Received for publication October 27, 2004.
Revised December 20, 2004.
Accepted for publication December 22, 2004.

The size of a single residue of the sulfonylurea receptor dictates the effectiveness of K_ATP channel openers

Abstract

K_ATP channel openers are a diverse group of molecules able to activate ATP-sensitive K⁺ channels in a tissue-dependent manner by binding to the channel regulatory subunit, the sulfonylurea receptor (SUR), an ABC protein. Residues crucial to this action were previously identified in the last transmembrane (TM) helix of SUR, transmembrane helix 17. This study examined the residue at the most important position, 1253 in the muscle isoform SUR2A and the matching 1290 in the pancreatic/neuronal isoform SUR1 (rat numbering). At this position in either isoform, a threonine enables action of openers while a methionine prohibits it. Using single-point mutagenesis, we have examined the physicochemical basis of this phenomenon and discovered that it relied uniquely on side-chain volume and not on shape, polarity, or hydrogen-bonding capacity of the residue. Moreover, the aromatic nature of neighboring residues conserved in SUR1 and SUR2A was found necessary for SUR2A to sustain the wild-type levels of channel activation by the openers tested, the cromakalim analogue SR47063 and the pinacidil analogue P1075. These observations suggest that these residues can interact with openers via non-specific stacking interactions provided that access is not obstructed by the adjacent 1253/1290 residue. The smaller Thr1253 of SUR2A would permit activation while the bulky Met1290 of SUR1 would not. This hypothesis is discussed in the context of a simple molecular model of transmembrane helix 17.

Key words: Ion transporters (SERCA, Na/K ATPase, CFTR), MDR/p-Glycoprotein, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches, Structure/function/mechanism, Ischemia/Reperfusion

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