title: Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels.
abstract: 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 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) 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 microM) 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 (approximately 10 microM) 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.
authors.affiliation: Department of Pharmacology II, Faculty of Medicine and Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Chachin
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Akikazu
authors.initials: A
authors.lastname: Fujita
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsushita
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate / Q000378:metabolism; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology*; D004594:Electrophysiology; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000737:chemistry
chemical_list: D018528:ATP-Binding Cassette Transporters; D003510:Cyclohexanes; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; C092520:uK-ATP-1 potassium channel; D000077715:Nateglinide; D010649:Phenylalanine; D000244:Adenosine Diphosphate