Regulation of Calcium Channels By Protein Phosphorylation

Abstract

There are many types of voltage-activated Ca²⁺ channels that are found in a wide variety of excitable and nonexcitable cells. While voltage is the primary factor that determines whether these Ca²⁺ channels are opened or closed, many Ca²⁺ channels are regulated by receptor-dependent events (1-3). An example of this type of regulation can be seen with the dihydropyridine (DHP)-sensitive Ca²⁺ channels. In cardiac cells, activation of -adrenergic receptors leads to an increase in the probability that these channels will open in response to a given membrane depolarization (1-3). This ‘activation’ of the channels is believed to occur by two distinct regulatory processes. The first and most well understood is thought to involve regulation of the channels by protein phosphorylation. In this case, -adrenergic receptor-mediated increases in cyclic AMP (cAMP) and subsequent activation of cAMP-dependent protein kinase (PKA) is thought to result in phosphorylation of either the channel proteins or associated regulatory proteins (1-3). The phosphorylation event is believed to result in the increased probability of channel opening. The second receptor-dependent regulatory mechanism involves receptor-mediated activation of stimulatory GTP binding regulatory proteins (G proteins) which in turn are believed to directly interact with and activate the channels (4,5). Ca²⁺ channels in other types of cells are also believed to be regulated by a variety of G proteins and by protein phosphorylation catalyzed by a variety of protein kinases (1-4).