title: Prenatal cocaine exposure uncouples mGluR1 from Homer1 and Gq Proteins.
abstract: Cocaine exposure during gestation causes protracted neurobehavioral changes consistent with a compromised glutamatergic system. Although cocaine profoundly disrupts glutamatergic neurotransmission and in utero cocaine exposure negatively affects metabotropic glutamate receptor-type 1 (mGluR1) activity, the effect of prenatal cocaine exposure on mGluR1 signaling and the underlying mechanism responsible for the prenatal cocaine effect remain elusive. Using brains of the 21-day-old (P21) prenatal cocaine-exposed rats, we show that prenatal cocaine exposure uncouples mGluR1s from their associated synaptic anchoring protein, Homer1 and signal transducer, Gq/11 proteins leading to markedly reduced mGluR1-mediated phosphoinositide hydrolysis in frontal cortex (FCX) and hippocampus. This prenatal cocaine-induced effect is the result of a sustained protein kinase C (PKC)-mediated phosphorylation of mGluR1 on the serine residues. In support, phosphatase treatment of prenatal cocaine-exposed tissues restores whereas PKC-mediated phosphorylation of saline-treated synaptic membrane attenuates mGluR1 coupling to both Gq/11 and Homer1. Expression of mGluR1, Homer1 or Gα proteins was not altered by prenatal cocaine exposure. Collectively, these data indicate that prenatal cocaine exposure triggers PKC-mediated hyper-phosphorylation of the mGluR1 leading to uncoupling of mGluR1 from its signaling components. Hence, blockade of excessive PKC activation may alleviate abnormalities in mGluR1 signaling and restores mGluR1-regulated brain functions in prenatal cocaine-exposed brains.
authors.affiliation: Departments of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York, United States of America.
authors.forename: Kalindi
authors.initials: K
authors.lastname: Bakshi
authors.affiliation: Departments of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York, United States of America.
authors.forename: Raminder
authors.initials: R
authors.lastname: Parihar
authors.affiliation: Departments of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York, United States of America.
authors.forename: Satindra K
authors.initials: SK
authors.lastname: Goswami
authors.affiliation: Departments of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Departments of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York, United States of America.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Departments of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, The City University of New York Medical School, New York, New York, United States of America.
authors.forename: Hoau-Yan
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000009:adverse effects*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D000072233:Homer Scaffolding Proteins; D006868:Hydrolysis; D008297:Male; D018811:Maternal Exposure; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D012694:Serine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D003042:Cocaine