title: Distinct modulation of Kv1.2 channel gating by wild type, but not open form, of syntaxin-1A.
abstract: SNARE proteins, syntaxin-1A (Syn-1A) and SNAP-25, inhibit delayed rectifier K(+) channels, K(v)1.1 and K(v)2.1, in secretory cells. We showed previously that the mutant open conformation of Syn-1A (Syn-1A L165A/E166A) inhibits K(v)2.1 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(v)1.2, 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(v)1.2 current magnitude. Of interest, wild-type Syn-1A caused a right shift in the activation curves of K(v)1.2 without affecting its steady-state availability, an inhibition profile opposite to its effects on K(v)2.1 (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(v)1.2 in an expression system, open-form Syn-1A failed to reduce K(v)1.2 current magnitude or affect its gating. This is in contrast to the reported more potent effect of open-form Syn-1A on K(v)2.1 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.
authors.affiliation: Department of Medicine and Physiology, University Health Network, University of Toronto, Toronto, Canada.
authors.forename: Leila
authors.initials: L
authors.lastname: Neshatian
authors.forename: Yuk M
authors.initials: YM
authors.lastname: Leung
authors.forename: Youhou
authors.initials: Y
authors.lastname: Kang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gao
authors.forename: Huanli
authors.initials: H
authors.lastname: Xie
authors.forename: Robert G
authors.initials: RG
authors.lastname: Tsushima
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Diamant
mesh_terms: D000818:Animals; D002415:Cats; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051663:Kv1.2 Potassium Channel / Q000502:physiology*; D008297:Male; D051938:Munc18 Proteins / Q000096:biosynthesis; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D011487:Protein Conformation; D051381:Rats; D050827:Syntaxin 1 / Q000494:pharmacology*
chemical_list: D051663:Kv1.2 Potassium Channel; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D050827:Syntaxin 1; C103912:Unc13a protein, rat