title: mGluR1-mediated excitation of cerebellar GABAergic interneurons requires both G protein-dependent and Src-ERK1/2-dependent signaling pathways.
abstract: Stimulation of type I metabotropic glutamate receptors (mGluR1/5) in several neuronal types induces slow excitatory responses through activation of transient receptor potential canonical (TRPC) channels. GABAergic cerebellar molecular layer interneurons (MLIs) modulate firing patterns of Purkinje cells (PCs), which play a key role in cerebellar information processing. MLIs express mGluR1, and activation of mGluR1 induces an inward current, but its precise intracellular signaling pathways are unknown. We found that mGluR1 activation facilitated spontaneous firing of mouse cerebellar MLIs through an inward current mediated by TRPC1 channels. This mGluR1-mediated inward current depends on both G protein-dependent and -independent pathways. The nonselective protein tyrosine kinase inhibitors genistein and AG490 as well as the selective extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors PD98059 and SL327 suppressed the mGluR1-mediated current responses. Following G protein blockade, the residual mGluR1-mediated inward current was significantly reduced by the selective Src tyrosine kinase inhibitor PP2. In contrast to cerebellar PCs, GABAB receptor activation in MLIs did not alter the mGluR1-mediated inward current, suggesting that there is no cross-talk between mGluR1 and GABAB receptors in MLIs. Thus, activation of mGluR1 facilitates firing of MLIs through the TRPC1-mediated inward current, which depends on not only G protein-dependent but also Src-ERK1/2-dependent signaling pathways, and consequently depresses the excitability of cerebellar PCs.
authors.affiliation: Materials Management, Medical Hospital, Tokyo Medical and Dental University (TMDU), Bunkyo, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kubota
authors.affiliation: Laboratory for Motor Learning Control, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Obata Research Unit, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Obata
authors.affiliation: Laboratory for Motor Learning Control, RIKEN Brain Science Institute, Wako, Saitama, Japan; Obata Research Unit, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Hirono
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050052:TRPC Cation Channels / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D018079:Receptors, GABA; D018094:Receptors, Metabotropic Glutamate; D050052:TRPC Cation Channels; C104077:metabotropic glutamate receptor type 1; D008734:Methoxyhydroxyphenylglycol; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; C010117:3,4-dihydroxyphenylglycol