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A novel pathway of cGMP


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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Correspondence to Michaela Kuhn.

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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Kuhn, M., Dankworth, B., Kruse, M. et al. A novel pathway of cGMP. BMC Pharmacol 11 (Suppl 1), O28 (2011).

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