurons in mammals and cephalopods utilizing a toxin fraction (FTX) from funnel-web spider poison. Proc Natl Acad Sci USA 86, 1689–1693.
Lopez GA, Jan YN & Jan LY (1994). Evidence that the S6 segments of the Shaker voltage-gated potassium channel comprises part of the pore. Nature 367, 179–182.[CrossRef][Medline]
Lopez-Barneo J, Hoshi T, Heinemann SH & Aldrich RW (1993). Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels. Receptors Channels 1, 61–71.[Medline]
Marksteiner R, Schurr P, Berjukow S, Margreiter E, Perez-Reyes E & Hering S (2001). Inactivation determinants in segment IIIS6 of Ca(v)3.1. J Physiol 537, 27–34.
McCormick KA, Srinivasan J, White K, Scheuer T & Catterall WA (1999). The extracellular domain of the beta1 subunit is both necessary and sufficient for ß1-like modulation of sodium channel gating. J Biol Chem 274, 32638–32646.
McPhee JC, Ragsdale DS, Scheuer T & Catterall WA (1994). A mutation in segment IVS6 disrupts fast inactivation of sodium channels. Proc Natl Acad Sci USA 91, 12346–12350.
McRory JE, Hamid J, Doering CJ, Garcia E, Parker R, Hamming K et al. (2004). The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution. J Neurosci (in press).
McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Baillie DL, Stea A & Snutch TP (2001). Molecular and functional characterization of a family of rat brain T-type calcium channels. J Biol Chem 276, 3999–4011.
Mikami A, Imoto K, Tanabe T, Niidome T, Mori Y, Takeshima H, Narumiya S & Numa S (1989). Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature 340, 230–233.[CrossRef][Medline]
Niidome T, Kim MS, Friedrich T & Mori Y (1992). Molecular cloning and characterization of a novel calcium channel from rabbit brain. FEBS Lett 308, 7–13.[CrossRef][Medline]
Nowycky MC, Fox AP & Tsien RW (1985). Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316, 440–443.[CrossRef][Medline]
Olcese R, Qin N, Schneider T, Neely A, Wei X, Stefani E & Birnbaumer L (1994). The amino terminus of a calcium channel b subunit sets rates of channel inactivation independently of the subunit's effect on activation. Neuron 13, 1433–1438.[CrossRef][Medline]
Orrenius S, McConkey DJ, Bellomo G & Nicotera P (1989). Role of Ca2+ in toxic cell killing. Trends Pharmacol Sci 10, 281–285.[CrossRef][Medline]
Orrenius S & Nicotera P (1994). The calcium ion and cell death. J Neural Transmsupplement 43, 1–11.[Medline]
Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M & Lee JH (1998). Molecular characterization of a neuronal low voltage-activated T-type calcium channel. Nature 391, 896–900.[CrossRef][Medline]
Peterson BZ, Demaria CD, Adelman JP & Yue DT (1999). Calmodulin is the Ca2+ sensor for Ca2+-dependent inactivation of 1-type calcium channels. Neuron 22, 549–558.[CrossRef][Medline]
Pragnell M, De Waard M, Mori Y, Tanabe T, Snutch TP & Campbell KP (1994). Calcium channel beta-subunit binds to a conserved motif in the I–II cytoplasmic linker of the alpha 1-subunit. Nature 368, 67–70.[CrossRef][Medline]
Qin N, Olcese R, Zhou J, Cabello OA, Birnbaumer L & Stefani E (1996). Identification of a second region of the b-subunit involved in regulation of calcium channel inactivation. Am J Physiol 271, C1539–C1545.[Medline]
Qin N, Platano D, Olcese R, Costantin JL, Stefani E & Birnbaumer L (1998). Unique regulatory properties of the type 2a Ca2+ channel ß subunit caused by palmitoylation. Proc Natl Acad Sci USA 95, 4690–4695.
Restituito S, Cens T, Barrere C, Geib S, Galas S, De Waard M & Charnet P (2000). The ß2a subunit is a molecular groom for the Ca2+ channel inactivation gate. J Neurosci 20, 9046–9052.
Richmond JE, Featherstone DE, Hartmann HA & Ruben PC (1998). Slow inactivation in human cardiac sodium channels. Biophys J 74, 2945–2952.
