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Title page for ETD etd-03112010-001429


Type of Document Dissertation
Author Abiria, Sunday
Author's Email Address sunday.abiria@vanderbilt.edu
URN etd-03112010-001429
Title Ca2+/Calmodulin-dependent Protein Kinase II Anchoring to L-type Ca2+ Channels by the Beta Subunits Enhances Regulatory Phosphorylation at Thr498
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Kevin P.M. Currie Committee Chair
Hassane Mchaourab Committee Member
Louis J. DeFelice Committee Member
Roger J.Colbran Committee Member
Keywords
  • Calcium
  • Channel
  • Phosphorylation
  • Beta
  • CaMKII
Date of Defense 2009-11-03
Availability unrestricted
Abstract
Calcium/calmodulin-dependent kinase II (CaMKII) facilitates L-type calcium channel (LTCC) activity physiologically, but may exacerbate LTCC-dependent pathophysiology. We previously showed that CaMKII forms stable complexes with voltage-gated calcium channel (VGCC) β1b or β2a subunits, but not with the β3 or β4 subunits (Grueter et al. 2008). CaMKII-dependent facilitation of CaV1.2 LTCCs requires Thr498 phosphorylation in the β2a subunit (Grueter et al. 2006), but the relationship of this modulation to CaMKII interactions with LTCC subunits is unknown. Here we show that CaMKII co-immunoprecipitates with forebrain LTCCs that contain CaV1.2α1 and β1 or β2 subunits, but is not detected in LTCC complexes containing β4 subunits. CaMKIIα can be specifically tethered to the I/II linker of CaV1.2 α1 subunits in vitro by the β1b or β2a subunits. Efficient targeting of CaMKIIα to the full-length CaV1.2α1 subunit in transfected HEK293 cells requires CaMKII binding to the β2a subunit. Moreover, disruption of CaMKII binding substantially reduced phosphorylation of β2a at Thr498 within the LTCC complex, without altering overall phosphorylation of CaV1.2α1 and β subunits. These findings demonstrate a biochemical mechanism underlying LTCC facilitation by CaMKII.
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