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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 25, 2002; DOI: 10.1124/jpet.102.044917

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Vol. 304, Issue 3, 1025-1032, March 2003

Nateglinide, a D-Phenylalanine Derivative Lacking Either a Sulfonylurea or Benzamido Moiety, Specifically Inhibits Pancreatic beta -Cell-Type KATP Channels

Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita and Yoshihisa Kurachi

Department of Pharmacology II, Faculty of Medicine and Graduate School of Medicine, Osaka University, Osaka, Japan (M.C., M.Y., T.M., K.M., Y.K.); and Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Science, Osaka Prefecture University. Osaka, Japan (A.F.)

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+ (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.

0022-3565/03/3043-1025$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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