Channelopathies in Ca(v)1.1, Ca(v)1.3, and Ca(v)1.4 voltage-gated L-type Ca(2+) channels

Voltage-gated Ca(2+) channels couple membrane depolarization to Ca(2+)-dependent intracellular signaling events. This is achieved by mediating Ca(2+) ion influx or by direct conformational coupling to intracellular Ca(2+) release channels. The family of Ca(v)1 channels, also termed L-type Ca(2+) channels (LTCCs), is uniquely sensitive to organic Ca(2+) channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca(2+) channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Ca(v)1.1 α1), incomplete congenital stationary night blindness (CSNB2; Ca(v)1.4 α1), and Timothy syndrome (Ca(v)1.2 α1; reviewed separately in this issue). Ca(v)1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca(2+) channelopathies affecting non-LTCCs, such as Ca(v)2.1 α1 in tottering mice. Ca(2+) channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function.