Beta cells preferentially exchange cationic molecules via connexin 36 gap junction channels

Aims/hypothesis: Pancreatic beta cells are connected by gap junction channels made of connexin 36 (Cx36), which permit intercellular exchanges of current-carrying ions (ionic coupling) and other molecules (metabolic coupling). Previous studies have suggested that ionic coupling may extend to larger regions of pancreatic islets than metabolic coupling. The aim of the present study was to investigate whether this apparent discrepancy reflects a difference in the sensitivity of the techniques used to evaluate beta cell communication or a specific characteristic of the Cx36 channels themselves. Methods: We microinjected several gap junction tracers, differing in size and charge, into individual insulin-producing cells and evaluated their intercellular exchange either within intact islets of control, knockout and transgenic mice featuring beta cells with various levels of Cx36, or in cultures of wild-type and Cx36-transfected MIN6 cells. Results: We found that (1) Cx36 channels favour the exchange of cations and larger positively charged molecules between beta cells at the expense of anionic molecules; (2) this exchange occurs across sizable portions of pancreatic islets; and (3) during glibenclamide (known as glyburide in the USA and Canada) stimulation beta cell coupling increases to an extent that varies for different gap junction-permeant molecules. Conclusions/interpretation: The data show that beta cells are extensively coupled within pancreatic islets via exchanges of mostly positively charged molecules across Cx36 channels. These exchanges selectively increase during stimulation of insulin secretion. The identification of this permselectivity is expected to facilitate the identification of endogenous permeant molecules and of the mechanism whereby Cx36 signalling significantly contributes to the modulation of insulin secretio