Key result
DHP receptor mutations in HypoPP myotubes altered calcium currents, reducing maximum L-type current density in R1239H (-0.53 vs -1.41 pA/pF) and shifting inactivation voltage in R528H.
Absolute Event Rate: -0.53% vs -1.41%
Mutations in the DHP receptor alpha 1-subunit associated with hypokalaemic periodic paralysis alter calcium currents in human myotubes, specifically reducing L-type current density or shifting voltage dependence of inactivation.
Patient myotube data suggest channel dysfunction in HypoPP; leaves open causal role in vivo and need for confirmatory models.
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)
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Sipos et al. (1995) studied Familial hypokalaemic periodic paralysis (HypoPP). DHP receptor alpha 1-subunit mutations (R528H and R1239H) vs. Normal control myotubes was evaluated on Maximum L-type current density (pA pF-1) for the IVS4 mutation (R1239H). DHP receptor mutations in HypoPP myotubes altered calcium currents, reducing maximum L-type current density in R1239H (-0.53 vs -1.41 pA/pF) and shifting inactivation voltage in R528H.
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