Syntaxin 1 A regulates surface expression of β - cell ATP - sensitive 1 potassium channels

26 The pancreatic ATP-sensitive potassium (KATP) channel consisting of four Kir6.2 and 27 four sulfonylurea receptor SUR1 subunits play a key role in insulin secretion by 28 linking glucose metabolism to membrane excitability. Syntaxin 1A is a plasma 29 membrane protein important for membrane fusion during exocytosis of insulin 30 granules. Here, we show that syntaxin 1A and KATP channels endogenously expressed 31 in the insulin-secreting cell INS-1 interact. Up-regulation of syntaxin-1A by 32 overexpression in INS-1 leads to a decrease, whereas down-regulation of syntaxin 1A 33 by siRNA leads to an increase, in surface expression of KATP channels. Using COSm6 34 cells as a heterologous expression system for mechanistic investigation, we found that 35 syntaxin 1A interacts with SUR1 but not Kir6.2. Further, syntaxin 1A decreases 36 surface expression of KATP channels via two mechanisms. One involves accelerated 37 endocytosis of surface channels. The other involves decreased biogenesis and 38 processing of channels in the early secretory pathway. This regulation is KATP channel 39 specific as syntaxin 1A has no effect on another inward rectifier potassium channel, 40 Kir3.1/3.4. Our results demonstrate that in addition to a previously documented role 41 in modulating KATP channel gating, syntaxin 1A also regulates KATP channel 42 expression in β-cells. We propose that physiological or pathological changes in 43 syntaxin 1A expression may modulate insulin secretion by altering glucose-secretion 44 coupling via changes in KATP channel expression. 45