title: Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism.
abstract: The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa2+-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, but not with l-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of l-3,4-dihydroxyphenylalanine (L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Universita di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Daniela
authors.initials: D
authors.lastname: Mauceri
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007980:Levodopa; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C501449:Dlg4 protein, rat; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C085903:autocamtide-2; C033652:postsynaptic density proteins; C072105:KN 93; D000096926:Benzenesulfonamides