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The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation.: FHM-1 mutations promote G-protein deinhibition of Cav2.1 channels

Abstract : Familial hemiplegic migraine type 1 (FHM-1) is caused by mutations in CACNA1A, the gene encoding for the Ca(v)2.1 subunit of voltage-gated calcium channels. Although various studies attempted to determine biophysical consequences of these mutations on channel activity, it remains unclear exactly how mutations can produce a FHM-1 phenotype. A lower activation threshold of mutated channels resulting in increased channel activity has been proposed. However, hyperactivity may also be caused by a reduction of the inhibitory pathway carried by G-protein-coupled-receptor activation. The aim of this study is to determine functional consequences of the FHM-1 S218L mutation on direct G-protein regulation of Ca(v)2.1 channels. In HEK 293 cells, DAMGO activation of human mu-opioid receptors induced a 55% Ba(2+) current inhibition through both wild-type and S218L mutant Ca(v)2.1 channels. In contrast, this mutation considerably accelerates the kinetic of current deinhibition following channel activation by 1.7- to 2.3-fold depending on membrane potential values. Taken together, these data suggest that the S218L mutation does not affect G-protein association onto the channel in the closed state but promotes its dissociation from the activated channel, thereby decreasing the inhibitory G-protein pathway. Similar results were obtained with the R192Q FHM-1 mutation, although of lesser amplitude, which seems in line with the less severe associated clinical phenotype in patients. Functional consequences of FHM-1 mutations appear thus as the consequence of the alteration of both intrinsic biophysical properties and of the main inhibitory G-protein pathway of Ca(v)2.1 channels. The present study furthers molecular insight in the physiopathology of FHM-1.
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https://www.hal.inserm.fr/inserm-00376518
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Submitted on : Thursday, October 29, 2009 - 7:00:02 AM
Last modification on : Friday, November 6, 2020 - 3:46:13 AM
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Norbert Weiss, Alejandro Sandoval, Ricardo Felix, Arn van den Maagdenberg, Michel de Waard. The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation.: FHM-1 mutations promote G-protein deinhibition of Cav2.1 channels. Pflügers Archiv European Journal of Physiology, Springer Verlag, 2008, 457 (2), pp.315-26. ⟨10.1007/s00424-008-0541-2⟩. ⟨inserm-00376518⟩

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