Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channelsin patients with hypokalemic periodic paralysis

The adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel is the most a bundant K+ channel active in the skeletal muscle fibers of humans and anima ls. In the present work, we demonstrate the involvement of the muscular K-A TP channel in a skeletal muscle disorder known as hypokalemic periodic para lysis (HOPP), which is caused by mutations of the dihydropyridine receptor of the Ca2+ channel. Muscle biopsies excised from three patients with HOPP carrying the R528H mutation of the dihydropyridine receptor showed a reduce d sarcolemma K-ATP current that was not stimulated by magnesium adenosine d iphosphate (MgADP; 50-100 mu M) and was partially restored by cromakalim. I n contrast, large K-ATP currents stimulated by MgADP were recorded in the h ealthy subjects. At channel level, an abnormal K-ATP channel showing severa l subconductance states was detected in the patients with HOPP. None of the se were surveyed in the healthy subjects. Transitions of the K-ATP channel between subconductance states were also observed after in vitro incubation of the rat muscle with low-K+ solution. The lack of the sarcolemma K-ATP cu rrent observed in these patients explains the symptoms of the disease, i.e. , hypokalemia, depolarization of the fibers, and possibly the paralysis fol lowing insulin administration.