The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance

Abstract

Skeletal muscle excitation-contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca²⁺ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and L-type Ca²⁺ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca²⁺ channel is still enigmatic. Here we show that Ca²⁺ influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca²⁺ influx is eliminated. Homozygous knock-in mice display SR Ca²⁺ release, locomotor activity, motor coordination, muscle strength and susceptibility to fatigue comparable to wild-type controls, without any compensatory regulation of multiple key proteins of the EC coupling machinery and Ca²⁺ homeostasis. These findings support the hypothesis that the DHPR-mediated Ca²⁺ influx in mammalian skeletal muscle is an evolutionary remnant.In mammalian skeletal muscle, the DHPR functions as a voltage sensor to trigger muscle contraction and as a Ca²⁺ channel. Here the authors show that mice where Ca²⁺ influx through the DHPR is eliminated display no difference in skeletal muscle function, suggesting that the Ca²⁺ influx through this channel is vestigial.