1. Mutations in the gene encoding the alpha 1-subunit of the skeletal muscle dihydropyridine (DHP) receptor are responsible for familial hypokalaemic periodic paralysis (HypoPP), an autosomal dominant muscle disease. We investigated myotubes cultured from muscle of patients with arginine-to-histidine substitutions in putative voltage sensors, IIS4 (R528H) and IVS4 (R1239H), of the DHP receptor alpha 1-subunit. 2. Analysis of the messenger ribonucleic acid (mRNA) in the myotubes from such patients indicated transcription from both the normal and mutant genes. 3. In control myotubes, the existence of the slow L-type current and of two rapidly activating and inactivating calcium current components (T-type with a maximum at about -20 mV and 'third type' with a maximum at +10 to +20 mV) was confirmed. In the myotubes from patients with either mutation, the third-type current component was seen more frequently and, on average, with larger amplitude. 4. In myotubes with the IVS4 mutation (R1239H) the maximum L-type current density was smaller than control (-0.53 +/- 0.31 vs. -1.41 +/- 0.71 pA pF-1). The voltage dependence of activation was normal, and hyperpolarizing prepulses to -120 mV for 20 s did not increase the reduced current amplitude during test pulses. 5. In myotubes with the IIS4 mutation (R528H) the L-type current-voltage relation, determined at a holding potential of -90 mV, was normal. However, the voltage dependence of inactivation was shifted by about 40 mV to more negative potentials (voltage at half-maximum inactivation, V1/2 = -41.5 +/- 8.2 vs. -4.9 +/- 4.3 mV in normal controls).(ABSTRACT TRUNCATED AT 250 WORDS)