Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle alpha(1S) subunit as expressed in mouse L cells.

Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant muscle disease which has been linked to point mutations in the skeletal muscle L-type calcium channel al subunit (alpha(1S)). Here,,ve have introduced one of the point mutations causing HypoPP (R528H) into cDNA of the rabbit alpha(1S). Expression of either the wild-type alpha(1S) or the mutant R528H alpha(1S) (alpha(1S-R528H)) subunits was obtained in mouse Ltk(-) cells using a selectable expression vector. The alpha(1S-R528H) subunit led to the expression of functional L-type Ca2+ channels. Corresponding whole-cell Ba2+ currents exhibit very slow activation and inactivation kinetics, typical for recombinant skeletal Ca2+ channel currents. Voltage-dependent activation and inactivation properties were similar for alpha(1S)-and alpha(1S-R528H), as well as their sensitivity to the dihydropyridine agonist Bay K 8644. Differences in alpha(1S)-and alpha(1S-R528H)-directed channels reside in the Ba2+ current density, which was significantly reduced 3.2 fold in cells expressing alpha(1S-R528H). It was concluded that the R528H mutation of als results in minor differences in the electrophysiological properties but significantly reduces the whole-cell Ca channel current in its amplitude.