Received for publication September 26, 2002.
Revised October 24, 2002.
Accepted for publication November 1, 2002.

Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic -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 effects of nateglinide on recombinant ATP-sensitive K⁺ (K_ATP) channels expressed in HEK293T cells. The cells were transfected with Kir6.2 subunits, and either sulfonylurea receptor (SUR) 1, SUR2A or 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 nmol/L and 114 µmol/L) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low-affinity (Ki = 105 and 111 µmol/L, respectively). Nateglinide inhibited the K_ATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with the low affinity (Ki = 290 µmol/L) 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. Nateglinide more strongly inhibited SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels in the presence than absence of MgADP or MgUDP (100 µmol/L). MgADP also enhanced the inhibitory effect of nateglinide on SUR1/Kir6.2(K185Q) channels, which were not inhibited by MgADP. MgADP, however, did not do so for the SUR1(K1384A) /Kir6.2 channels, which were not activated by MgADP. These results indicate that therapeutic concentrations of nateglinide (10 µmol/L) may selectively inhibit pancreatic -cell 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.

Key words: ATP-sensitive potassium channel, antidiabetic agent, inwardly rectifying potassium channel, nateglinide, pancreatic beta cell, sulfonylurea receptor

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