PT - JOURNAL ARTICLE AU - Motohiko Chachin AU - Mitsuhiko Yamada AU - Akikazu Fujita AU - Tetsuro Matsuoka AU - Kenji Matsushita AU - Yoshihisa Kurachi TI - Nateglinide, a <span class="sc">d</span>-Phenylalanine Derivative Lacking Either a Sulfonylurea or Benzamido Moiety, Specifically Inhibits Pancreatic β-Cell-Type K<sub>ATP</sub> Channels AID - 10.1124/jpet.102.044917 DP - 2003 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1025--1032 VI - 304 IP - 3 4099 - http://jpet.aspetjournals.org/content/304/3/1025.short 4100 - http://jpet.aspetjournals.org/content/304/3/1025.full SO - J Pharmacol Exp Ther2003 Mar 01; 304 AB - A novel antidiabetic agent, nateglinide, is ad-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+(KATP) 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 (Ki = 75 nM and 114 μM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (Ki = 105 and 111 μM, respectively). Nateglinide inhibited the KATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (Ki = 290 μM) 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 μM) 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 (∼10 μM) 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. The American Society for Pharmacology and Experimental Therapeutics