Calmodulin Regulation of Voltage-Gated Calcium Channels

Ben-Johny, Manu; Dick, Ivy E.

doi:10.1007/978-3-031-08881-0_9

Cited by 6 publications

(3 citation statements)

References 161 publications

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“…CDI is initiated by CaM-dependent conformational changes in the cytosolic domain of Ca V channels ( Budde et al, 2002 ; Halling et al, 2005 ; Minor and Findeisen, 2010 ; Ben Johny and Yue, 2015 ). Ca 2+ binding to the individual N- and C-lobes of CaM can trigger distinct forms of channel regulation ( Lee et al, 2000 ; DeMaria et al, 2001 ; Liang et al, 2003 ), a phenomenon known as “functional bipartition” of CaM ( Kink et al, 1990 ; Saimi and Kung, 1994 ).…”

Section: Discussionmentioning

confidence: 99%

Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

del Rivero Morfin,

Kochiss,

Liedl

et al. 2024

Journal of General Physiology

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Voltage-dependent and Ca2+-dependent inactivation (VDI and CDI, respectively) of CaV channels are two biologically consequential feedback mechanisms that fine-tune Ca2+ entry into neurons and cardiomyocytes. Although known to be initiated by distinct molecular events, how these processes obstruct conduction through the channel pore remains poorly defined. Here, focusing on ultrahighly conserved tryptophan residues in the interdomain interfaces near the selectivity filter of CaV1.3, we demonstrate a critical role for asymmetric conformational changes in mediating VDI and CDI. Specifically, mutagenesis of the domain III–IV interface, but not others, enhanced VDI. Molecular dynamics simulations demonstrate that mutations in distinct selectivity filter interfaces differentially impact conformational flexibility. Furthermore, mutations in distinct domains preferentially disrupt CDI mediated by the N- versus C-lobes of CaM, thus uncovering a scheme of structural bifurcation of CaM signaling. These findings highlight the fundamental importance of the asymmetric arrangement of the pseudotetrameric CaV pore domain for feedback inhibition.

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Section: Discussionmentioning

confidence: 99%

Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

del Rivero Morfin,

Kochiss,

Liedl

et al. 2024

Journal of General Physiology

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show abstract

“…CDI is initiated by CaM-dependent conformational changes in the cytosolic domain of CaV channels (Budde et al, 2002;Halling et al, 2006;Minor and Findeisen, 2010;Ben Johny and Yue, 2015). Ca 2+ binding to the individual N-and C-lobes of CaM can trigger distinct forms of channel regulation (Lee et al, 2000;DeMaria et al, 2001;Liang et al, 2003), a phenomenon known 'functional bipartition' of CaM (Kink et al, 1990;Saimi and Kung, 1994).…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Contribution of a Selectivity Filter Gate in Triggering Inactivation of Ca_V1.3 Channels

del Rivero Morfin,

Kochiss,

Liedl

et al. 2023

Preprint

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Voltage-dependent and Ca2+-dependent inactivation (VDI and CDI, respectively) of CaV channels are two biologically consequential feedback mechanisms that fine-tune Ca2+ entry into neurons and cardiomyocytes. Although known to be initiated by distinct molecular events, how these processes obstruct conduction through the channel pore remains poorly defined. Here, focusing on ultra-highly conserved tryptophan residues in the inter-domain interfaces near the selectivity filter of CaV1.3, we demonstrate a critical role for asymmetric conformational changes in mediating VDI and CDI. Specifically, mutagenesis of the domain III-IV interface, but not others, enhanced VDI. Molecular dynamics simulations demonstrate that mutations in distinct selectivity filter interfaces differentially impact conformational flexibility. Furthermore, mutations in distinct domains preferentially disrupt CDI mediated by the N- versus C-lobes of CaM, thus uncovering a scheme of structural bifurcation of CaM signaling. These findings highlight the fundamental importance of the asymmetric arrangement of the pseudo-tetrameric CaV pore domain for feedback inhibition.

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“…When Ca V 1.2 opens in response to an action potential, calcium ions enter the cell, and calmodulin registers the increased calcium concentration. Calcium binding to calmodulin induces a conformational change that propagates to the Ca V 1.2 channel and signals channel closure; a process called calcium-dependent inactivation (CDI) (14). Calmodulin variants in LQTS patients reduce or completely abolish CDI (15).…”

Section: Introductionmentioning

confidence: 99%

Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects

Jensen,

Brohus,

Hussey

et al. 2024

Preprint

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Calmodulin acts as a vital calcium sensor in cells, crucial for relaying calcium signals to different protein partners. While rare missense variants in calmodulin are linked to cardiac arrhythmia, particularly long QT syndrome (LQTS), their role in schizophrenia remains unexplored. We investigated missense variants in the calmodulin-encoding genesCALM1-3in a large-scale sequencing effort involving 24,248 schizophrenia patients and 97,322 controls. Seven carriers were found among cases and twenty among controls. Notably, all schizophrenia variants affected the C-terminal lobe of the protein, compared to only five in controls, linking calmodulin C-lobe missense variants and schizophrenia risk (odds ratio 5.62,P=0.043). Functional analyses revealed two classes of calmodulin variants in schizophrenia: 1) loss-of-function variants that reduce calcium affinity and impair the interaction with voltage-gated calcium channel 1.2 (CaV1.2), akin to LQTS variants but with smaller effect size, and 2) gain-of-function variants that unexpectedly enhance calcium affinity with no impact on CaV1.2 gating. This study for the first time statistically and functionally links calmodulin missense variants to a neurological disorder, expanding the phenotypic spectrum of calmodulinopathies to include schizophrenia.SignificanceNeurons use calmodulin to monitor calcium signals and modulate hundreds of target proteins, thereby regulating key processes such as neuronal firing and memory and learning. Here, we link genetic variants in calmodulin to schizophrenia risk. Moreover, these genetic variants have divergent consequences for calmodulin protein function. Our results expand the current understanding of calmodulin variants, which are primarily reported in cardiac arrhythmia patients, and generally have a strong loss-of-function effect on the protein. We here provide the first identification and characterization of calmodulin variants in non-cardiac patients. This broadens our view of the physiological and functional consequences of human calmodulin variants and presents novel mechanistic entries to understanding the molecular mechanisms of schizophrenia.

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Calmodulin Regulation of Voltage-Gated Calcium Channels

Cited by 6 publications

References 161 publications

Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

Asymmetric Contribution of a Selectivity Filter Gate in Triggering Inactivation of Ca_V1.3 Channels

Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects

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Calmodulin Regulation of Voltage-Gated Calcium Channels

Cited by 6 publications

References 161 publications

Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

Asymmetric Contribution of a Selectivity Filter Gate in Triggering Inactivation of CaV1.3 Channels

Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects

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Asymmetric Contribution of a Selectivity Filter Gate in Triggering Inactivation of Ca_V1.3 Channels