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Voltage-Dependent Inactivation of Voltage Gated Calcium Channels

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The fast inactivation of voltage-dependent calcium channels is an important, intrinsic regulatory mechanism that helps to precisely control the amount of calcium entering excitable cells during membrane depolarizations. The association with ancillary β-subunits regulates the inactivation characteristics of the α1 subunit through functional (and possibly direct) interactions between the β subunit and N-terminal region of the a1 subunit. Moreover, palmitoylation of the β subunit N-terminus has emerged as a key regulatory mechanism of inactivation kinetics. Recent advances have provided novel insights into the calcium channel a1 subunit structural determinants of inactivation, revealing key roles for the S6 transmembrane regions, as well as intracellular linker such as the domain I-II and II-II linkers, and the C-terminus region. Current models include a mechanism of inactivation in which cytoplasmic loops may act as a gating particle that docks to the cytoplasmic end of the S6 transmembrane segments to block calcium flux. Here, we review the calcium channel structural determinants of fast, voltage-dependent inactivation of these channels.


The inactivation of ion channels is a fundamental biological process that prevents the breakdown of ionic gradients, and determines action potential duration and the refractory period of excitable tissues. It can be defined as a transition into a nonconducting state following channel opening. At the whole cell level, inactivation is seen as a decay of current levels during the course of the membrane depolarization, and a decreased availability for channel opening at more depolarized membrane potentials. In calcium channels, inactivation serves several unique purposes. It is a key mechanism by which cells are able to tightly control intracellular calcium levels. Such regulation of the temporal precision of calcium signals is of particular significance in view of the pivotal role of calcium as a cytoplasmic messenger in processes such as gene transcription or synaptic transmission.1-4 For example, in nerve terminals, the inactivation of calcium currents may contribute to the short term depression of neurosecretion.5-6 Conversely, calcium channel inactivation also helps to prevent the accumulation of excessive, cytotoxic levels of intracellular calcium.7-9 Calcium channel inactivation also regulates cellular excitability. For example, in T-type Ca2+ channels, voltage-dependent inactivation is of added significance as it is a key determinant of pattern behaviour and pacemaker activity in neurons. Calcium influx through T-type calcium channels during prolonged high frequency stimulation is critically dependent on the inactivation characteristics of the channels.10-11 Changes in the inactivation properties of P/Q-type calcium channels are induced by naturally occurring mutations in the Cav2.1 a1 subunit (see fig. 1),12-14 raising the possibility that inappropriate inactivation of certain types of calcium channels may result in CNS malfunction. Finally, the inactivated calcium channel conformation can result in dramatic increases in the affinity of the channel for a number of pharmacological agents, including many clinically used calcium channel therapeutics (see also Chapter 18).15-17

Figure 1. Schematic representation of the calcium channel α1 subunit depicting the loci of naturally occurring point mutations,, and CAG repeats that have been shown to affect inactivation properties of various types of voltage-gated calcium channels.

Figure 1

Schematic representation of the calcium channel α1 subunit depicting the loci of naturally occurring point mutations,, and CAG repeats that have been shown to affect inactivation properties of various types of voltage-gated calcium channels.

In principle, voltage gated calcium channels are capable of undergoing multiple types of inactivation processes. Calcium dependent inactivation can be observed predominantly with L-type channels,18-19 although more recent evidence suggests that other types of high voltage-activated channels also undergo changes in inactivation kinetics in response to calcium entry.20 This is reviewed in detail in Chapter 11, and will not be discussed further here. Slow inactivation occurs only after very prolonged membrane depolarizations (~1 minute) and remains poorly understood. 21-22 Here, we shall discuss aspects of fast voltage dependent inactivation.

What Have We Learnt from Other Types of Voltage Gated Cation Channels?

