ArticlePflugers Archiv : European journal of physiology2008
The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation.
Article in Pflugers Archiv : European journal of physiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 49 citations in OpenAlex.
- Hemiplegic migraine: genetics and pathophysiology.The Journal of clinical investigation · 2026Review
- Pathophysiology of homocysteine: insights into ion channel dysfunction.Pflugers Archiv : European journal of physiology · 2026Review
- The complexities of CACNA1A in clinical neurogenetics.Journal of neurology · 2022Article
- Opioid Receptor Regulation of Neuronal Voltage-Gated Calcium Channels.Cellular and molecular neurobiology · 2021Review
- Migraine: Calcium Channels and Glia.International journal of molecular sciences · 2021Review
- Rare CACNA1A mutations leading to congenital ataxia.Pflugers Archiv : European journal of physiology · 2020Review
- Genetics of migraine aura: an update.The journal of headache and pain · 2020Review
- Zebrafish as a Model System for the Study of Severe CaFrontiers in molecular neuroscience · 2019Review
- Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.PLoS genetics · 2017Article
- Calcium channels and synaptic transmission in familial hemiplegic migraine type 1 animal models.Biophysical reviews · 2014Review
- Article
- Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies.Molecular genetics & genomic medicine · 2013Article
- Surface expression and function of Cav3.2 T-type calcium channels are controlled by asparagine-linked glycosylation.Pflugers Archiv : European journal of physiology · 2013Article
- Regulation of Ca(V)2 calcium channels by G protein coupled receptors.Biochimica et biophysica acta · 2013Review
- Article
- A Ca(v)3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis.The Journal of biological chemistry · 2012Article
- Rim1 modulates direct G-protein regulation of Ca(v)2.2 channels.Pflugers Archiv : European journal of physiology · 2011Article
- Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential.Journal of neurophysiology · 2010Article
- CaV2.1 channelopathies.Pflugers Archiv : European journal of physiology · 2010Review
- Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine.The Journal of physiology · 2010Review
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Authors and funding
5 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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