Channelopathies in Cav1.1 Cav1.3 and Cav1.4 voltage-gated L-type Ca2+ channels

摘要

Voltage-gated Ca²⁺ channels couple membrane depolarization to Ca²⁺-dependent intracellular signaling events. This is achieved by mediating Ca²⁺ ion influx or by direct conformational coupling to intracellular Ca²⁺ release channels. The family of Cav1 channels, also termed L-type Ca²⁺ channels (LTCCs), is uniquely sensitive to organic Ca²⁺ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca²⁺ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 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 Ca²⁺ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca²⁺ 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.