title: Interactions of CaMKII with dopamine D2 receptors: roles in levodopa-induced dyskinesia in 6-hydroxydopamine lesioned Parkinson's rats.
abstract: Ca(2+)/calmodulin-dependent protein kinase II is a synapse-enriched kinase in mammalian brains. This kinase interacts with various synaptic proteins to regulate expression and function of interacting proteins and thereby modulates synaptic transmission. CaMKII and its interacting partners are also believed to play a pivotal role in the pathogenesis of various neurological and neurodegenerative disorders, such as Parkinson's disease (PD). In this study, we found that CaMKIIα binds to dopamine D2 receptors (D2R) in vitro. A distal region in the D2R third intracellular loop harbors CaMKIIα binding. Endogenous CaMKIIα was also found to interact with native D2Rs in rat striatal neurons in which D2Rs are expressed at a high level. In addition, in a rat 6-hydroxydopamine lesioned model of PD, chronic levodopa administration induced characteristic dyskinesia. In parallel, levodopa induced an increase in CaMKIIα-D2R interactions in striatal neurons. Intrastriatal injection of a Tat-fusion and CaMKIIα-D2R interaction-dead peptide (Tat-D2Ri) reversed this increase in the interaction between two proteins. Tat-D2Ri also alleviated dyskinetic behaviors induced by levodopa. These results reveal a new interaction between CaMKIIα and D2Rs in striatal neurons which is sensitive to long-term administration of levodopa in PD rats. Prevention of the response of CaMKIIα-D2R interactions to levodopa can alleviate levodopa-induced dyskinesia.
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, Shanghai, China.
authors.forename: SuFang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, Shanghai, China.
authors.forename: ChengLong
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, Shanghai, China.
authors.forename: ZhenGuo
authors.initials: Z
authors.lastname: Liu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000209:etiology; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017448:Receptors, Dopamine D2; D007980:Levodopa; D016627:Oxidopamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2