TY - JOUR TI - Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding AU - Dayal, Anamika AU - Fernández-Quintero, Monica L AU - Liedl, Klaus R AU - Grabner, Manfred A2 - Colecraft, Henry M A2 - Swartz, Kenton J A2 - Colecraft, Henry M A2 - Cannon, Stephen VL - 10 PY - 2021 DA - 2021/06/01 SP - e63435 C1 - eLife 2021;10:e63435 DO - 10.7554/eLife.63435 UR - https://doi.org/10.7554/eLife.63435 AB - 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. KW - voltage-gated ca2+ channel KW - non-conducting dhpr KW - ca2+ permeation KW - ca2+ selectivity KW - pore binding affinity KW - skeletal muscle excitation-contraction coupling KW - nc dhpr JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -