The Ca(2+) 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(2+) release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and l-type Ca(2+) channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca(2+) channel is still enigmatic. Here we show that Ca(2+) influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca(2+) influx is eliminated. Homozygous knock-in mice display SR Ca(2+) 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(2+) homeostasis. These findings support the hypothesis that the DHPR-mediated Ca(2+) influx in mammalian skeletal muscle is an evolutionary remnant.