Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding

eLife

Anamika Dayal¹  Manfred Grabner¹  Klaus R Liedl²  Monica L Fernández-Quintero² 

[1] Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria;Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria;

关键词: voltage-gated ca channel;    non-conducting dhpr;    ca permeation;    ca selectivity;    pore binding affinity;    skeletal muscle excitation-contraction coupling;    nc;    Mouse;   

DOI  :  10.7554/eLife.63435

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Skeletal muscle excitation-contraction (EC) coupling roots in Ca2+-influx-independent inter-channel signaling between the sarcolemmal dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR1) in the sarcoplasmic reticulum. Although DHPR Ca2+ influx is irrelevant for EC coupling, its putative role in other muscle-physiological and developmental pathways was recently examined using two distinct genetically engineered mouse models carrying Ca2+ non-conducting DHPRs: DHPR(N617D) (Dayal et al., 2017) and DHPR(E1014K) (Lee et al., 2015). Surprisingly, despite complete block of DHPR Ca2+-conductance, histological, biochemical, and physiological results obtained from these two models were contradictory. Here, we characterize the permeability and selectivity properties and henceforth the mechanism of Ca2+ non-conductance of DHPR(N617). Our results reveal that only mutant DHPR(N617D) with atypical high-affinity Ca2+ pore-binding is tight for physiologically relevant monovalent cations like Na+ and K+. Consequently, we propose a molecular model of cooperativity between two ion selectivity rings formed by negatively charged residues in the DHPR pore region.

【 授权许可】

CC BY