HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 546/2/337    most recent 2002.026716v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Melliti, K. Articles by Seabrook, G. R. Search for Related Content PubMed PubMed Citation Articles by Melliti, K. Articles by Seabrook, G. R.

The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca_V2.1) calcium channels expressed in human embryonic kidney cells

Karim Melliti, Manfred Grabner* and Guy R. Seabrook

Familial hemiplegic migraine is associated with at least 13 different missense mutations in the 1A Ca²⁺ channel subunit. Some of these mutations have been shown to affect the biophysical properties of 1A 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 (~1 s), pertussis toxin-sensitive inhibition of 1A_WT and 1A_R192Q Ca²⁺ currents, consistent with the activation of a membrane-delimited pathway. 1A_WT Ca²⁺ currents were inhibited by 62.9 ± 0.9 % (n = 27), whereas 1A_R192Q Ca²⁺ 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 (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 G 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.

This article has been cited by other articles:

				C. F. Barrett, Y.-Q. Cao, and R. W. Tsien Gating Deficiency in a Familial Hemiplegic Migraine Type 1 Mutant P/Q-type Calcium Channel J. Biol. Chem., June 24, 2005; 280(25): 24064 - 24071. [Abstract] [Full Text] [PDF]

				Y.-Q. Cao and R. W. Tsien Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission PNAS, February 15, 2005; 102(7): 2590 - 2595. [Abstract] [Full Text] [PDF]

				H. Khosravani, C. Altier, B. Simms, K. S. Hamming, T. P. Snutch, J. Mezeyova, J. E. McRory, and G. W. Zamponi Gating Effects of Mutations in the Cav3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy J. Biol. Chem., March 12, 2004; 279(11): 9681 - 9684. [Abstract] [Full Text] [PDF]