What can naturally occurring mutations tell us about Ca(v)1.x channel function?

ABSTRACT

Voltage-gated Ca²âº channels allow for Ca²âº-dependent intracellular signaling by directly mediating Ca²âº ion influx, by physical coupling to intracellular Ca²âº release channels or functional coupling to other ion channels such as Ca²âº activated potassium channels. L-type Ca²âº channels that comprise the family of Ca(v)1 channels are expressed in many electrically excitable tissues and are characterized by their unique sensitivity to dihydropyridines. In this issue, we summarize genetic defects in L-type Ca²âº channels and analyze their role in human diseases (Ca²âº channelopathies); e.g. mutations in Ca(v)1.2 α1 cause Timothy and Brugada syndrome, mutations in Ca(v)1.3 α1 are linked to sinoatrial node dysfunction and deafness while mutations in Ca(v)1.4 α1 are associated with X-linked retinal disorders such as an incomplete form of congenital stationary night blindness. Herein, we also put the mutations underlying the channel's dysfunction into the structural context of the pore-forming α1 subunit. This analysis highlights the importance of combining functional data with structural analysis to gain a deeper understanding for the disease pathophysiology as well as for physiological channel function. This article is part of a Special Issue entitled Calcium channels.