Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels.
| Autor: | Del Rivero Morfin PJ; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., Kochiss AL; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., Liedl KR; Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck , Innsbruck, Austria., Flucher BE; Department of Physiology and Medical Physics, Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria., Fernández-Quintero MLI; Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck , Innsbruck, Austria., Ben-Johny M; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of general physiology [J Gen Physiol] 2024 Feb 05; Vol. 156 (2). Date of Electronic Publication: 2024 Jan 04. |
| DOI: | 10.1085/jgp.202313365 |
| Abstrakt: | 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. (© 2024 del Rivero Morfin et al.) |
| Databáze: | MEDLINE |
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