ELECTROPHYSIOLOGICAL PROPERTIES OF THE HYPOKALEMIC PERIODIC PARALYSISMUTATION (R528H) OF THE SKELETAL-MUSCLE ALPHA(1S) SUBUNIT AS EXPRESSED IN MOUSE L-CELLS

Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant musc le disease which has been linked to point mutations in the skeletal mu scle L-type calcium channel al subunit (alpha(1S)). Here,,ve have intr oduced 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+ channel s. Corresponding whole-cell Ba2+ currents exhibit very slow activation and inactivation kinetics, typical for recombinant skeletal Ca2+ chan nel currents. Voltage-dependent activation and inactivation properties were similar for alpha(1S)-and alpha(1S-R528H), as well as their sens itivity to the dihydropyridine agonist Bay K 8644. Differences in alph a(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 resu lts in minor differences in the electrophysiological properties but si gnificantly reduces the whole-cell Ca channel current in its amplitude .