Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 37, Pages 14198-14203Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806558105
Keywords
auxiliary subunit; modular structure; regulation
Categories
Funding
- Deutsche Forschung Gemeinschaft [FOR 450]
- Anillo de Ciencia y Tecnologia [ACT-46]
- German-Chilean Scientific Cooperation Program [DFG-CONICYT]
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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 Cav2.3 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.
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