A novel pathway of cGMP

Background

Cardiac atrial natriuretic peptide (ANP) regulates arterial blood pressure, moderates cardiomyocyte growth, and stimulates angiogenesis and metabolism. ANP binds to the transmembrane guanylyl cyclase (GC) receptor, GC-A to exert its diverse functions. This involves a cGMP-dependent signaling pathway preventing pathological [Ca²⁺]_i raises in myocytes. In chronic cardiac hypertrophy, however, ANP levels are markedly increased and GC-A/cGMP responses to ANP are blunted due to receptor desensitization.

Results

Here we show that in this situation ANP binding to GC-A stimulates a novel cGMP-independent signaling pathway in cardiac myocytes, resulting in pathologically elevated intracellular Ca²⁺ levels ([Ca²⁺_i]). This pathway involves the activation of TRPC3/C6 Ca²⁺ channels (transient receptor potential canonical channel 3/6) by GC-A which forms a stable complex with TRPC3/C6 channels. Our results indicate that the resulting TRPC3/C6-mediated Ca²⁺ entry then stimulates Calmodulin Kinase II (CaMKII) to phosphorylate L-type Ca²⁺ channels leading to increased L-type Ca²⁺ channel mediated Ca²⁺ current and a rise in intracellular Ca²⁺ levels.

Conclusion

These observations reveal a dual role of the ANP/GC-A signaling pathway in the regulation of cardiac myocyte Ca²⁺_i-homeostasis. Under physiological conditions, activation of a cGMP-dependent pathway moderates the Ca²⁺_i-enhancing action of hypertrophic factors such as Angiotensin II. By contrast, a cGMP-independent pathway predominates under pathophysiological conditions, when GC-A is desensitized by high ANP levels. The concomitant rise in [Ca²⁺_i] is likely to increase the propensity to cardiac hypertrophy and arrhythmias.