Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 546, Issue 2, Pages 337-347Publisher
WILEY
DOI: 10.1113/jphysiol.2002.026716
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Familial hemiplegic migraine is associated with at least 13 different missense mutations in the alpha1A Ca2+ channel subunit. Some of these mutations have been shown to affect the biophysical properties of alpha1A currents. To date, no study has examined the influence of such mutations on the G-protein regulation of channel function. Because G-proteins inhibit movement of the voltage sensor, we examined the effects of the R192Q mutation, which neutralizes a positive charge in the first S4 segment. Human wild-type (WT) or R192Q mutant channels were expressed in human embryonic kidney tsA-201 cells along with dopamine D2 receptors. Application of quinpirole induced fast (similar to1 s), pertussis toxin-sensitive inhibition of alpha1A(WT) and alpha1A(R192Q) Ca2+ currents, consistent with the activation of a membrane-delimited pathway. alpha1A(WT) Ca2+ currents were inhibited by 62.9 +/- 0.9 % (n = 27), whereas alpha1A(R192Q) Ca2+ currents were inhibited by only 47.9 +/- 1.8 % (n = 35; P < 0.00 1). Concentration-response analysis showed that only the extent of inhibition was affected, with no change in agonist potency (EC50 = 1 nm). Prepulse facilitation, which is a characteristic of voltage-dependent inhibition, was also reduced by the R192Q mutation. However, the kinetics of facilitation and slow activation were not affected, suggesting that G-protein-Ca2+ channel affinity was unchanged. These results show that the R192Q mutation reduces the G-protein inhibition of P/Q-type Ca2+ channels, probably by altering mechanisms by which Gbetagamma subunit binding induces a change in channel gating. Altered G-protein modulation and the consequent reduced presynaptic inhibition may contribute to migraine attacks by favouring a persistent state of hyperexcitability.
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