Received for publication December 19, 2005.
Revised May 31, 2006.
Accepted for publication May 31, 2006.

t-SNAREs regulate differently activation and inactivation gating of Kv2.2 and Kv2.1; implications on pancreatic islet cell Kv channels

Abstract

Previously, we hypothesized that the plasma membrane protein components of the exocytotic SNARE complex, syntaxin 1A and SNAP-25, distinctly regulate different voltage-gated K⁺ (Kv) channels that are differentially distributed. Neuroendocrine islet cells (,,) uniformly contain both syntaxin 1A and SNAP-25. However, using immunohystochemistry, we show that the different pancreatic islet cells contain distinct dominant Kv channels, including Kv2.1 in -cells and Kv2.2 in and -cells, whose interactions with the SNARE proteins would respectively regulate insulin, glucagon and somatostatin secretion. We therefore examined the regulation by syntaxin 1A and SNAP-25 of these two channels. Previously, we showed that islet -cell Kv2.1 interacts with syntaxin 1A and SNAP-25 and, based on studies in oocytes, suggested a model of two distinct modes of interaction of syntaxin 1A and the complex syntaxin 1A/SNAP-25 with the C-terminus of the channel. Here, we characterized the interactions of syntaxin 1A and SNAP-25 with Kv2.2 which is highly homologous to Kv2.1, except for the C-terminus. Comparative two-electrode voltage clamp analysis in oocytes between Kv2.2 and Kv2.1 shows that Kv2.2 interacts only with syntaxin 1A and, in contrast to Kv2.1, it does not interact with the syntaxin 1A/SNAP-25 complex, and hence is not sensitive to the assembly/disassembly state of the complex. The distinct regulation of these closely related channels by SNAREs may be attributed to differences in their C-termini. Together with the differential distribution of these channels among islet cells, their distinct regulation suggests that the documented profound down-regulation of islets SNAREs levels in diabetes could distort differently islet cell ion channels and secretory responses, ultimately contributing to the abnormal glucose homeostasis.

Key words: Ion channel regulation, Structure-activity relationships and modeling

This article has been cited by other articles:

				D. P. Mohapatra, H. Vacher, and J. S. Trimmer The Surprising Catch of a Voltage-Gated Potassium Channel in a Neuronal SNARE Sci. Signal., July 3, 2007; 2007(393): pe37 - pe37. [Abstract] [Full Text] [PDF]

				D. Singer-Lahat, A. Sheinin, D. Chikvashvili, S. Tsuk, D. Greitzer, R. Friedrich, L. Feinshreiber, U. Ashery, M. Benveniste, E. S. Levitan, et al. K+ Channel Facilitation of Exocytosis by Dynamic Interaction with Syntaxin J. Neurosci., February 14, 2007; 27(7): 1651 - 1658. [Abstract] [Full Text] [PDF]