Half-calcified Calmodulin Promotes Basal Activity and Inactivation of the Calcium Channel Ca V 1.2
Year: 2022
Type: preprint
Abstract: ABSTRACT The L-type Ca 2+ channel Ca V 1.2 controls gene expression, cardiac contraction, and neuronal activity. Calmodulin (CaM) governs Ca V 1.2 open probability (Po) and Ca 2+ -dependent inactivation (CDI) but the mechanisms remain unclear. We identified a half Ca 2+ -saturated CaM species (Ca 2 /CaM) with Ca 2+ bound solely at the third and fourth EF-hands (EF3 and EF4) under resting Ca 2+ concentrations (50-100 nM) that constitutively pre-associates with Ca V 1.2 to promote Po and CDI. We present an NMR structure of a complex between the Ca V 1.2 IQ motif (residues 1644-1665) and Ca 2 /CaM 12’ , a calmodulin mutant in which Ca 2+ binding to EF1 and EF2 is completely disabled. The CaM 12’ N-lobe does not interact with the IQ motif. The CaM 12’ C-lobe bound two Ca 2+ ions and formed close contacts with IQ residues I1654 and Y1657. I1654A and Y1657D mutations impaired CaM binding, CDI, and Po, as did disabling Ca 2+ binding to EF3 and EF4 in the CaM 34 mutant when compared to wildtype CaM. Accordingly, a previously unappreciated Ca 2 /CaM species promotes Ca V 1.2 Po and CDI identifying Ca 2 /CaM as an important mediator of Ca signaling.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: L-type Ca2+ Channel Regulation by Calmodulin and CaBP1, Coupling of vascular CaV1.2 channels in health and disease, Training Program in Molecular and Cellular Biology, UC Davis Training Program in Chemical Biology, Membrane targeting calcium sensors in vision, G6209256292, Initiative for Maximizing Student Development, Postsynaptic Signaling by Norepinephrine and cAMP, Dysregulation of Cav1.2 by beta amyloid peptide
OpenAlex ID: W4283513537