Voltage-Dependent Calcium Channels: Structure and Regulation in Normal and Abnormal States

Abstract

Calcium (Ca) is an essential element for many cell processes. The major pathway by which Ca enters cells is through Ca channels located in cell membranes. Different types of Ca channels exist, and are generally classified as either voltage-dependent or receptor-dependent Ca channels. Voltage-dependent Ca channels are opened in response to a change in membrane potential, while receptor-dependent Ca channels are opened in response to the activation of an associated receptor. The subject of this review is a subclass of voltage-dependent Ca channels known as L-type or slow Ca channels [1–4]. These channels conduct a long-lasting current of large conductance [1] and are found in excitable (see refs. [2,3]) and nonexcitable [5] cells. L-type Ca channels are opened and closed in response to changes in membrane potential, but, in addition, they are regulated by receptor-dependent processes [3,6,7]. Considerable evidence from electrophy- siological studies suggests that L-type Ca channels are regulated by a cAMP- dependent phosphorylation event. In cardiac cells, any agent that elevates cAMP, such as β-adrenergic agonists, increases the probability of opening of L channels in response to a given change in membrane potential [6,7]. L-type Ca channels in other cells, including skeletal muscle [8,9], also are regulated by cAMP. Application of the purified catalytic subunit of cAMP-dependent protein kinase mimics the effects of cAMP [10, 11], and the inhibitor of this protein kinase prevents the effects [12]. Furthermore, the widely observed rundown of Ca channel activity over time in patch-clamp experiments has been slowed by cAMP-dependent protein kinase and ATP [13, 14]. Taken together, the results support the hypothesis that certain L channels are regulated by the cAMP-dependent phosphorylation of the channel itself or a regulatory protein. However, until recently biochemical evidence to support this hypothesis has been lacking because the protein(s) that comprise Ca channels were not known. Recently, considerable progress has been made in our understanding of the structure and biochemical properties of L channels, and insights into the biochemical events involved in the regulation of the channels is now possible. This review will focus on our current understanding of the structure and regulation of Ca channels. Disease-related defects in L-type Ca channels will also be addressed.