A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide
A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide
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DOI：
10.1073/pnas.1103300108
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发表时间：
2011-11-08
影响因子：
11.1
通讯作者：
Kuhn, Michaela
中科院分区：
文献类型：
--
作者：
Klaiber, Michael;Dankworth, Beatrice;Kuhn, Michaela
心脏心房利钠肽（ANP）调节动脉血压，调节心肌细胞生长，刺激血管生成和代谢。ANP与鸟苷酸环化酶（GC）受体GC-A结合，发挥其多种功能。这一过程涉及cGMP依赖性信号通路，防止心肌细胞中病理性[Ca（2+）]（i）增加。然而，在慢性心肌肥厚中，由于受体脱敏，ANP水平显著增加，并且GC-A/cGMP对ANP的反应减弱。在这里，我们表明，在这种情况下，心钠素结合GC-A刺激一个独特的cGMP非依赖性信号通路在心肌细胞，导致病理性升高的细胞内Ca（2+）水平。该途径涉及通过GC-A激活Ca（2+）可渗透的瞬时受体电位典型3/6（TRPC 3/C6）阳离子通道，其与TRPC 3/C6通道形成稳定的复合物。我们的研究结果表明，由此产生的阳离子流入激活电压依赖性L型Ca（2+）通道，并最终增加心肌细胞Ca（i）（2+）水平。这些观察结果揭示了ANP/GCA-信号通路在调节心肌细胞Ca（i）（2+）稳态中的双重作用。在生理条件下，cGMP依赖性途径的激活可调节肥大因子（如血管紧张素II）的Ca（i）（2+）增强作用。相比之下，cGMP非依赖性途径占主导地位的病理生理条件下，当GC-A是脱敏的高ANP水平。[Ca（2+）]（i）的伴随升高可能增加心脏肥大和心律失常的倾向。
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 process involves a cGMP-dependent signaling pathway preventing pathological [Ca(2+)](i) increases 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 unique cGMP-independent signaling pathway in cardiac myocytes, resulting in pathologically elevated intracellular Ca(2+) levels. This pathway involves the activation of Ca(2+)-permeable transient receptor potential canonical 3/6 (TRPC3/C6) cation channels by GC-A, which forms a stable complex with TRPC3/C6 channels. Our results indicate that the resulting cation influx activates voltage-dependent L-type Ca(2+) channels and ultimately increases myocyte Ca(i)(2+) levels. These observations reveal a dual role of the ANP/GCA- signaling pathway in the regulation of cardiac myocyte Ca(i)(2+) homeostasis. Under physiological conditions, activation of a cGMP-dependent pathway moderates the Ca(i)(2+)-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 [Ca(2+)](i) might increase the propensity to cardiac hypertrophy and arrhythmias.