The Rab3 GTPase cycle modulates cardiomyocyte exocytosis and atrial natriuretic peptide release.

Abstract

Natriuretic peptides are produced predominantly by atrial cardiomyocytes in response to cardiovascular stress and attenuate cardiac maladaptation by reducing blood pressure, blood volume, and cardiac workload primarily through activation of natriuretic peptide receptors in the kidney and vasculature. However, mechanisms underlying cardiomyocyte exocytosis and natriuretic peptide secretion remain poorly defined. Manipulation of Rab3a GTPase activity by Rab3gap1 was recently found to modulate atrial natriuretic peptide (ANP) release by cardiomyocytes. Here, we examined upstream signaling mechanisms and the role of the Rab3a GTPase cycle in exocytosis and ANP secretion by cardiomyocytes. Pharmacological inhibition of the heterotrimeric G protein subunit G⍺q suppressed ANP secretion at baseline and prevented GTP loading of Rab3a and ANP release in neonatal rat cardiomyocytes in response to phenylephrine (PE). Similar to agonist-induced activation of ANP secretion, genetic overexpression of a constitutively active, GTP-loaded Rab3a mutant (Q81L) in neonatal rat cardiomyocytes resulted in enhanced intracellular distribution of Rab3a at endomembranes peripheral to the Golgi and promotion of ANP release, indicating that enhancement of Rab3a activity is sufficient to elicit ANP secretion by cardiomyocytes. Collectively, these data indicate G⍺q signaling downstream of receptor activation and Rab3a-regulated secretory pathway activity and exocytosis facilitate ANP release by cardiomyocytes that could potentially be harnessed to antagonize hypertension and adverse cardiac remodeling in cardiovascular disease.