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Familial hemiplegic migraine type 1 mutations W1684R and V1696I alter G protein-mediated regulation of Ca(V)2.1 voltage-gated calcium channels.
Garza-López E., Sandoval A., González-Ramírez R., Gandini M. A., Van den Maagdenberg A., De Waard M., Felix R.
BBA - Biochimica et Biophysica Acta 1822, 8 (2012) 1238-46 - http://www.hal.inserm.fr/inserm-00757116
Familial hemiplegic migraine type 1 mutations W1684R and V1696I alter G protein-mediated regulation of Ca(V)2.1 voltage-gated calcium channels.
Edgar Garza-López1, Alejandro Sandoval2, Ricardo González-Ramírez3, María Gandini1, Arn Van den Maagdenberg4, Michel De Waard5, Ricardo Felix () 1
1 :  Department of Cell Biology
Avenida IPN #2508, Mexico City, CP 07300
2 :  School of Medicine FES Istacala
National Autonomous University of Mexico
3 :  Department of Molecular Biology and Histocompatibility
Dr. Manuel Gea González General Hospital
Calzada de Tlalpan 4800, Sección XVI, Tlalpan, 14080 Ciudad de México
4 :  Departments of Human Genetics & Neurology
Leiden University Medical Center (LUMC)
Albinusdreef 2, 2333 ZA Leiden
5 :  GIN - U836 - Grenoble Institut des Neurosciences
INSERM : U836 – Université Joseph Fourier - Grenoble I – CHU Grenoble – CEA : DSV/IRTSV
UJF - Site Santé La Tronche - BP 170 - 38042 Grenoble Cedex 9
INSERM U836, équipe 3, Canaux calciques, fonctions et pathologies
Familial hemiplegic migraine type 1 (FHM-1) is a monogenic form of migraine with aura that is characterized by recurrent attacks of a typical migraine headache with transient hemiparesis during the aura phase. In a subset of patients, additional symptoms such as epilepsy and cerebellar ataxia are part of the clinical phenotype. FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the pore-forming subunit of Ca(V)2.1 voltage-gated Ca(2+) channels. Although the functional effects of an increasing number of FHM-1 mutations have been characterized, knowledge on the influence of most of these mutations on G protein regulation of channel function is lacking. Here, we explored the effects of G protein-dependent modulation on mutations W1684R and V1696I which cause FHM-1 with and without cerebellar ataxia, respectively. Both mutations were introduced into the human Ca(V)2.1α(1) subunit and their functional consequences investigated after heterologous expression in human embryonic kidney 293 (HEK-293) cells using patch-clamp recordings. When co-expressed along with the human μ-opioid receptor, application of the agonist [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibited currents through both wild-type (WT) and mutant Ca(V)2.1 channels, which is consistent with the known modulation of these channels by G protein-coupled receptors. Prepulse facilitation, which is a way to characterize the relief of direct voltage-dependent G protein regulation, was reduced by both FHM-1 mutations. Moreover, the kinetic analysis of the onset and decay of facilitation showed that the W1684R and V1696I mutations affect the apparent dissociation and reassociation rates of the Gβγ dimer from the channel complex, suggesting that the G protein-Ca(2+) channel affinity may be altered by the mutations. These biophysical studies may shed new light on the pathophysiology underlying FHM-1.
Sciences du Vivant/Neurosciences
Sciences du Vivant/Biochimie, Biologie Moléculaire

Articles dans des revues avec comité de lecture
BBA - Biochimica et Biophysica Acta (Biochim Biophys Acta)
Publisher Elsevier
ISSN 0006-3002 

Conacyt (128707); PAPIIT (IN221011);
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