zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1

Kobina Essandoh; Arasakumar Subramani; Olivia A Ferro; James P Teuber; Sribharat Koripella; Matthew J Brody

doi:10.1016/j.jacbts.2022.11.003

zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1

JACC Basic Transl Sci. 2023 Feb 22;8(5):518-542. doi: 10.1016/j.jacbts.2022.11.003. eCollection 2023 May.

Authors

Kobina Essandoh¹, Arasakumar Subramani¹, Olivia A Ferro¹, James P Teuber¹, Sribharat Koripella¹, Matthew J Brody^{1

2}

Affiliations

¹ Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
² Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Abstract

Production and release of natriuretic peptides by the stressed heart reduce cardiac workload by promoting vasodilation, natriuresis, and diuresis, which has been leveraged in the recent development of novel heart-failure pharmacotherapies, yet the mechanisms regulating cardiomyocyte exocytosis and natriuretic peptide release remain ill defined. We found that the Golgi S-acyltransferase zDHHC9 palmitoylates Rab3gap1 resulting in its spatial segregation from Rab3a, elevation of Rab3a-GTP levels, formation of Rab3a-positive peripheral vesicles, and impairment of exocytosis that limits atrial natriuretic peptide release. This novel pathway potentially can be exploited for targeting natriuretic peptide signaling in the treatment of heart failure.

Keywords: Rab3; atrial natriuretic peptide; exocytosis; heart failure; palmitoylation.

Grants and funding

R00 HL136695/HL/NHLBI NIH HHS/United States