Cooperative Activation of the T-type CaV3.2 Channel

Demers-Giroux, Pierre-Olivier; Bourdin, Benoîte; Sauvé, Rémy; Parent, Lucie

doi:10.1074/jbc.m113.500975

Cited by 10 publications

(12 citation statements)

References 65 publications

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“…Each voltage-sensing domain is adjacent to the neighboring pore domain (e.g. see [35]), with the S4 of one domain forming hydrophobic interactions with the S5 of the adjacent domain (Fig. 1d).…”

Section: Architecture Of the Cav11 And Cav12 Channelmentioning

confidence: 99%

Calcium channel gating

Hering

Zangerl-Plessl

Beyl

et al. 2018

Pflugers Arch - Eur J Physiol

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Tuned calcium entry through voltage-gated calcium channels is a key requirement for many cellular functions. This is ensured by channel gates which open during membrane depolarizations and seal the pore at rest. The gating process is determined by distinct sub-processes: movement of voltage-sensing domains (charged S4 segments) as well as opening and closure of S6 gates. Neutralization of S4 charges revealed that pore opening of CaV1.2 is triggered by a “gate releasing” movement of all four S4 segments with activation of IS4 (and IIIS4) being a rate-limiting stage. Segment IS4 additionally plays a crucial role in channel inactivation. Remarkably, S4 segments carrying only a single charged residue efficiently participate in gating. However, the complete set of S4 charges is required for stabilization of the open state. Voltage clamp fluorometry, the cryo-EM structure of a mammalian calcium channel, biophysical and pharmacological studies, and mathematical simulations have all contributed to a novel interpretation of the role of voltage sensors in channel opening, closure, and inactivation. We illustrate the role of the different methodologies in gating studies and discuss the key molecular events leading CaV channels to open and to close.Electronic supplementary materialThe online version of this article (10.1007/s00424-018-2163-7) contains supplementary material, which is available to authorized users.

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Section: Architecture Of the Cav11 And Cav12 Channelmentioning

confidence: 99%

Calcium channel gating

Hering

Zangerl-Plessl

Beyl

et al. 2018

Pflugers Arch - Eur J Physiol

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“…Indeed, LVA Ca 2+ channels contain a large conserved external loop (residues 211-336 for Ca V 3.1 channel) between the S5 transmembrane segment and the P pore loop of domain I [17], which is different in length with respect to the other three external loops and supports the pseudo-symmetry in LVA channels. At least two different reports have explored the role of pore-lining S6 segment residues in Ca V 1.2 and Ca V 3.2 channels [20,23]. The distal S6 transmembrane segment seems to be especially important for the voltage sensitivity of activation and the activation and deactivation kinetics of Ca V 1.2 channel; substitution of S6 pore region residues of domain I (IS6 L(434), domain II (IIS6; I781) or domain III (IIIS6; G1193) transformed the Ca V 1.2 from a HVA into a LVA Ca 2+ channel, probably for altering backbone-backbone helix interactions in a hydrophobic environment (reviewed in [20]).…”

Section: Discussionmentioning

confidence: 99%

“…In the case of Ca V 3.2 channels, the S4-S5 helix linker of domain II (IIS4-S5) interacts with the distal S6 pore region of domains II (IIS6) and III (IIIS6). In particular residues V907 and T911 of S4-S5 helix linker of domain II (IIS4-S5) interact with S6 of domains II (IIS6; I1013) and III (IIIS6; N1548) demonstrating that S4-S5 and S6 helices from adjacent domains are coupled in LVA Ca 2+ channels [23].…”

Section: Discussionmentioning

confidence: 99%

CaV3.1 channel pore pseudo-symmetry revealed by selectivity filter mutations in their domains I/II

