|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
2
|
|
pubmed:dateCreated |
2008-11-21
|
|
pubmed:abstractText |
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.
|
|
pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-10024348,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-10734061,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-11409427,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-11821897,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-12235360,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-12527722,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-14979299,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-15003170,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-15448138,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-15743764,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-16009433,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-16061523,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-16973229,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-16987552,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-17132857,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-17171365,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-17502463,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-4041774,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-7908596,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-8898206,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-9006977,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-9009193,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18581134-9488686
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CACNA1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cacna2d1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Cacnb4 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channels, N-Type,
http://linkedlifedata.com/resource/pubmed/chemical/Enkephalin, Ala(2)-MePhe(4)-Gly(5)-,
http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Protein alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Opioid, mu,
http://linkedlifedata.com/resource/pubmed/chemical/voltage-dependent calcium channel...
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Nov
|
|
pubmed:issn |
0031-6768
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:volume |
457
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
315-26
|
|
pubmed:dateRevised |
2010-9-21
|
|
pubmed:meshHeading |
pubmed-meshheading:18581134-Animals,
pubmed-meshheading:18581134-Calcium Channels,
pubmed-meshheading:18581134-Calcium Channels, N-Type,
pubmed-meshheading:18581134-Cell Line,
pubmed-meshheading:18581134-Enkephalin, Ala(2)-MePhe(4)-Gly(5)-,
pubmed-meshheading:18581134-GTP-Binding Protein alpha Subunits, Gi-Go,
pubmed-meshheading:18581134-Genotype,
pubmed-meshheading:18581134-Humans,
pubmed-meshheading:18581134-Ion Channel Gating,
pubmed-meshheading:18581134-Kinetics,
pubmed-meshheading:18581134-Membrane Potentials,
pubmed-meshheading:18581134-Migraine with Aura,
pubmed-meshheading:18581134-Mutation,
pubmed-meshheading:18581134-Phenotype,
pubmed-meshheading:18581134-Rats,
pubmed-meshheading:18581134-Receptors, Opioid, mu,
pubmed-meshheading:18581134-Transfection
|
|
pubmed:year |
2008
|
|
pubmed:articleTitle |
The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation.
|
|
pubmed:affiliation |
INSERM U836, Site Santé la Tronche, BP 170, 38042, Grenoble Cedex 9, France.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
