title: Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression.
abstract: Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity-dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation-dependent long-term depression (LTD). Although it has been established that intracellular Ca(2+) and the Gq-regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca(2+) regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca(2+) sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N-[4-aminobutyl]-5-chloro-2-naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5-stimulated activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p70-S6 kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist-induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca(2+) /CaM-dependent protein kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM-CaMK-ERK1/2 signaling cascade suppressed the mGluR1/5-stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca(2+) and protein upregulation and regulating mGluR1/5-mediated synaptic modification.
authors: Genetics Program, Michigan State University, East Lansing, Michigan.
authors: Ferzin
authors: F
authors: Sethna
authors: Department of Physiology, Michigan State University, East Lansing, Michigan.|Neuroscience Program, Michigan State University, East Lansing, Michigan.|Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
authors: Ming
authors: M
authors: Zhang
authors: Center for Neural Science, New York University, New York, New York.|Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
authors: Hanoch
authors: H
authors: Kaphzan
authors: Center for Neural Science, New York University, New York, New York.
authors: Eric
authors: E
authors: Klann
authors: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors: Dawn
authors: D
authors: Autio
authors: Department of Physiology, Michigan State University, East Lansing, Michigan.|Neuroscience Program, Michigan State University, East Lansing, Michigan.
authors: Charles L
authors: CL
authors: Cox
authors: Department of Physiology, Michigan State University, East Lansing, Michigan.|Neuroscience Program, Michigan State University, East Lansing, Michigan.
authors: Hongbing
authors: H
authors: Wang
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002147:Calmodulin; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C104077:metabotropic glutamate receptor type 1; C033772:N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide
keywords: AB_2265913; AB_331647; AB_823494; AB_823592; AB_887694; Arc; ERK1/2; calmodulin; mGluR1/5; signal transduction; synaptic depression