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Submitted on February 3, 2002
Accepted on June 24, 2002
1 Departments of Physiology, Medicine, and Surgery, University of Toronto, Toronto, Canada; Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Surgery, University of Alberta, Edmonton, Canada
* To whom correspondence should be addressed. E-mail: herbert.gaisano{at}utoronto.ca .
Insulin secretion is initiated by ionic events involving membrane depolarization and Ca2+ entry, while exocytic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins mediate exocytosis itself. In the present study we characterize the interaction of the SNARE protein SNAP-25 (synaptosome associated protein of 25 kDa) with the ß-cell voltage-dependent K+ channel Kv2.1. Expression of Kv2.1, SNAP-25 and syntaxin 1A was detected in human islet lysates by western blot, and co-immunoprecipitation studies showed that heterologously expressed SNAP-25 and syntaxin 1A associate with Kv2.1. SNAP-25 reduced currents from recombinant Kv2.1 channels by approximately 70% without affecting channel localization. This inhibitory effect could be partially alleviated by co-dialysis of a Kv2.1N-terminal peptide that can bind in vitro SNAP-25, but not the Kv2.1C-terminal peptide. Similarly, SNAP-25 blocked voltage-dependent outward K+ currents from rat ß-cells by approximately 40%, an effect that was completely reversed by co-dialysis of the Kv2.1N fragment. Finally, SNAP-25 had no effect on outward K+ currents in ß-cells where Kv2.1 channels had been functionally knocked out using a dominant-negative approach, indicating that the interaction is specific to Kv2.1 channels as compared with other ß-cell Kv channels. This study demonstrates that SNAP-25 can regulate Kv2.1 through an interaction at the channel N-terminus and supports the hypothesis that SNARE proteins modulate secretion through their involvement in regulation of membrane ion channels in addition to exocytic membrane fusion.
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