Author(s):
Gowrisankaran, Sindhuja ; Houy, Sébastien ; Del Castillo, Johanna G Peña ; Steubler, Vicky ; Gelker, Monika ; Kroll, Jana ; Pinheiro, Paulo S. ; Schwitters, Dirk ; Halbsgut, Nils ; Pechstein, Arndt ; van Weering, Jan R. T. ; Maritzen, Tanja ; Haucke, Volker ; Raimundo, Nuno ; Sørensen, Jakob B. ; Milosevic, Ira
Date: 2020
Persistent ID: https://hdl.handle.net/10316/106508
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): Acyltransferases; Adaptor Proteins, Vesicular Transport; Animals; Chromaffin Cells; Cytoplasmic Vesicles; Disease Models, Animal; Endocytosis; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurosecretory Systems
Description
Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A's role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.
Schram-Stiftung T287/25457 and Deutsche Forschungsgemeinschaft (Emmy Noether Young Investigator Award MI- 1702/1) to I.M., SySy fellowship to S.G., the Lundbeck foundation (P.S.P., S.H., J.B.S.), ERC Starting Grant 337327 (N.R.), ZonMW 91111009 (J.R.T.v.W.), Alzheimer’s Associaton AARG-17498856 (J.R.T.v.W.), the Novo Nordisk Foundation (J.B.S.) and the Independent Research Fund Denmark (S.H., J.B.S.).
