Intracellular Electroporation as Part of the Mechanism of Fusion Pore Formation in Exocytosis

Abstract

The molecular physics of fusion pore formation has remained an open question for the past half century following the confirmation of exocytosis as the pathway of cellular secretion. While a number of proteins have been found to be required for docking and exocytotic secretion in a variety of biological systems, the physical mechanism of fusion of secretory vesicle and plasma membrane remains a mystery. It is possible that the role of SNARE and “fusion proteins” together with a final cytosolic Ca2+ spike may simply be to create close apposition between secretory vesicle and plasma membranes as a prelude to electroporation and fusion pore formation. In the early 1990's the similarities between electropores in secretory granule membranes generated by high electric fields and fusion pores between secretory granules and plasma membranes were pointed out by Oberhauser and Fernandez (1993, Biophys. J. 65: 1844-1852). Then in 1998, Rosenheck, (Biophys. J. 75: 1237-1243) in a theoretical analysis concluded that the electrostatic field strength generated from the inner face of the chromaffin cell membrane by negatively charged phosphatidylserine is sufficient to electroporate the chromaffin granule membrane when the latter is in close proximity (< 30 A). Further confirmation of this conclusion was recently put forward by Lutiel and coworkers ( 2007, J. Biomol. Struct & Dynamics 24: 495-503). In this poster these and related results will be presented for consideration and their strengths and limitations discussed. An essential feature of the proposed model is the idea that fusion pore formation starts as an electrostatic field-induced perturbation in the structure of the lipid bilayer of the secretory vesicle membrane. The proposed model offers new insights into the physics underlying exocytotic membrane fusion.