Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic β-cell-type KATP channels

A novel antidiabetic agent, nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of nateglinide on recombinant ATP-sensitive K+ (K-ATP) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K-i = 75 nM and 114 muM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K-i = 105 and 111 muM, respectively). Nateglinide inhibited the KATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K-i = 290 muM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1( S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide. MgADP or MgUDP (100 muM) augmented the inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1( S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2( K185Q) channel, which was not inhibited by MgADP, but not with the SUR1( K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of nateglinide (similar to10 muM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.