Hybrid assemblies of ATP-sensitive K+ channels determine their muscle-type-dependent biophysical and pharmacological properties

ATP-sensitive K channels (KATP) are an octameric complex of inwardly rectifying K channels (Kir6.1 and Kir6.2) and sulfonylurea receptors (SUR1 and SUR2AB), 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 KATP channels of fast-twitch and slowtwitch muscles were compared by combining patch-clamp experiments with measurements of gene expression. We found that the density of KATP currentsarea was muscle-type specific, being higher in fast-twitch muscles compared with the slow-twitch muscle. The density of KATP currentsarea 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, SUR2AB agonist cromakalim, SUR1 antagonist tolbutamide, and the SUR1SUR2A/B-antagonist glibenclamide matched the SURs expression pattern. Muscle-specific KATP subunit compositions contribute to the physiological performance of different muscle fiber types and determine the pharmacological actions of drugs modulating KATP activity in muscle diseases.