Crosstalk between L-type calcium channels and protein kinases in cardiovascular diseases

Abstract

Cardiovascular diseases (CVDs) represent the primary cause of mortality globally, accounting for around 17.9 million fatalities annually. These conditions frequently arise from structural and functional injuries in heart, including cardiac hypertrophy, vascular stiffening and impaired muscle contraction. A major contributor to many forms of CVD is dysregulation of calcium-dependent cardiomyocyte contraction. The entry of calcium ions (Ca²⁺) via L-type voltage-dependent calcium channels (L-VDCCs) is essential for contraction of cardiac and smooth muscle cells. These channels are on plasma membrane and T-tubules in cardiomyocytes, along with trafficking and scaffold proteins. A range of transmitters and hormones are known for regulating Ca_v1.2 and have been linked to CVDs, many of which also involve protein kinase C (PKC). Activation of Gq-coupled receptors and subsequent activation of protein lipase C (PLC) are among the most common mechanisms of PKC activation in cardiac and smooth muscle cells. Both in vitro and in vivo, Ca_v1.2 found to be regulated, phosphorylated, and linked with PKC. In addition to PKC-mediated regulation, β-adrenergic receptors are stimulated, and adenylate cyclase produces more cyclic adenosine monophosphate, which activates protein kinase A (PKA) and phosphorylates L-VDCC. This review highlights functional significance of L-VDCCs in cardiac physiology and examines therapeutic potential of calcium channel blockers (CCBs) in clinical trials.