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- W1993508070 abstract "The past decade has witnessed many discoveries about the early events that underlie calmodulin (CaM) regulation of Ca2+ channels. Much is known about the positioning of apoCaM (Ca2+-free) on channels, and the initial Ca2+/CaM interaction sites. Beyond this, precious little is clear about the eventual actions of this central genre of Ca2+ channel modulation. Does CDI involve hinged-lid occlusion, selectivity filter collapse, or allosteric inhibition of activation gating? Do CDI and VDI reach the same ultimate conformation? All these proposals remain in flux. Here, we deduce that mutations within the S6 activation gates would produce discriminating effects on activation and inactivation, depending on which mechanism holds true. For the first two end-stage mechanisms (hinged-lid occlusion and selectivity filter collapse), S6 mutations that enhance channel opening are predicted to strengthen channel inactivation. By contrast, for an allosteric mechanism, such mutations would actually weaken inactivation. These predictions motivated exhaustive mutagenesis of the S6 segments of all four homologous domains of CaV1.3. We find that S6 mutations affect VDI and CDI in strikingly different ways, indicating a fundamental divergence of their end-stage mechanisms. The pattern seen for CDI agrees remarkably well with that predicted for an allosteric mechanism. By contrast, VDI effects cannot be fully explained by any previously described end-stage mechanism. Instead, mapping the functional VDI effects onto a structural homology model of CaV1.3 reveals a telling structural pattern, suggestive of a novel ‘hinged-lid-shield’ mechanism. In this scheme, CaV1.3 channels feature a specialized distal S6 ‘shield’ that repels lid closure. We validate this proposal with experiments in which the integrity of the shield and the mobility of the hinge-lid are independently modified. In all, these advances furnish a rich mechanistic backdrop for the many Ca2+ channelopathies involving S6 domains." @default.
- W1993508070 created "2016-06-24" @default.
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- W1993508070 date "2009-02-01" @default.
- W1993508070 modified "2023-09-29" @default.
- W1993508070 title "End-stage Mechanisms Underlying Voltage and Ca2+/Calmodulin-Dependent Inactivation (VDI and CDI) of CaV1.3 Channels" @default.
- W1993508070 doi "https://doi.org/10.1016/j.bpj.2008.12.1928" @default.
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