CaMKII associates with CaV1.2 L-type calcium channels via selected beta subunits to enhance regulatory phosphorylation.
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) beta(1b) or beta(2a) subunits, but not with the beta(3) or beta(4) subunits (Grueter et al. 2008). CaMKII-dependent facilitation of Ca(V)1.2 LTCCs requires Thr498 phosphorylation in the beta(2a) 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 Ca(V)1.2alpha(1) and beta(1) or beta(2) subunits, but is not detected in LTCC complexes containing beta(4) subunits. CaMKIIalpha can be specifically tethered to the I/II linker of Ca(V)1.2 alpha(1) subunits in vitro by the beta(1b) or beta(2a) subunits. Efficient targeting of CaMKIIalpha to the full-length Ca(V)1.2alpha(1) subunit in transfected HEK293 cells requires CaMKII binding to the beta(2a) subunit. Moreover, disruption of CaMKII binding substantially reduced phosphorylation of beta(2a) at Thr498 within the LTCC complex, without altering overall phosphorylation of Ca(V)1.2alpha(1) and beta subunits. These findings demonstrate a biochemical mechanism underlying LTCC facilitation by CaMKII.
Abiria
Sunday A
SA
Brain Institute, Vanderbilt University, Nashville, Tennessee, USA.
Colbran
Roger J
RJ
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000502:physiology; D016548:Prosencephalon / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D021122:Protein Subunits; C493217:calcium channel, l type beta2c subunit, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2