The SNARE protein syntaxin 1A (Syn1A) is known to inhibit delayed rectifier K+ channels of the K(v)1 and K(v)2 families with heterogeneous effects on their gating properties. In this study, we explored whether Syn1A could directly modulate K(v)4.3, a rapidly inactivating K-v channel with important roles in neuroendocrine cells and cardiac myocytes. Immunoprecipitation studies in HEK293 cells coexpressing Syn1A and K(v)4.3 revealed a direct interaction with increased trafficking to the plasma membrane without a change in channel synthesis. Paradoxically, Syn1A inhibited K(v)4.3 current density. In particular, Syn1A produced a left-shift in steady-state inactivation of K(v)4.3 without affecting either voltage dependence of activation or gating kinetics, a pattern distinct from other K-v channels. Combined with our previous reports, our results further verify the notion that the mechanisms involved in Syn1A-K-v interactions vary significantly between K-v channels, thus providing a wide scope for Syn1A modulation of exocytosis and membrane excitability. (c) 2007 Elsevier Inc. All rights reserved.