DHPR

The dihydropyridine receptor (DHPR) is the L-type voltage-gated calcium channel complex that serves as the voltage sensor in skeletal muscle excitation-contraction coupling. In adult skeletal muscle, the DHPR is primarily the Cav1.1 α1S subunit (encoded by CACNA1S) and it associates with auxiliary subunits β1a, α2δ1, and γ1. The DHPR is located in the transverse tubule membrane at triadic junctions, closely apposed to the ryanodine receptor RyR1 on the adjacent sarcoplasmic reticulum.

Mechanism and role in contraction: Depolarization of the transverse tubule during an action potential induces conformational changes in the DHPR Cav1.1 that mechanically gates RyR1, triggering release of Ca2+ from the sarcoplasmic reticulum into the cytosol and initiating muscle contraction. Unlike in cardiac muscle, skeletal muscle EC coupling relies largely on this direct mechanical coupling rather than Ca2+-induced Ca2+ release through Ca2+ influx. Ca2+ entry through Cav1.1 channels can occur but is not essential for ECC in mature skeletal muscle.

Additional components and regulation: The proper function of the DHPR depends on several proteins that link the t-tubule membrane to the sarcoplasmic reticulum, including STAC3, junctophilins, and the β1a subunit, which influence trafficking and coupling efficiency. The DHPR also binds dihydropyridine class blockers, such as nifedipine, which inhibit Ca2+ entry through the channel.

Clinical and pharmacological relevance: Mutations in CACNA1S and other DHPR components can cause skeletal myopathies and periodic paralysis. The DHPR is a pharmacological target for calcium channel blockers used in treating hypertension and certain cardiac arrhythmias, though skeletal muscle EC coupling is less directly affected by these agents.

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