MECHANISM OF CLONED ATP-SENSITIVE POTASSIUM CHANNEL ACTIVATION BY OLEOYL-COA

Insulin secretion from pancreatic beta cells is coupled to cell metabo lism through closure of ATP-sensitive potassium (K-ATP,) channels, whi ch comprise Kir6.2 and sulfonylurea receptor (SUR1) subunits. Although metabolic regulation of K-ATP, channel activity is believed to be med iated principally by the adenine nucleotides, other metabolic intermed iates, including long chain acyl-CoA esters, may also be involved. We recorded macroscopic and single-channel currents from Xenopus oocytes expressing either Kir6.2/SUR1 or Kir6.2 Delta C36 (which forms channel s in the absence of SUR1), Oleoyl-CoA (1 mu M) activated both wild-typ e Kir6.2/SUR1 and Kir6.2 Delta C36 macroscopic currents, similar to 2- fold, by increasing the number and open probability of Kir6.2/SUR1 and Kir6.2 Delta C36 channels. It was ineffective on the related Kir subu nit Kir1.1a. Oleoyl-CoA also impaired channel inhibition by ATP, incre asing the K-i values for both Kir6.2/SUR1 and Kir6.2 Delta C36 current s by similar to 3-fold. Our results indicate that activation of K-ATP channels by oleoyl-CoA results from an interaction with the Kir6.2 sub unit, unlike the stimulatory effects of MgADP and diazoxide which are mediated through SUR1. The increased activity and reduced ATP sensitiv ity of K-ATP, channels by oleoyl-CoA might contribute to the impaired insulin secretion observed in non-insulin-dependent diabetes mellitus.