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A novel pathway of cGMP
BMC Pharmacology volume 11, Article number: O28 (2011)
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.
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.
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.
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Kuhn, M., Dankworth, B., Kruse, M. et al. A novel pathway of cGMP. BMC Pharmacol 11, O28 (2011) doi:10.1186/1471-2210-11-S1-O28
- Cardiac Hypertrophy
- Atrial Natriuretic Peptide
- Guanylyl Cyclase
- Receptor Desensitization
- Concomitant Rise