Robertson B (1997). The real life of voltage-gated K+ channels: more than model behavior. Trends Pharmacol Sci 18, 474–483.[Medline]
Roullet JB, Spaetgens RL, Burlingame T, Feng ZP & Zamponi GW (1999). Modulation of neuronal voltage-gated calcium channels by farnesol. J Biol Chem 274, 25439–25446.
Rousset M, Cens T, Restituito S, Barrere C, Black JL III, McEnery MW & Charnet P (2001). Functional roles of gamma2, gamma3 and gamma4, three new Ca2+ channel subunits, in P/Q-type Ca2+ channel expressed in Xenopus oocytes. J Physiol 532, 583–593.
Sandoz G, Bichet D, Cornet V, Mori Y, Felix R & De Waard M (2001). Distinct properties and differential beta subunit regulation of two C-terminal isoforms of the P/Q-type Ca(2+)-channel alpha(1A) subunit. Eur J Neurosci 14, 987–997.[CrossRef][Medline]
Shi C & Soldatov NM (2002). Molecular determinants of voltage-dependent slow inactivation of the Ca2+ channel. J Biol Chem 277, 6813–6821.
Sokolov S, Weiss RG, Timin EN & Hering S (2000). Modulation of slow inactivation in class A Ca2+ channels by ß-subunits. J Physiol 527, 445–454.
Soldatov NM, Oz M, O'Brien KA, Abernethy DR & Morad M (1998). Molecular determinants of 1-type Ca2+ channel inactivation. Segment exchange analysis of the carboxyl-terminal cytoplasmic motif encoded by exons 40–42 of the human 1C subunit gene. J Biol Chem 273, 957–963.
Soong TW, Demaria CD, Alvania RS, Zweifel LS, Liang MC, Mittman S, Agnew WS & Yue DT (2002). Systematic identification of splice variants in human P/Q-type channel alpha1(2.1) subunits: implications for current density and Ca2+-dependent inactivation. J Neurosci 22, 10142–10152.
Spaetgens RL & Zamponi GW (1999). Multiple structural domains contribute to voltage-dependent inactivation of rat brain alpha(1E) calcium channels. J Biol Chem 274, 22428–22436.
Staes M, Talavera K, Klugbauer N, Prenen J, Lacinova L, Droogmans G, Hofmann F & Nilius B (2001). The amino side of the C-terminus determines fast inactivation of the T-type calcium channel alpha1G. J Physiol 530, 35–45.
Stea A, Soong TW & Snutch TP (1995). Voltage-gated calcium channels. In Handbook of Receptors and Channels: Ligand- and Voltage-Gated Ion Channels ed. North, RA, pp. 113–152. CRC, Boca Raton, FL, USA.
Stephens GJ, Page KM, Bogdanov Y & Dolphin AC (2000). The a1B Ca2+ channel amino terminus contributes determinants for b subunit-mediated voltage-dependent inactivation properties. J Physiol 525, 377–390.
Stotz SC, Hamid J, Spaetgens RL, Jarvis SE & Zamponi GW (2000). Fast inactivation of voltage-dependent calcium channels. A hinged-lid mechanism?J Biol Chem 275, 24575–24582.
Stotz SC & Zamponi GW (2001). Identification of inactivation determinants in the domain IIS6 region of high voltage-activated calcium channels. J Biol Chem 276, 33001–33010.
Stotz SC & Zamponi GW (2002). The role of the calcium channel carboxy-terminus in voltage-dependent inactivation. Soc Neurosci Abstract 251 5, 17.
Sun J & Triggle DJ (1995). Calcium channel antagonists: cardiovascular selectivity of action. J Pharmacol Exp Ther 274, 419–426.
Tanabe T, Mikami A, Numa S & Beam KG (1990). Cardiac-type excitation-contraction coupling in dysgenic skeletal muscle injected with cardiac dihydropyridine receptor cDNA. Nature 344, 451–453.[CrossRef][Medline]
Tanabe T, Takeshima H, Mikami A, Flockerzi V, Takahashi H, Kangawa K, Kojima M, Matsuo H, Hirose T & Numa S (1987). Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 32, 313–318.
Varadi G, Lory P, Schultz D, Varadi M & Schwartz A (1991). Acceleration of activation and inactivation by the ß subunit of the skeletal muscle calcium channel. Nature 352, 159–162.[CrossRef][Medline]
Vassilev PM, Scheuer T & Catterall WA (1988). Identification of an intracellular peptide segment involved in sodium channel inactivation. Science 241, 1658–1661.
