The Ca Influx Through the Mammalian Skeletal Muscle Dihydropyridine Receptor is Irrelevant for Muscle Performance

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) Ca release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and L-type Ca channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca channel is still enigmatic. Here we show that Ca influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca influx is eliminated. Homozygous knock-in mice display SR Ca 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 Ca homeostasis. These findings support the hypothesis that the DHPR-mediated Ca 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 Ca channel. Here the authors show that mice where Ca influx through the DHPR is eliminated display no difference in skeletal muscle function, suggesting that the Ca influx through this channel is vestigial.