Evidence for a unique long chain acyl-CoA ester binding site on the ATP-regulated potassium channel in mouse pancreatic beta cells

The mechanism by which long chain acyl-CoA (LC-CoA) esters affect the ATP-regulated potassium channel (K-ATP channel) was studied in inside-out patches isolated from mouse pancreatic beta cells, Addition of LC-CoA esters dramatically increased K-ATP, channel activity. The stimulatory effect of the esters could be explained by the induction of a prolonged open state of the channel and did not involve alterations in single channel unitary conductance. Under central conditions, absence of adenine nucleotides, the distribution of K-ATP channel open time could be described by a single exponential, with a time constant of about 25 ms, Exposing the same patch to LC-CoA esters resulted in the appearance of an additional component with a time constant of >150 ms, indicating a conformational change of the channel protein, LC-CoA esters were also able to potently activate channel activity at different ratios of ATP/ADP. Simultaneous additions of MgADP and LC-CoA esters resulted in a supra-additive effect on channel mean open time, characterized by openings of very long duration. Following modification of the K-ATP channel by a short exposure of the patch rep the protease trypsin, the stimulatory effect of ADP oil channel activity was lost while activation by LC-CoA testers still persisted, This indicates that LC-CoA esters and MgADP do not bind to the same site, We conclude that LC-CoA esters may play an important role in the physiological regulation of the K-ATP channel in the pancreatic beta cell by binding to a unique site and thereby inducing repolarization of the beta cell-membrane potential.