Cardiac Signal Transduction Mechanisms (G-Protein and IP₃-Linked)

There are several major signal transduction mechanisms found in cells of the cardiovascular system, the most important being the G-protein, IP₃, and nitric oxide-cyclic GMP pathways. Described below are the G-protein and IP₃ pathways found in the heart. Signal transduction mechanisms regulating vascular smooth muscle contraction and relaxation are found elsewhere (Click Here).

Gs-Protein and Gi-Protein Coupled Signal Transduction

G-proteins are linked to an enzyme, adenylyl cyclase, that dephosphorylates ATP to form cyclic AMP (cAMP). Gs-protein (stimulatory G-protein) activation (e.g., via β-adrenoceptors) increases cAMP. This activates PK-A (cAMP stimulated protein kinase) and causes increased influx of Ca⁺⁺ by phosphorylation and activation of L-type calcium channels, and enhanced release of Ca⁺⁺ by the sarcoplasmic reticulum in the heart. These and other intracellular events increase inotropy, chronotropy, dromotropy and lusitropy. Activation of Gi-proteins (inhibitory G-protein), for example by adenosine and muscarinic receptor activation, decreases cAMP and PK-A activation, decreases Ca⁺⁺ entry and release, and increases outward, hyperpolarizing K⁺ currents. Activation of the Gi-protein pathway therefore enhances repolarization.

Gi-protein activation produces effects that are opposite to those elicited by Gs-protein activation; however, Gi-protein effects are primarily directed toward the SA node and AV node to decrease sinus rate and AV nodal conduction velocity, respectively, with minimal effects on muscle contractility. In contrast, Gs-protein strongly stimulates muscle contraction in addition to its nodal effects.

IP₃- Coupled Signal Transduction

The IP₃ pathway is linked to activation of α₁-adrenoceptors, angiotensin II (AII) receptors, and endothelin-1 (ET-1) receptors and therefore is stimulated by alpha-agonists, angiotensin II and endothelin-1. These receptors are coupled to a phospholipase C (PL-C)-coupled Gq-protein, which when activated, stimulates the formation of inositol triphosphate (IP₃) from phosphatidylinositol biphosphate (PIP₂). Increased IP₃ stimulates Ca⁺⁺ release by the sarcoplasmic reticulum in the heart, thereby increasing inotropy as one of its actions.

Altered Signal Transduction in Heart Disease

Altered signal transduction mechanisms have a significant role in the loss of inotropy in heart failure.  For example, desensitization of β₁-adrenoceptors in the heart decreases inotropic responses to sympathetic activation. Uncoupling of the β₁-adrenoceptor and the Gs-protein reduces the ability to activate adenylyl cyclase.  If the ability of protein kinase A to phosphorylate L-type calcium channels is impaired, then calcium influx into the cell would be reduced, leading to a smaller release of calcium by the sarcoplasmic reticulum.  Reduced calcium release would impair excitation-contraction coupling, thereby decreasing inotropy.

Revised 07/16/2007