RGD Reference Report - The guanylate kinase domain of the beta-subunit of voltage-gated calcium channels suffices to modulate gating. - Rat Genome Database

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The guanylate kinase domain of the beta-subunit of voltage-gated calcium channels suffices to modulate gating.

Authors: Gonzalez-Gutierrez, Giovanni  Miranda-Laferte, Erick  Nothmann, Doreen  Schmidt, Silke  Neely, Alan  Hidalgo, Patricia 
Citation: Gonzalez-Gutierrez G, etal., Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14198-203. doi: 10.1073/pnas.0806558105. Epub 2008 Sep 5.
RGD ID: 13432277
Pubmed: PMID:18776052   (View Abstract at PubMed)
PMCID: PMC2544601   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0806558105   (Journal Full-text)

Inactivation of voltage-gated calcium channels is crucial for the spatiotemporal coordination of calcium signals and prevention of toxic calcium buildup. Only one member of the highly conserved family of calcium channel beta-subunits--Ca(V)beta--inhibits inactivation. This unique property has been attributed to short variable regions of the protein; however, here we report that this inhibition actually is conferred by a conserved guanylate kinase (GK) domain and, moreover, that this domain alone recapitulates Ca(V)beta-mediated modulation of channel activation. We expressed and refolded the GK domain of Ca(V)beta(2a), the unique variant that inhibits inactivation, and of Ca(V)beta(1b), an isoform that facilitates it. The refolded domains of both Ca(V)beta variants were found to inhibit inactivation of Ca(V)2.3 channels expressed in Xenopus laevis oocytes. These findings suggest that the GK domain endows calcium channels with a brake restraining voltage-dependent inactivation, and thus facilitation of inactivation by full-length Ca(V)beta requires additional structural determinants to antagonize the GK effect. We found that Ca(V)beta can switch the inactivation phenotype conferred to Ca(V)2.3 from slow to fast after posttranslational modifications during channel biogenesis. Our findings provide a framework within which to understand the modulation of inactivation and a new functional map of Ca(V)beta in which the GK domain regulates channel gating and the other conserved domain (Src homology 3) may couple calcium channels to other signaling pathways.



Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cacnb1Ratidentical protein binding enablesIPIUniProtKB:P54283PMID:18776052IntAct 
Cacnb2Ratidentical protein binding enablesIPIUniProtKB:Q8VGC3-2PMID:18776052IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Cacnb1  (calcium voltage-gated channel auxiliary subunit beta 1)
Cacnb2  (calcium voltage-gated channel auxiliary subunit beta 2)


Additional Information