It has been known for more than two decades that the exposure of sodium channels to cytoplasmically applied proteolytic enzymes results in a loss of inactivation.23 Based on these initial findings, Armstrong et al23 coined the “ball and chain mechanism of inactivation”, in which inactivation was proposed to occur via occlusion of the channel pore by a cytoplasmic gating particle that was assumed to be physically tethered to the channel. Additional evidence for such a mechanism came from experiments that involved an anti-peptide antibody directed towards the short intracellular segment connecting sodium channel domains III and IV. Application of these antibodies to excised inside out patches resulted in the inhibition of inactivation. 24-25 The first conclusive molecular biological confirmation of the ball and chain mechanism was derived from experiments on the Shaker B potassium channels.26-27 The amino terminus of the Shaker B α subunit contains a 22 amino acid cluster comprised of hydrophobic and polar domains. Tryptic cleavage of this cluster, or deletion of the region by molecular biological means results in a dramatic slowing of inactivation kinetics.26 But more strikingly, the application of synthetic peptides corresponding to the deleted regions restores the fast inactivation of mutated channels lacking the amino terminal,27 with characteristics resembling those of typical open channel block with regard to concentration dependence of the open times.28 Interestingly, the Shaker B amino terminal “ball” peptide is capable of inducing inactivation-like pore block of other types of potassium channels that do not inactivate under normal conditions.29 Taken together, these results suggest a simple structural basis for the ldquo;ball and chain” inactivation model, with the N-terminus acting as the gating ball, and the remainder of the N-terminus serving as a ~50 amino acid long “chain” like tether for the ball.

Since voltage gated potassium channels are tetramers, each channel contains as many as four inactivation particles, but it is believed that only one may block the pore at a given time.30 Less information is available on the exact binding site for the ball region, although functional studies indicate that the cytoplasmic linker between the fourth and fifth transmembrane segment of the α subunit may be involved.31 However, the inactivation mechanism in potassium channels is complicated by the fact that certain types of potassium channel β subunits (e.g., Kv β1.1 and Kv β3) contain regions that structurally and functionally resemble gating balls. Indeed, coexpression of these ancillary subunits with certain types of noninactivating Kv α subunits (i.e., Kv1.1, Kv1.2 or Kv1.5, but not Kv 1.6) produces rapidly inactivating currents.32-33

In the sodium channel field, it is more difficult to provide unequivocal evidence for the existence of a gating particle structure. It was shown that expression of the α subunit as two separate proteins (i.e., one corresponding to the first three domains, and one corresponding to the fourth domain) resulted in functional channels which inactivated, however, only very slowly.34 Together with the antibody experiments mentioned earlier, this suggested a critical involvement of the domain III-IV linker region of the sodium channel α subunit in sodium channel inactivation. Indeed, site-directed mutagenesis of three adjacent hydrophobic amino acid residues in this region (I1488, F1489, M1490) to glutamine abolished fast inactivation,35 which could be partially restored by cytoplasmic application of a pentapeptide containing the IFM motif.36 This resembles in many ways the findings obtained with potassium channels, with the exception that a cytoplasmic loop rather than the N-terminal region is involved. Thus, the domain III-IV linker might act as a “hinged lid” that can dock to the pore and prevent current flow. There is evidence suggesting that the “hinge” might be formed by glycine and proline residues flanking the III-IV linker,37 whereas the docking site for the “lid” structure may include the intracellular regions between the fourth and fifth transmembrane segments in domains III38 and IV,39 and the sixth transmembrane segment in domain IV.40 The inactivation properties of the sodium channel α subunit are also modified through the noncovalent association of the auxiliary β1 subunit which results in acceleration of inactivation kinetics, a speeding of the recovery from inactivation, and a negative shift in the voltage dependence of inactivation in both brain and skeletal muscle sodium channels.41 Although the exact mechanism by which this occurs is not understood, it has been suggested that part of the effects of the β subunits may be due to a switch in gating modes of the channel.42

Both sodium and potassium channels undergo a second, often slower inactivation process (termed slow inactivation in sodium channels and C-type inactivation in potassium channels) which is thought to occur via global conformational changes in channel structure in response to depolarization. For both sodium and potassium channels, this process appears to depend on regions flanking the pore43-47 and may involve pore constriction.

In summary, in sodium and potassium channels, there is a common fast inactivation mechanism involving physical occlusion of the pore by an intracellular channel structure. Moreover, both sodium and potassium channel inactivation is regulated by ancillary subunits. As we will outline below, these two general principles may also apply to voltage gated calcium channels, although the molecular details are somewhat different.

