Hybrid assemblies of ATP-sensitive K+ channels determine their muscle-type-dependent biophysical and pharmacological properties.
ATP-sensitive K(+) channels (K(ATP)) are an octameric complex of inwardly rectifying K(+) channels (Kir6.1 and Kir6.2) and sulfonylurea receptors (SUR1 and SUR2A/B), which are involved in several diseases. The tissue-selective expression of the subunits leads to different channels; however, the composition and role of the functional channel in native muscle fibers is not known. In this article, the properties of K(ATP) channels of fast-twitch and slow-twitch muscles were compared by combining patch-clamp experiments with measurements of gene expression. We found that the density of K(ATP) currents/area was muscle-type specific, being higher in fast-twitch muscles compared with the slow-twitch muscle. The density of K(ATP) currents/area was correlated with the level of Kir6.2 expression. SUR2A was the most abundant subunit expressed in all muscles, whereas the vascular SUR2B subunit was expressed but at lower levels. A significant expression of the pancreatic SUR1 was also found in fast-twitch muscles. Pharmacological experiments showed that the channel response to the SUR1 agonist diazoxide, SUR2A/B agonist cromakalim, SUR1 antagonist tolbutamide, and the SUR1/SUR2A/B-antagonist glibenclamide matched the SURs expression pattern. Muscle-specific K(ATP) subunit compositions contribute to the physiological performance of different muscle fiber types and determine the pharmacological actions of drugs modulating K(ATP) activity in muscle diseases.
Tricarico
Domenico
D
Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona no. 4, 70120 Bari, Italy.
Mele
Antonietta
A
Lundquist
Andrew L
AL
Desai
Reshma R
RR
George
Alfred L
AL
Conte Camerino
Diana
D
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001703:Biophysics / Q000379:methods*; D019806:Cromakalim / Q000378:metabolism / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels; D007700:Kinetics; D008297:Male; D015233:Models, Statistical; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011188:Potassium / Q000737:chemistry / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D019806:Cromakalim; D017931:DNA Primers; D003981:Diazoxide; D005905:Glyburide; D007004:Hypoglycemic Agents; D054086:KATP Channels; D011188:Potassium; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat; C092520:uK-ATP-1 potassium channel