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NEUROREGULATION AND MOTILITY

Distinct modulation of K_v1.2 channel gating by wild type, but not open form, of syntaxin-1A

¹Departments of Medicine and Physiology, and ²Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Canada

Submitted 12 October 2006 ; accepted in final form 16 January 2007

SNARE proteins, syntaxin-1A (Syn-1A) and SNAP-25, inhibit delayed rectifier K⁺ channels, K_v1.1 and K_v2.1, in secretory cells. We showed previously that the mutant open conformation of Syn-1A (Syn-1A L165A/E166A) inhibits K_v2.1 channels more optimally than wild-type Syn-1A. In this report we examined whether Syn-1A in its wild-type and open conformations would exhibit similar differential actions on the gating of K_v1.2, a major delayed rectifier K⁺ channel in nonsecretory smooth muscle cells and some neuronal tissues. In coexpression and acute dialysis studies, wild-type Syn-1A inhibited K_v1.2 current magnitude. Of interest, wild-type Syn-1A caused a right shift in the activation curves of K_v1.2 without affecting its steady-state availability, an inhibition profile opposite to its effects on K_v2.1 (steady-state availability reduction without changes in voltage dependence of activation). Also, although both wild-type and open-form Syn-1A bound equally well to K_v1.2 in an expression system, open-form Syn-1A failed to reduce K_v1.2 current magnitude or affect its gating. This is in contrast to the reported more potent effect of open-form Syn-1A on K_v2.1 channels in secretory cells. This finding together with the absence of Munc18 and/or 13-1 in smooth muscles suggested that a change to an open conformation Syn-1A, normally facilitated by Munc18/13-1, is not required in nonsecretory smooth muscle cells. Taken together with previous reports, our results demonstrate the multiplicity of gating inhibition of different K_v channels by Syn-1A and is compatible with versatility of Syn-1A modulation of repolarization in various secretory and nonsecretory (smooth muscle) cell types.

ion channels; electrophysiology; SNARE protein

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