Vassilev P, Scheuer T & Catterall WA (1989). Inhibition of inactivation of sodium channels by a site-directed antibody. Proc Natl Acad Sci USA 86, 8147–8181.
Vilin YY, Makita N, George Al JR & Ruben PC (1999). Structural determinants of slow inactivation in human cardiac and skeletal muscle sodium channels. Biophys J 77, 1384–1393.
Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, Groschner K, Glossmann H, Kraus RL, Grabner M & Striessnig J (2002). Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 277, 6960–6966.
West JW, Patton DE, Scheuer T, Wang Y, Goldin AL & Catterall WA (1992). A cluster of hydrophobic amino acid residues required for fast sodium channel inactivation. Proc Natl Acad Sci USA 89, 10910–10914.
Wheeler DB, Randall A & Tsien RW (1994). Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264, 107–111.
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB & Harpold MM (1992). Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron 8, 71–84.[CrossRef][Medline]
Zagotta WN, Hoshi T & Aldrich RW (1990). Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB. Science 250, 506–507.
Zamponi GW, Bourinet E & Snutch TP (1996). Nickel block of a family of neuronal calcium channels: subtype- and subunit-dependent action at multiple sites. J Membr Biol 151, 77–90.[CrossRef][Medline]
Zamponi GW & Snutch TP (1996). Evidence for a specific site for modulation of calcium channel activation by external calcium ions. Pflugers Arch 431, 470–472.[Medline]
Zhang JF, Ellinor PT, Aldrich RW & Tsien RW (1994). Molecular determinants of voltage-dependent inactivation in calcium channels. Nature 372, 97–100.[CrossRef][Medline]
Zhang JF, Randall AD, Ellinor PT, Horne WA, Sather WA, Tanabe T, Schwarz TL & Tsien RW (1993). Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons. Neuropharmacology 32, 1075–1088.[CrossRef][Medline]
Zuhlke RD, Pitt GS, Deisseroth K, Tsien RW & Reuter H (1999). Calmodulin supports both inactivation and facilitation of 1-type calcium channels. Nature 399, 159–162.[CrossRef][Medline]
|
Acknowledgements |
|---|
S. C. Stotz and S. E. Jarvis contributed equally to this work.
This article has been cited by other articles:
|
|
 |
|
  Y. Zhang, Y.-h. Chen, S. D. Bangaru, L. He, K. Abele, S. Tanabe, T. Kozasa, and J. Yang Origin of the Voltage Dependence of G-Protein Regulation of P/Q-type Ca2+ Channels J. Neurosci., December 24, 2008; 28(52): 14176 - 14188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gonzalez-Gutierrez, E. Miranda-Laferte, D. Naranjo, P. Hidalgo, and A. Neely Mutations of Nonconserved Residues within the Calcium Channel {alpha}1-interaction Domain Inhibit {beta}-Subunit Potentiation J. Gen. Physiol., September 1, 2008; 132(3): 383 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Z. Lao, E. Kobrinsky, J. B. Harry, A. Ravindran, and N. M. Soldatov New Determinant for the CaV{beta}2 Subunit Modulation of the CaV1.2 Calcium Channel J. Biol. Chem., June 6, 2008; 283(23): 15577 - 15588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Vitko, I. Bidaud, J. M. Arias, A. Mezghrani, P. Lory, and E. Perez-Reyes The I-II Loop Controls Plasma Membrane Expression and Gating of Cav3.2 T-Type Ca2+ Channels: A Paradigm for Childhood Absence Epilepsy Mutations J. Neurosci., January 10, 2007; 27(2): 322 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Raybaud, Y. Dodier, P. Bissonnette, M. Simoes, D. G. Bichet, R. Sauve, and L. Parent The Role of the GX9GX3G Motif in the Gating of High Voltage-activated Ca2+ Channels J. Biol. Chem., December 22, 2006; 281(51): 39424 - 39436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Khosravani and G. W. Zamponi Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev, July 1, 2006; 86(3): 941 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Hoda, F. Zaghetto, A. Koschak, and J. Striessnig Congenital Stationary Night Blindness Type 2 Mutations S229P, G369D, L1068P, and W1440X Alter Channel Gating or Functional Expression of Cav1.4 L-type Ca2+ Channels J. Neurosci., January 5, 2005; 25(1): 252 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
