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

Abstract

The pancreatic ATP-sensitive potassium (K(ATP)) channel consisting of four inwardly rectifying potassium channel 6.2 (Kir6.2) and four sulfonylurea receptor SUR1 subunits plays a key role in insulin secretion by linking glucose metabolism to membrane excitability. Syntaxin 1A (Syn-1A) is a plasma membrane protein important for membrane fusion during exocytosis of insulin granules. Here, we show that Syn-1A and K(ATP) channels endogenously expressed in the insulin-secreting cell INS-1 interact. Upregulation of Syn-1A by overexpression in INS-1 leads to a decrease, whereas downregulation of Syn-1A by small interfering RNA (siRNA) leads to an increase, in surface expression of K(ATP) channels. Using COSm6 cells as a heterologous expression system for mechanistic investigation, we found that Syn-1A interacts with SUR1 but not Kir6.2. Furthermore, Syn-1A decreases surface expression of K(ATP) channels via two mechanisms. One mechanism involves accelerated endocytosis of surface channels. The other involves decreased biogenesis and processing of channels in the early secretory pathway. This regulation is K(ATP) channel specific as Syn-1A has no effect on another inward rectifier potassium channel Kir3.1/3.4. Our results demonstrate that in addition to a previously documented role in modulating K(ATP) channel gating, Syn-1A also regulates K(ATP) channel expression in β-cells. We propose that physiological or pathological changes in Syn-1A expression may modulate insulin secretion by altering glucose-secretion coupling via changes in K(ATP) channel expression.

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…It was suggested that the lower expression of K ATP channels at the membrane is caused by an accelerated endocytosis and a decreased biogenesis, as well as altered traffic to the membrane of these channels. The authors even proposed that physiologic and pathologic changes in Syn-1A expression may control the K ATP channel expression, thus modulating insulin secretion (Chen et al, 2011).…”

Carbamazepine as a Novel Small Molecule Corrector of Trafficking-impaired ATP-sensitive Potassium Channels Identified in Congenital Hyperinsulinism

“…The beads were washed three times with lysis buffer, and proteins were eluted by incubation with SDS sample buffer. Eluted proteins were separated by SDS-PAGE, and SUR1 was detected with an anti-SUR1 antibody as described previously (49).…”

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

“…K ATP channel activity is suppressed by a SNARE protein, syntaxin 1A, via protein-protein interactions with the SUR subunits [72][73][74][75] . Syntaxin 1A decreases the activity [76] and the membrane expression level of K ATP channels [77] . Syntaxin 1A binding to the SUR1 subunit also attenuates the effect of K + channel openers, such as diazoxide, NNC55-0462, P1075, and cromakalim [78,79] .…”