α1 Subunit Structural Inactivation Determinants in High Voltage Activated Channels

Based on work carried out in transient expression systems, the ability of voltage dependent calcium channels to inactivate appears to be an intrinsic feature of the α1 subunit, since expression of this subunit alone produces inactivating currents. Unlike in sodium and potassium channels, there have been no reports that show a loss of inactivation following intracellular application of proteolytic enzymes such as pronase or trypsin, suggesting the possibility that inactivation in calcium channels could perhaps be fundamentally different from that of other voltage-gated channels. This idea was supported by work of Zhang et al48 who created a series of chimeric calcium channels that combined the structural features of rat Cav2.1 and marine ray Cav2.3 calcium channel α1 subunits (Zhang et al 1994). Based on functional studies carried out with these chimeras in Xenopus oocytes, the authors concluded that the differences in inactivation kinetics observed between the wild type channels could be attributed to the domain I S6 region. The apparent lack of involvement of a cytoplasmic loop led the authors to suggest the possibility that calcium channel inactivation might occur via a pore collapse mediated by the S6 segment, similar to what has been proposed for slow inactivation of potassium channels.49-51 A similar possibility was raised by Spaetgens and Zamponi52 based on chimera studies with hybrid Cav1.2 - Cav2.3 channels, which showed that all four transmembrane domains contributed to the rate and/or voltage-dependence of inactivation, with domains II and III mediating the largest effects. To test the hypothesis that the S6 segments might control inactivation in Cav2.3 channels, Stotz et al53 exchanged the domain IIS6 and IIIS6 segments between Cav1.2 and Cav2.3 channels individually, or in combination. Consistent with the hypothesis, transfer of the domain IIS6 or the domain IIIS6 regions from the Cav2.3 channel onto the normally slowly inactivating Cav1.2 channel could confer the rapid inactivation kinetics seen with the rapidly inactivating wild type Cav2.3 channel. However, the converse experiment (i.e., slowing of inactivation of Cav2.3 with Cav1.2 sequence) did not alter inactivation rates, even when both the domain IIS6 and IIIS6 region were substituted concomitantly, suggesting that there had to be other structures that could independently maintain rapid inactivation kinetics. Indeed, only when the IIS6, IIIS6 and I-II linker regions were substituted together could Cav2.3 channel inactivation be slowed. Conversely, replacement of the Cav1.2 I-II linker with that of Cav2.3 conferred faster inactivation kinetics, suggesting that the domain I-II linker acts as a key structure in the inactivation process.53 It is peculiar, however, that substitution of only the first two thirds of the Cav1.2 linker with Cav2.3 sequence mediates the opposite effect, namely a complete disruption of inactivation, yielding ultraslow inactivation kinetics (see also fig.2).54-55 This may indicate that the structural integrity of this region may be critical for appropriate function. It is interesting to note that the domain IS6 chimera described by Zhang et al48 involved a short stretch of the domain I-II linker being substituted, a notion that may perhaps serve to reconcile the apparently contradictory results with those of Spaetgens and Zamponi.52 An involvement of the domain I-II linker region in calcium channel inactivation is also supported by a number of other studies on mutant calcium channels,56-57 as well as from data obtained with a naturally occurring splice variant of Cav2.1 in which a single valine residue is inserted in this region which results in virtually complete loss of inactivation.58 Indeed, this splicing event effectively converts Cav2.1 between a P-type and Q-type channel. Finally, Cens et al59 reported that overexpression of peptides corresponding the domain I-II linker of Cav2.1 speeds the inactivation kinetics of transiently expressed Cav2.1 channels, which is consistent with the possibility of the domain I-II linker acting as a gating particle.

Figure 2. Regions of the calcium channel α1 subunits that have been implicated in inactivation (shown in dark gray-blue in online version).

Figure 2

Regions of the calcium channel α1 subunits that have been implicated in inactivation (shown in dark gray-blue in online version). Inset: Current traces obtained from wild type Cav1.2 calcium channels, a Cav1.2 mutant in which residue T823 in IIS6 (more...)

The involvement of the domain IIS6 and IIIS6 regions in calcium channel inactivation is supported by several other studies based on artificial mutants60-61 and, perhaps more interestingly, based on naturally occurring mutations linked to disorders such as familial hemiplegic migraine (see fig. 1).12-14 A systematic investigation of residues involved in inactivation has been carried out for the domain II and IVS6 region of voltage gated calcium channels. Berjukov et al62 reported that substitution of reissue M1811 in the domain IV S6 region of Cav2.1 calcium channels with glutamine results in a 75-fold increase in inactivation rates. Conversely, the authors showed that inactivation kinetics could be slowed by substitution of residue V1818. Stotz and Zamponi54 systematically examined inactivation determinants in the IIS6 region of the Cav1.2 channel. The authors showed that replacement of two out of seven of amino acids in this region that were not conserved between Cav1 .2 and Cav2.3 could mimic the effect of exchanging the entire domain IIS6 segment between these channels. Moreover, a systematic replacement of these residues with a variety of different amino acids revealed that increasing size in position 823 slowed inactivation kinetics, whereas hydrophobicity was a more important determinant in position 829. Indeed, replacing F823 with alanine induced rapid inactivation kinetics resembling those typically only seen with T-type calcium channels, but neither recovery from inactivation, nor the voltage-dependence of inactivation were affected. These results indicate that only the rate of entry into the inactivated conformation, but not its stability was controlled by these residues. Taken together, the data of Berjukov et al,62 Stotz et al,53 Zhang et al,48 and Stotz and Zamponi54 suggest that all four S6 segments of the calcium channel α1 subunit contribute to inactivation.

