cAMP/PKA Signalling Cascade Regulation of Cardiac L-type Calcium Channel Activity

The influx of Ca²⁺ ions into cardiac myocytes through voltage-gated, L-type Ca²⁺ channels is an essential component of cardiac excitability and the coupling of cell excitation to contraction. The ions create a depolarising current (I_Ca) that contributes to the plateau phase of the cardiac action potential, and it also contributes to pacemaker activity in nodal cells. The increase in intracellular [Ca²⁺] generated by I_Ca has a positive feedback effect, triggering the release of more intracellular Ca²⁺ from stores within the sarcoplasmic reticulum. This increase in intracellular Ca²⁺ then results in the activation of myofilament contraction.

In many cases of cardiovascular disease, including atrial fibrillation, heart failure and ischemia, the density and function of the L-type Ca²⁺ channels are disrupted. Therefore, better understanding of how L-type Ca²⁺ channels are regulated in healthy cardiac myocytes may give insight into how these diseases may be better treated.

A variety of different hormones, neurotransmitters and cytokines regulate cardiac L-type Ca²⁺ channels. A wide array of different receptors and signalling pathways interact to provide dynamic regulation of I_Ca in the heart. These pathways include the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signalling cascade (see Figure 1 below). Multiple G-protein coupled receptors act through the cAMP/PKA signal transduction pathway to regulate L-type Ca²⁺ channel activity. These receptors are coupled to G-proteins which either stimulate (G_s) or inhibit (G_i) the enzyme adenylate cyclase (AC). Active AC catalyses the conversion of ATP to cAMP, which then activates PKA. In turn this enzyme phosphorylates the L-type Ca²⁺ channels, and the I_Ca is enhanced.

The description of this signal transduction pathway was based on a paper by Kamp and Hell (2000), which investigates the regulation of cardiac L-type calcium channels by protein kinases. The complete original paper reference is cited below:

Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C, Timothy J. Kamp and Johannes W. Hell, 2000, Circulation Research, 87, 1095-1102. (Full text and PDF versions of the article are available to subscribers on the Circulation Research website.)