DIFFERENTIAL REGULATED INTERACTIONS OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II WITH ISOFORMS OF VOLTAGE GATED CALCIUM CHANNEL BETA SUBUNITS

Chad E Grueter; Sunday A Abiria; Yunji Wu; Mark E Anderson; Roger J Colbran

doi:10.1021/bi701755q

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DIFFERENTIAL REGULATED INTERACTIONS OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II WITH ISOFORMS OF VOLTAGE GATED CALCIUM CHANNEL BETA SUBUNITS

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DIFFERENTIAL REGULATED INTERACTIONS OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II WITH ISOFORMS OF VOLTAGE GATED CALCIUM CHANNEL BETA SUBUNITS

Chad E Grueter, Sunday A Abiria, Yunji Wu, Mark E Anderson and Roger J Colbran

Biochemistry (Easton), Vol.47(6), pp.1760-1767

02/12/2008

DOI: 10.1021/bi701755q

PMCID: PMC2814322

PMID: 18205403

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Abstract

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) phosphorylates the β 2a subunit of voltage-gated Ca 2+ channels at Thr498 to facilitate cardiac L-type Ca 2+ channels. CaMKII colocalizes with β 2a in cardiomyocytes and also binds to a domain in β 2a that contains Thr498 and exhibits amino acid sequence similarity to the CaMKII autoinhibitory domain and to a CaMKII binding domain in the NMDA receptor NR2B subunit (Grueter et al., 2006. Mol. Cell 23 :641). Here we explore the selectivity of the actions of CaMKII among Ca 2+ channel β subunit isoforms. CaMKII phosphorylates the β 1b , β 2a , β 3 and β 4 isoforms with similar initial rates and final stoichiometries of 6–12 mole phosphate per mole protein. However, activated/autophosphorylated CaMKII binds to β 1b and β 2a with similar apparent affinity, but does not bind to β 3 or β 4 . Pre-phosphorylation of β 1b and β 2a by CaMKII substantially reduces the binding of autophosphorylated CaMKII. Residues surrounding Thr498 in β 2a are highly conserved in β 1b , but are different in β 3 and β 4 . Site-directed mutagenesis of this domain in β 2a showed that Thr498 phosphorylation promotes dissociation of CaMKII-β 2a complexes in vitro and reduces interactions of CaMKII with β 2a in cells. Mutagenesis of Leu493 to Ala substantially reduces CaMKII binding in vitro and in intact cells but does not interfere with β 2a phosphorylation at Thr498. In combination, these data show that phosphorylation dynamically regulates the interactions of specific isoforms of the VGCC β subunits with CaMKII.

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Title: Subtitle: DIFFERENTIAL REGULATED INTERACTIONS OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II WITH ISOFORMS OF VOLTAGE GATED CALCIUM CHANNEL BETA SUBUNITS
Creators: Chad E Grueter - Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Sunday A Abiria - Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Yunji Wu - Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Mark E Anderson - Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Roger J Colbran - Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Resource Type: Journal article
Publication Details: Biochemistry (Easton), Vol.47(6), pp.1760-1767
DOI: 10.1021/bi701755q
PMID: 18205403
PMCID: PMC2814322
NLM abbreviation: Biochemistry
ISSN: 0006-2960
eISSN: 1520-4995
Language: English
Date published: 02/12/2008
Academic Unit: Cardiovascular Medicine; Craniofacial Anomalies Research Center; Internal Medicine
Record Identifier: 9984094316802771

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