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.
Highlights
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
A prerequisite for this Ca2+ -independent physical DHPR–RyR type-1 (RyR1) interaction was a transition in the ultrastructural positioning of the DHPRs from random clustering around the ryanodine receptors (RyR) to an arrangement into tetrads, i.e., four DHPRs positioned strictly adjacent to the homotetrameric RyR11, 18
One can only speculate that this DHPR Ca2+ inward current, might contribute in the form of excitation-coupled Ca2+ entry (ECCE)[19,20,21,22] and have a crucial role in Ca2+ homeostasis, e.g., by SR store filling, or is essential for skeletal muscle development via regulation of acetylcholine receptor pre-patterning and formation of neuromuscular junctions[23, 24], or has a negative inotropic effect[25,26,27,28,29], which is crucial for overall muscle health and fibre integrity[29], or is just an evolutionary remnant of the ancient Ca2+-induced Ca2+ release (CICR) stage[2, 3, 30]
Summary
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. The phylogenetic earliest mechanism involves muscle membrane depolarization, which triggers pore openings of the voltage-gated sarcolemmal L-type Ca2+ channel, or dihydropyridine receptor (DHPR), leading to a substantial and fast activating Ca2+ inward current[1,2,3] This sudden increase in intracellular Ca2+ concentration triggers Ca2+-sensitive Ca2+ release channels or ryanodine receptors (RyR) to open and release massive amounts of Ca2+ ions from sarcoplasmic reticulum (SR) stores into the cytoplasm, sufficient to induce muscle contraction[4,5,6]. A drawback of this interpretation is the negligence of the presence of a persisting permeation of monovalent cations through the mutant EK channel[31, 32, 34], which might, for instance, affect the membrane potential during muscle activity[32]
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