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ORIGINAL ARTICLE

Kv2.1 Channel Activation and Inactivation Is Influenced by Physical Interactions of Both Syntaxin 1A and the Syntaxin 1A/Soluble N-Ethylmaleimide-Sensitive Factor-25 (t-SNARE) Complex with the C Terminus of the Channel

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel (S.T., I.M., D.C., I.L.); School of Biology, University of Leeds, West Yorkshire, Leeds, United Kingdom (G.N.B.); and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas (R.H.)

Abstract

Kv2.1, the prevalent delayed-rectifier K⁺ channel in neuroendocrine and endocrine cells, was suggested previously by our group to be modulated in islet -cells by syntaxin 1A (Syx) and soluble N-ethylmaleimide-sensitive factor attachment protein-25 (SNAP-25). We also demonstrated physical interactions in neuroendocrine cells between Kv2.1, Syx, and SNAP-25, characterized their effects on Kv2.1 activation and inactivation in Xenopus laevis oocytes, and suggested that they pertain to the assembly/disassembly of the Syx/SNAP-25 (t-SNARE) complex. In the present work, we established the existence of a causal relationship between the physical and the functional interactions of Syx with the Kv2.1 channel using three different peptides that compete with the channel for binding of Syx when injected into oocytes already coexpressing Syx with Kv2.1 in the plasma membrane: one peptide corresponding to the Syx-binding region on the N-type Ca²⁺ channel, and two peptides corresponding to Syx-binding regions on the Kv2.1 C terminus. All peptides reversed the effects of Syx on Kv2.1, suggesting that the hyperpolarizing shifts of the steady-state inactivation and activation of Kv2.1 caused by Syx result from cell-surface protein-protein interactions and point to participation of the C terminus in such an interaction. In line with these findings, the effects of Syx were dissipated by partial deletions of the C terminus. Furthermore, the t-SNARE complex was shown to bind to the Kv2.1 C terminus, and its effects on the inactivation of Kv2.1 were dissipated by partial deletions of the C terminus. Taken together, these findings suggest that physical interactions of both Syx and the t-SNARE complex with the C terminus of Kv2.1 are involved in channel regulation.

Address correspondence to: Dr. Ilana Lotan, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, 69978 Ramat-Aviv, Israel. E-mail: ilotan{at}post.tau.ac.il

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