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 slowtwitch 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.