JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells.

Journal of Physiology 2003 January 16
Familial hemiplegic migraine is associated with at least 13 different missense mutations in the alpha1A Ca(2+) 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 (approximately 1 s), pertussis toxin-sensitive inhibition of alpha1A(WT) and alpha1A(R192Q) Ca(2+) currents, consistent with the activation of a membrane-delimited pathway. alpha1A(WT) Ca(2+) currents were inhibited by 62.9 +/- 0.9 % (n = 27), whereas alpha1A(R192Q) Ca(2+) currents were inhibited by only 47.9 +/- 1.8 % (n = 35; P < 0.001). Concentration-response analysis showed that only the extent of inhibition was affected, with no change in agonist potency (EC(50) = 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-Ca(2+) channel affinity was unchanged. These results show that the R192Q mutation reduces the G-protein inhibition of P/Q-type Ca(2+) 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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