Garza-López

Aldana

Darszon

et al. 2019

Preprint

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There is growing evidence indicating that the pore structure of voltage-gated ion channels (VGICs) influences gating besides their conductance. Regarding low voltage-activated (LVA) Ca2+ channels, it has been demonstrated that substitutions of the pore aspartate (D) by a glutamate (D-to-E substitution) in domains III and IV alter channel gating properties such as a positive shift in the channel activation voltage dependence. In the present report, we evaluated the effects of E-to-D substitution in domains I and II on the CaV3.1 channel gating properties. Our results indicate that substitutions in these two domains differentially modify the gating properties of CaV3.1 channels. The channel with a single mutation in domain I (DEDD) presented slower activation and faster inactivation kinetics and a slower recovery from inactivation, as compared with the WT channel. In contrast, the single mutant in domain II (EDDD) presented a small but significant negative shift of activation voltage dependence with faster activation and slower deactivation kinetics. Finally, the double mutant channel (DDDD) presented intermediate properties with respect to the two single mutants but with fastest deactivation kinetics. Overall, our results indicate that single amino acid modification of the selectivity filter of LVA Ca2+ channels in distinct domains differentially influence their gating properties, suggesting a pore pseudo-symmetry.Statement of significancePrevious reports of low voltage-activated (LVA) Ca2+ channels have demonstrated that pore aspartate (D) in domains III and IV equally modulates the channel gating properties, supporting a hypothesis of pore symmetry in LVA Ca2+ channels. In the present report, we evaluated the effects of glutamate (E)-to-D pore substitution in domains I and II on the CaV3.1 channel gating properties. Our results indicate that substitutions in these two domains differentially modify the gating properties of CaV3.1 channels, therefore suggesting a pore pseudo-symmetry in them. Interestingly, our pore mutations affect inactivation of CaV3.1 Ca2+ channels indicating a selectivity filter contribution to this process similar to the recent proposed paradigm for high voltage-activated Ca2+ channels.

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“…In the present study, we found that IIS4 voltage sensor, with an important contribution of some residues from the S4-S5 linker, has the most dominant effect, followed by the IVS4 segment, in the low-voltage activation behavior of Ca V 3.3 channels. In this regard, a more recent study has shown that the activation of Ca V 3.2 channels might be the result of cooperative contribution of residues from the S4-S5 linker of Domain II and the S6 helices from Domains II and III [ 58 ]. In such a scenario, the results presented here for Ca V 3.3 channel might be due to the disruption of structural interactions between S4 voltage sensors, S4-S5 linkers, and S6 helices, that leads to the gating of the channel and, therefore, it can be anticipated that such interactions could be more relevant in the case of Domain II of Ca V 3.3 channels.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, it has been shown in Ca V 3.2 channels that single and double mutations of residues in IIS4-S5 linker and IIIS6 helix led to a 25 mV negative shift in the steady-state inactivation curve [ 58 ]. Therefore, one possible explanation of our results in Ca V 3.3 channels could be that IS4 segment, the IS4-S5 linker or even the IS6 segment, have structural interactions with the “gating brake” structure localized in the I-II loop, and that the substitution of this voltage sensor with that of Ca V 1.2 does not restore such interactions leading the channels to inactive from closed states at very negative potentials.…”

Section: Discussionmentioning

confidence: 99%

Contribution of S4 segments and S4-S5 linkers to the low-voltage activation properties of T-type CaV3.3 channels

et al. 2018

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Voltage-gated calcium channels contain four highly conserved transmembrane helices known as S4 segments that exhibit a positively charged residue every third position, and play the role of voltage sensing. Nonetheless, the activation range between high-voltage (HVA) and low-voltage (LVA) activated calcium channels is around 30–40 mV apart, despite the high level of amino acid similarity within their S4 segments. To investigate the contribution of S4 voltage sensors for the low-voltage activation characteristics of CaV3.3 channels we constructed chimeras by swapping S4 segments between this LVA channel and the HVA CaV1.2 channel. The substitution of S4 segment of Domain II in CaV3.3 by that of CaV1.2 (chimera IIS4C) induced a ~35 mV shift in the voltage-dependence of activation towards positive potentials, showing an I-V curve that almost overlaps with that of CaV1.2 channel. This HVA behavior induced by IIS4C chimera was accompanied by a 2-fold decrease in the voltage-dependence of channel gating. The IVS4 segment had also a strong effect in the voltage sensing of activation, while substitution of segments IS4 and IIIS4 moved the activation curve of CaV3.3 to more negative potentials. Swapping of IIS4 voltage sensor influenced additional properties of this channel such as steady-state inactivation, current decay, and deactivation. Notably, Domain I voltage sensor played a major role in preventing CaV3.3 channels to inactivate from closed states at extreme hyperpolarized potentials. Finally, site-directed mutagenesis in the CaV3.3 channel revealed a partial contribution of the S4-S5 linker of Domain II to LVA behavior, with synergic effects observed in double and triple mutations. These findings indicate that IIS4 and, to a lesser degree IVS4, voltage sensors are crucial in determining the LVA properties of CaV3.3 channels, although the accomplishment of this function involves the participation of other structural elements like S4-S5 linkers.

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Cooperative Activation of the T-type CaV3.2 Channel

Cited by 10 publications

References 65 publications

Calcium channel gating

Calcium channel gating

CaV3.1 channel pore pseudo-symmetry revealed by selectivity filter mutations in their domains I/II

Contribution of S4 segments and S4-S5 linkers to the low-voltage activation properties of T-type CaV3.3 channels

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