G protein-independent neuromodulatory action of adenosine on metabotropic glutamate signalling in mouse cerebellar Purkinje cells.
Adenosine receptors (ARs) are G protein-coupled receptors (GPCRs) mediating the neuromodulatory actions of adenosine that influence emotional, cognitive, motor, and other functions in the central nervous system (CNS). Previous studies show complex formation between ARs and metabotropic glutamate receptors (mGluRs) in heterologous systems and close colocalization of ARs and mGluRs in several central neurons. Here we explored the possibility of intimate functional interplay between G(i/o) protein-coupled A(1)-subtype AR (A1R) and type-1 mGluR (mGluR1) naturally occurring in cerebellar Purkinje cells. Using a perforated-patch voltage-clamp technique, we found that both synthetic and endogenous agonists for A1R induced continuous depression of a mGluR1-coupled inward current. A1R agonists also depressed mGluR1-coupled intracellular Ca(2+) mobilization monitored by fluorometry. A1R indeed mediated this depression because genetic depletion of A1R abolished it. Surprisingly, A1R agonist-induced depression persisted after blockade of G(i/o) protein. The depression appeared to involve neither the cAMP-protein kinase A cascade downstream of the alpha subunits of G(i/o) and G(s) proteins, nor cytoplasmic Ca(2+) that is suggested to be regulated by the beta-gamma subunit complex of G(i/o) protein. Moreover, A1R did not appear to affect G(q) protein which mediates the mGluR1-coupled responses. These findings suggest that A1R modulates mGluR1 signalling without the aid of the major G proteins. In this respect, the A1R-mediated depression of mGluR1 signalling shown here is clearly distinguished from the A1R-mediated neuronal responses described so far. These findings demonstrate a novel neuromodulatory action of adenosine in central neurons.
Tabata
Toshihide
T
Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Kawakami
Daisuke
D
Hashimoto
Kouichi
K
Kassai
Hidetoshi
H
Yoshida
Takayuki
T
Hashimotodani
Yuki
Y
Fredholm
Bertil B
BB
Sekino
Yuko
Y
Aiba
Atsu
A
Kano
Masanobu
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005470:Fluorometry; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C047235:N-(1-methyl-2-phenylethyl)adenosine; C058394:2-chloro-N(6)cyclopentyladenosine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000241:Adenosine; D002118:Calcium