Mechanism of cloned ATP-sensitive potassium channel activation by oleoyl-CoA

Insulin secretion from pancreatic beta cells is coupled to cell metabolism through closure of ATP-sensitive potassium (K-ATP,) channels, which comprise Kir6.2 and sulfonylurea receptor (SUR1) subunits. Although metabolic regulation of K-ATP, channel activity is believed to be mediated principally by the adenine nucleotides, other metabolic intermediates, 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 channels in the absence of SUR1), Oleoyl-CoA (1 mu M) activated both wild-type 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 subunit Kir1.1a. Oleoyl-CoA also impaired channel inhibition by ATP, increasing the K-i values for both Kir6.2/SUR1 and Kir6.2 Delta C36 currents 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 subunit, unlike the stimulatory effects of MgADP and diazoxide which are mediated through SUR1. The increased activity and reduced ATP sensitivity of K-ATP, channels by oleoyl-CoA might contribute to the impaired insulin secretion observed in non-insulin-dependent diabetes mellitus.