title: Differential CaMKII regulation by voltage-gated calcium channels in the striatum.
abstract: Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major calcium-dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ~2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Pasek
authors.affiliation: Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, United States; Vanderbilt International Scholar Program, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, United States; Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, United States; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States. Electronic address: roger.colbran@vanderbilt.edu.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000378:metabolism; D015398:Signal Transduction; D013111:Spider Venoms / Q000494:pharmacology
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D011758:Pyrroles; D017470:Receptors, Glutamate; C115521:SNX 482; D013111:Spider Venoms; C071658:FPL 64176; D004533:Egtazic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
keywords: L-type calcium channels; Medium spiny neuron; Subcellular fractionation; Synaptic plasticity; T-type calcium channels