The molecular basis of the specificity of action of K-ATP channel openers

K-ATP channels incorporate a regulatory subunit of the ATP-binding cassette (ABC) transporter family, the sulfonylurea receptor (SUR), which defines t heir pharmacology, The therapeutically important K+ channel openers (e.g. p inacidil, cromakalim, nicorandil) act specifically on the SUR2 muscle isofo rms but, except for diazoxide, remain ineffective on the SUR1 neuronal/panc reatic isoform. This SUR1/2 dichotomy underpinned a chimeric strategy desig ned to identify the structural determinants of opener action, which led to a minimal set of two residues within the last transmembrane helix of SUR, T ransfer of either residue from SUR2A to SUR1 conferred opener sensitivity t o SUR1, while the reverse operation abolished SUR2A sensitivity. It is ther efore likely that these residues form part of the site of interaction of op eners with the channel. Thus, openers would target a region that, in other ABC transporters, is known to be tightly involved with the binding of subst rates and other ligands, This first glimpse of the site of action of pharma cological openers should permit rapid progress towards understanding the st ructural determinants of their affinity and specificity.