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Adenosine receptor A 2A R is known to antagonize dopaminergic signaling in the striatum and its malfunctions have been implicated in various striatum-related diseases. Flajolet et al . show that A 2A R and fibroblast growth factor receptor interact to synergistically activate ERK1/2 pathway and that such interaction modulates the morphological changes of cultured neurons and synaptic plasticity of cortico-striatal synapses. Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A 2A receptors, antagonizes dopamine signaling at D2 receptors and A 2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein–coupled A 2A receptor (A 2A R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A 2A R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A 2A and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.

Cell surface receptor membrane localization is strongly dependent on protein-protein interactions often involving regulation by phosphorylation/dephosphorylation of the intracellular domains of membrane proteins. The present study was carried out to identify metabotropic glutamate receptor (mGluR) 3 regulatory binding proteins. Using the yeast two-hybrid technique, we found that the 50-aa C-terminal cytoplasmic tail of mGluR3 interacts specifically with protein phosphatase$2C\\alpha\\>(PP2C\\alpha)$. This interaction was confirmed by GST pull-down and coimmunoprecipitation assays. mGluR3 interacts with$PP2C\\alpha,\\>\\beta,\\>\\gamma$, and δ isoforms; however, among the mGluR family only mGluR3 interacted with PP2C. The minimal interacting domain of mGluR3 comprised residues 836-855. Alignment between mGluR3 and mGluR2, a closely related group II receptor, indicated that this domain is not conserved between the two receptors. The mGluR3 cytoplasmic C-terminal tail contains one phosphorylation site for protein kinase A (Ser-845), but the phosphatase that dephosphorylates this site has not been previously identified. We find that PP2C, but not PP1, PP2A, or PP2B, dephosphorylates the mGluR3 cytoplasmic tail in vitro. The dephosphorylated form of the mGluR3 cytoplasmic tail, but not the equivalent region of mGluR2, inhibited PP2C assayed by using [32P] casein as a substrate. However, phosphorylation of the mGluR3 cytoplasmic tail at Ser-845 inhibits the interaction with PP2C. These results indicate distinct functions for mGluR2 and mGluR3 and suggest a dynamic regulation of mGluR3 by PP2C.

Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in part due to fears of adverse effects of medications on the fetus during early pregnancy. In April 2013, the US Food and Drug Administration (FDA) approved doxylamine succinate 10 mg and pyridoxine hydrochloride (a vitamin B6 analog) 10 mg as a delayed-release combination pill called Diclegis for the treatment of NVP. Diclegis is currently the only medication that is FDA-approved for the indication of NVP. This review addresses the historical context, safety, efficacy, pharmacology, and practical role of doxylamine and pyridoxine for the management of NVP. The reintroduction of this doxylamine-pyridoxine combination pill into the American market fills a therapeutic gap in the management of NVP left by the removal of the same active drugs marketed over 30 years ago in the form of Bendectin. The substantial amount of safety data accumulated over the years makes it one of the few drugs that qualify for FDA Pregnancy Category A status. In the hierarchical approach to pharmacological treatment of NVP, the combination of doxylamine and pyridoxine should thus be first-tier.

Non-opioid analgesics are increasingly used as part of a multimodal regimen for pain management. This prospective, randomized, double-blinded, placebo-controlled study was designed to evaluate the effect of short-term postoperative administration of celecoxib on pain management and recovery outcomes following laparoscopic surgery. Eighty consenting ASA I-III outpatients undergoing laparoscopic surgery were randomly assigned to one of two treatment groups: Control (placebo) or Celecoxib (celecoxib, 400 mg x day(-1)). The initial dose (celecoxib 400 mg or placebo po) was administered in the recovery room, and celecoxib 200 mg (or a placebo) po bid was continued for three additional days after surgery. Postoperative pain scores and the need for opioid- containing analgesics were recorded at specific intervals in the recovery room. Follow-up evaluations were performed at 24 hr, 48 hr, 72 hr and seven days and one month after surgery to assess post-discharge pain, analgesic requirements, complications, quality of recovery, and resumption of normal activities, as well as patient satisfaction with their pain management. Celecoxib reduced mean pain scores and the need for analgesics at 24 hr and 48 hr postoperatively. Patient satisfaction with their postoperative pain management was also higher in the Celecoxib group (94 +/- 8 vs 80 +/- 25, P<0.05). Quality of recovery scores were significantly higher in the Celecoxib group on the first and second postoperative days (17 +/- 1 vs 15 +/- 2, and 18 +/- 1 vs 16 +/- 2, respectively). Finally, bowel function recovered an average of one day earlier and patients resumed activities of daily living two days earlier in the Celecoxib group (P<0.05). Short-term administration of celecoxib, 400 mg x day(-1) po, decreased postoperative pain and the need for opioid-containing analgesic medication, leading to an improved quality of recovery after outpatient laparoscopic surgery.

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A(2A) receptors, antagonizes dopamine signaling at D2 receptors and A(2A) receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A(2A) receptor (A(2A)R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A(2A)R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A(2A) and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A sub(2A) receptors, antagonizes dopamine signaling at D2 receptors and A sub(2A) receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A sub(2A) receptor (A sub(2A)R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A sub(2A)R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A sub(2A) and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co- transmitter and open new avenues for therapeutic interventions.

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and depression. Adenosine, by activation of A2A receptors, antagonizes dopamine signaling at D2 receptors and A2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We report here a direct physical interaction between the G protein-coupled A2A receptor and the receptor tyrosine kinase FGF receptor. Concomitant activation of these two classes of receptors, but not individual activation of either one alone, causes a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity induced by a novel A2AR/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A2A and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.