Besides the domain I-II linker, three other cytoplasmic regions have been implicated in inactivation. Data from Soldatov et al63 and Sandoz et al64 have implicated the C-terminal region in voltage dependent inactivation of calcium channels, whereas Stephens et al65 reported the N-terminal as an important regulator if inactivation. However, in both of these instances, this may be secondarily due to altered β subunit interactions with the pore forming α1 subunit. More recently, Geib et al66 have reported that inactivation of Cav2.1 channels is regulated by an intramolecular interaction between the domain I-II and the domain III-IV linker regions. Site-directed mutagenesis, or intracellular application of peptides designed to disrupt this interaction slows the inactivation kinetics of the channel, provided that the channel complex does not contain a β subunit. In follow up work, the authors67 suggested that the domain III-IV linker region might structurally resemble the Gγ subunit, and that this loop physically interacts with the Gβγ binding site68-69 in the domain I-II linker. The only remaining major intracellular loop, i.e., that connecting domains II and III, does not appear to be a major determinant of inactivation rate, since deletion of most of this region in a naturally occurring splice variant of the N-type channel produces normal current kinetics.70 However, in these splice variants, the half-inactivation voltage is shifted towards more depolarized potentials compared to full length channels. This is consistent with the effects of syntaxin 1A and SNAP25, which bind to this region and induce hyperpolarizing shifts in the voltage dependence of inactivation (see Chapter 8).

Taken together, the inactivation of high-activated calcium channels is a complex process that involves a number of α1 subunit structural determinants (see fig. 2), comprised predominantly of the S6 transmembrane segments. In addition, the domain I-II linker appears to be a key structure involved in this process, but its role in inactivation may be modulated by other cytoplasmic loops.

Members of the family of T-type calcium channels have only recently been cloned, therefore inactivation determinants have not yet been systematically examined for these channels. To date, there is conflicting information about what may be key structural requirements. Staes et al71 reported that the C-terminus region of the Cav3.1 channel is important for inactivation. In contrast, Marksteiner et al72 implicated the domain IIIS6 segment as a major inactivation determinant of these channels. Despite some apparent overlap in the structural determinants of inactivation, it remains at this point difficult to determine as to whether inactivation in low and high voltage activated calcium channel occurs via a functionally conserved mechanism. The fact that T-type calcium channel do not associate with calcium channel β subunits,73 and the low degree of sequence identity in the I-II linker regions of high versus low voltage activated channels may perhaps suggest that T-type channels could be unique among voltage-dependent calcium channels in terms of their inactivation mechanism. Future chimeric approaches will certainly shed light on this issue.

Role of Ancillary Subunits in Calcium Channel Inactivation

Although α1 subunits can inactivate when expressed alone, the ancillary β subunits are major modulators of the inactivation process.74-75 For many types of high voltage activated channels, coexpression with β;3 or β1b tends to increase the rate of inactivation, whereas β4, and particularly, the rat isoform of β2a slow inactivation kinetics.76-77 Using a chimeric approach, Olcese et al and coworkers78 showed that the N-terminal region of the rat β2a subunit was responsible for this subunit's dramatic slowing effect on inactivation. Deletion of the first 18 amino acids of the N-terminus removes the slowing effect.79 What is unique about the N-terminus of the rat β2a subunit is the presence of two cysteine residues that form sites for palmitoylation. Replacement of the cysteines with serines,77,80 or the block of palimitoylation via tunicamycin81 blocks the kinetic slowing effect of the rat β2a subunit. Replacement of the N-terminus with a transmembrane region such as the CD8 receptor can restore the ability of the β2a subunit to slow calcium channel inactivation.82 This is consistent with the role of palmitoylation, and suggests that membrane association of the N-terminus region is involved in regulating inactivation kinetics. Besides the N -terminus, additional interactions between the second variable region of the β2a subunit79 and the N-terminus of the calcium channel α1 subunit65 appear to contribute to the regulation of inactivation. Finally, for β4 subunits, it has been shown that the highly variable C-terminal region can interact with the Cav2.1 carboxy terminus to regulate inactivation kinetics.

