title: Functional cooperation of metabotropic adenosine and glutamate receptors regulates postsynaptic plasticity in the cerebellum.
abstract: G-protein-coupled receptors (GPCRs) may form heteromeric complexes and cooperatively mediate cellular responses. Although heteromeric GPCR complexes are suggested to occur in many neurons, their contribution to neuronal function remains unclear. We address this question using two GPCRs expressed in cerebellar Purkinje cells: adenosine A1 receptor (A1R), which regulates neurotransmitter release and neuronal excitability in central neurons, and type-1 metabotropic glutamate receptor (mGluR1), which mediates cerebellar long-term depression, a form of synaptic plasticity crucial for cerebellar motor learning. We examined interaction between these GPCRs by immunocytochemical, biochemical, and Förster resonance energy transfer analyses in cultured mouse Purkinje cells and heterologous expression cells. These analyses revealed that the GPCRs closely colocalized and formed heteromeric complexes on the cell surfaces. Furthermore, our electrophysiological analysis showed that CSF levels (40-400 nm) of adenosine or synthetic A1R agonists with comparable potencies blocked mGluR1-mediated long-term depression of the postsynaptic glutamate-responsiveness (glu-LTD) of cultured Purkinje cells. A similar dose of the A1R agonist decreased the ligand affinity of mGluR1 and did not affect depolarization-induced Ca(2+) influx, which is an essential factor in inducing glu-LTD. The A1R agonist did not affect glu-LTD mimicked by direct activation of protein kinase C. These results suggest that A1R blocked glu-LTD by decreasing the ligand sensitivity of mGluR1, but not the coupling efficacy from mGluR1 to the intracellular signaling cascades. These findings provide a new insight into neuronal GPCR signaling and demonstrate a novel regulatory mechanism of synaptic plasticity.
authors.affiliation: Department of Pharmacology, Juntendo University School of Medicine, Tokyo 113-8421, Japan, Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo113-0033, Japan, and Laboratory for Neural Information Technology, Graduate School of Sciences and Engineering, The University of Toyama, Toyama 930-8555, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimomura
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tabata
authors.forename: Taku
authors.initials: T
authors.lastname: Kashiyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Kenkichi
authors.initials: K
authors.lastname: Fukurotani
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004735:Energy Transfer; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D043682:Receptor, Adenosine A1; D018094:Receptors, Metabotropic Glutamate; D026941:Sodium Channel Blockers; C104077:metabotropic glutamate receptor type 1; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; C017069:bicuculline methiodide; D013779:Tetrodotoxin; D001640:Bicuculline