| Title: |
The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation. ; 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 |
| Authors: |
Weiss, Norbert; Sandoval, Alejandro; Felix, Ricardo; van den Maagdenberg, Arn; de Waard, Michel |
| Contributors: |
Grenoble Institut des Neurosciences (GIN); Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM); Department of Cell Biology; Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN); School of Medicine FES Istacala; Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM); Department of Human Genetics; Leiden University Medical Center Leiden (LUMC); Universiteit Leiden = Leiden University-Universiteit Leiden = Leiden University; Department of Neurology; EU project EUROHEAD (LSHM-CT-2004–504837, Inserm; Collaboration |
| Source: |
ISSN: 0031-6768. |
| Publisher Information: |
CCSD; Springer Verlag |
| Publication Year: |
2008 |
| Collection: |
Université Grenoble Alpes: HAL |
| Subject Terms: |
β-subunit; μ-opioid receptor; G-protein coupled receptor; G-protein; P/Q current; Cav2.1 subunit; Cav2.1 type calcium channel; R192Q mutation; S218L mutation; Familial hemiplegic migraine; MESH: Animals; MESH: Calcium Channels; MESH: Membrane Potentials; MESH: Migraine with Aura; MESH: Mutation; MESH: Phenotype; MESH: Rats; MESH: Receptors; Opioid; mu; MESH: Transfection; N-Type; MESH: Cell Line; MESH: Enkephalin; Ala(2)-MePhe(4)-Gly(5)-; MESH: GTP-Binding Protein alpha Subunits; Gi-Go; MESH: Genotype; MESH: Humans; MESH: Ion Channel Gating |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/18581134; PUBMED: 18581134 |
| DOI: |
10.1007/s00424-008-0541-2 |
| Availability: |
https://inserm.hal.science/inserm-00376518; https://inserm.hal.science/inserm-00376518v1/document; https://inserm.hal.science/inserm-00376518v1/file/inserm-00376518_edited.pdf; https://inserm.hal.science/inserm-00376518v1/file/Weiss_Manuscript_Final.pdf; https://doi.org/10.1007/s00424-008-0541-2 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.FAC4654B |
| Database: |
BASE |