The effects of α2-δ and γ subunit on inactivation have been less completely addressed, but the evidence to date suggests that both the α283 subunits and the δ84 subunits can regulate inactivation. Coexpression of Cav1.2 and Cav2.3 calcium channels with different α2-δ subunits shifts voltage dependence of inactivation, and alters inactivation kinetics.83 The γ subunit appears to be able to regulate inactivation kinetics by enhancing a slowly inactivating current component seen with Cav2.1 calcium channels.84 The mechanisms that underlie these effects have, however, not yet been fully explored.

Overall, of the ancillary calcium channel subunits, the βsubunit has by far the most profound effects on calcium channel inactivation. The picture emerges that these βsubunits interact in multiple ways with the calcium channel α1 subunit to regulate inactivation. Along these lines, the effect of mutagenesis of residues in the α1 subunit N-terminus65 or C-terminus63-64 may arise secondarily from a loss of β subunit regulation rather than indicating a direct involvement of these regions in the core inactivation process.

Possible Molecular Mechanism of Calcium Channel Inactivation

From the collective body of structure function studies, the picture emerges that the key structural determinants of inactivation are the domain I-II linker and the S6 segments in the four major transmembrane domains (see also Ref. 85). The involvement of the a cytoplasmic domain and of transmembrane helices lining the inner vestibule of the pore is consistent with a pore blocking mechanism of inactivation similar to that seen with sodium and potassium channels. In such a hinged-lid mechanism, the domain I-II linker may act as the inactivation lid that may dock to the S6 segments to prevent current flow through the channels.53-54 The intramolecular interaction with the domain III-IV loop,66 or the association of the I-II linker with a membrane associated calcium channel β subunit (such as rat β2a) may restrict the mobility of this putative inactivation gate, thus modulating the inactivation kinetics. The additional interactions between regions on the β subunit and the N-terminus65 and C-terminus64 regions of the α1 subunit may indirectly affect I-II linker function. Finally, a role of the I-II linker as an inactivation particle is consistent with the effects of overexpressed I-II linker peptides on inactivation rates.59

The observation that mutations in the domain IIS6 segment of Cav1.2 channels (i.e., F823, T829) modify the rate of inactivation, but not the recovery from inactivation suggests that only the rate of entry into the inactivated state is affected and once the channel is inactivated, the stability of the inactivated conformation does not involve these residues. Accordingly, Stotz and Zamponi54 proposed that in response to membrane depolarization, residues 823 and 829 may be involved in a conformational change in the II S6 segment that culminates in the availability of a docking site for the inactivation gate. Once docking has occurred, the lifetime of the docked state would then no longer be influenced by these two residues (see fig. 3). Based on work by several other groups,62,48 the authors proposed that this principle would likely apply to all four S6 segments, suggesting a concerted action of the four pore lining transmembrane segments in the inactivation process. It is worth noting that at their cytoplasmic ends, these four transmembrane helices carry several highly conserved residues, which when mutated, result in slowing of inactivation.22 Mutations in additional S6 segments produce incremental, additive effects. This raises the strong possibility that the S6 segments per se may form the docking site for the I-II linker region, but whether all four S6 segments act cooperatively to form a single site, or whether the inactivation gate has a choice of 4 different docking sites remains to be determined.

Figure 3. A.

Figure 3

A. Possible model for calcium channel inactivation. Following membrane deploarization, the S6 segments undergo a conformational channel that unmasks a docking site for the inactivation gate formed by the domain I-II linker. B. Reconciliation of the model (more...)

Taken together, the model proposed by Stotz and Zamponi54 can account for the bulk of the structure function data reported in the literature to date. However, it is important to remember that this is merely a model whose validity is difficult to confirm without detailed structural information.

Concluding Remarks

Many structural determinants of high voltage activated calcium channel inactivation have been identified over the past 8 years. To date, the model that is most consistent with the currently available literature is that of a hinged-lid mechanism of inactivation, in which the mobility of the lid is regulated by other intracellular loops and ancillary subunits. The basic mechanism of calcium channel inactivation therefore appears to be a common feature to voltage gated sodium and potassium channels, which reaffirms the fundamental importance of the inactivation process in the physiology of excitable cells.


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