A conserved inhibitory and differential stimulatory action of nucleotides on K(IR)6.0/SUR complexes is essential for excitation-metabolism coupling by K(ATP) channels.
The mechanism by which ubiquitous adenine nucleotide-gated K(IR)6.0(4)/SUR(4) channels link membrane excitability with cellular metabolism is controversial. Is a decreased sensitivity to inhibitory ATP required, or is the Mg-ADP/ATP-dependent stimulatory action of the ATPase, sulfonylurea receptor (SUR), on K(IR) sufficient to elicit a physiologically significant open channel probability? To evaluate the roles of nucleotide inhibition versus stimulation, we compared K(IR)6.1-based K(NDP) channels with K(IR)6.2-based K(ATP) channels and all possible K(IR)6.1/6.2 hybrids. Although K(NDP) channels are thought to be poorly sensitive to inhibitory ATP and to require Mg-nucleotide diphosphates for activity, we demonstrate that, like K(ATP), and hybrid channels, they are inhibited with an IC(50(ATP)) 100-fold lower than [ATP](i). K(IR)6.1 is, however, more efficiently stimulated by SUR than K(IR)6.2, thus providing a mechanism for differential nucleotide regulation, in addition to the known differential interactions of Mg-nucleotides with SUR isoforms. The on-cell and spontaneous activities of K(NDP), K(ATP), and hybrid channels identified in native cells, are different; thus, their similar IC(50(ATP)) values argue the regulatory "beta" SUR subunits play a preeminent role in coupling excitation to metabolism and pose questions about the physiologic significance of models, which assume the ATP insensitivity of open K(IR)s.
Babenko
A P
AP
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ababenko@bcm.tmc.edu
Bryan
J
J
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D006321:Heart / Q000187:drug effects; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D014475:Uncoupling Agents / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000378:metabolism
D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D014530:Uridine Diphosphate; D000255:Adenosine Triphosphate; D008274:Magnesium