G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors

Lü, Wei; Xiong, Zhi‐Gang; Lei, Saobo; Orser, Beverley A.; Dudek, Ellen M.; Browning,; MacDonald, John F.

doi:10.1038/7243

Cited by 350 publications

(324 citation statements)

References 35 publications

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“…Src-family kinases can phosphorylate NR2B subunits at tyrosine residue 1472, which is critical for NR2B subunit-containing NMDAR surface expression and functional potentiation (Ali and Salter, 2001;Groveman et al, 2012;Lu et al, 1999a;Salter, 1998;Salter and Kalia, 2004;Sinai et al, 2010;Stramiello and Wagner, 2008). The present study revealed that NR2B phosphorylation at Y1472 in the DH increased following testing in the cocaine-paired context, relative to home cage exposure.…”

Section: Discussionmentioning

confidence: 49%

“…Five members of the family have been identified in the mammalian brain, including Src, Fyn, Lyn, Yes, and Lck (Salter and Kalia, 2004). In cultured hippocampal neurons or brain slices, activation of Src-family kinases increases the phosphorylation of NR2B NMDAR subunits (Lu et al, 1999a;Stramiello and Wagner, 2008), which is required for NR2B subunit surface expression and NMDAR function (Ali and Salter, 2001;Groveman et al, 2012;Lu et al, 1999a;Salter and Kalia, 2004;Stramiello and Wagner, 2008). Conversely, pharmacological inhibition of Src-family kinases in the dorsomedial striatum decreases the phosphorylation of NR2B subunits and the expression of drugprimed alcohol-seeking behavior (Wang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

Xie

Arguello

Wells

et al. 2013

Neuropsychopharmacol

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Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaineseeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaineseeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mg/0.5 ml/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 ml/hemisphere), Ro25-6981 (NR2B subunitcontaining NMDAR antagonist; 0.2 or 2 mg/0.5 ml/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments. Cocaine-seeking behavior during the first 20 min of the test session in the cocaine-paired context was associated with an increase in NR2B subunit activation, and intra-DH PP2 pretreatment disrupted this relationship. Together, these findings suggest that Src-family kinase activation, NMDAR stimulation, and likely Src-family kinase-mediated NR2B subunit-containing NMDAR activation in the DH are necessary for incentive motivational and/or memory processes that promote contextual cocaine-seeking behavior.

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Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

Xie

Arguello

Wells

et al. 2013

Neuropsychopharmacol

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“…SFKs can be modulated by tyrosine phosphatases, G-protein-coupled receptors, receptor protein tyrosine kinase signaling, the Ras pathway, and the cytokine receptor and integrin pathways. Many of the physiological actions of NMDA receptors are critically dependent upon SFKs (Gingrich et al, 2004;Hayashi and Huganir, 2004;Kalia and Salter, 2003;Lu et al, 1999). As an example, SFKs are necessary for the induction of long-term potentiation in the CA1 region of hippocampus (Salter and Kalia, 2004).…”

Section: Discussionmentioning

confidence: 99%

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Dickerson

Sharp

2005

Neuropsychopharmacol

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Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine, ketamine, and MK-801 produce schizophrenia-like psychosis in humans. The same NMDA antagonists injure retrosplenial cortical neurons in adult rats. We examined the effects of atypical antipsychotics and an inhibitor of nonreceptor tyrosine kinase pp60 (Src) on the cortical injury produced by MK-801. An atypical antipsychotic (either clozapine, ziprasidone, olanzapine, quetiapine, or risperidone) or vehicle was administered to adult female Sprague-Dawley rats. PP1 (Src inhibitor), PP3 (nonfunctional analog of PP1) or vehicle (DMSO) was administered to another group of animals. After pretreatment, animals were injected with MK-801, killed 24 h after the MK-801, and injury to retrosplenial cortex assessed by neuronal Hsp70 protein expression. All atypical antipsychotics examined significantly attenuated MK-801-induced cortical damage. PP1 protected compared to vehicle, whereas PP3 did not protect. The ED50s (decrease injury by 50%) were as follows: PP1 o0.1 mg/kg; olanzapine 0.8 mg/kg; risperdal 1 mg/kg; clozapine 3 mg/kg; ziprasidone 32 mg/kg; and quetiapine 45 mg/kg. The data show that the atypical antipsychotics tested as well as a Src kinase inhibitor prevent the injury produced by the psychomimetic MK-801, and the potency of the atypical antipsychotics for preventing cortical injury was roughly similar to the potency of these drugs for treating psychosis in patients.

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“…Several lines of evidence support a role for PKC in potentiating NMDA receptor function (39,40). PKC phosphorylates GluN2B subunit on serine residues (Ser 1303 or Ser 1323 ) located in its carboxylterminal domain (41), and each of these phosphorylations induces a potentiation of NMDA currents (41,42).…”

Section: Resultsmentioning

confidence: 99%

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Barre

Berthoux

Bundel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT) 2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT 2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT 2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT 2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT 2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.T he prefrontal cortex (PFC) is a brain region critical for many high-level cognitive processes, such as executive functions, attention, and working and contextual memories (1). Pyramidal neurons located in layer V of the PFC integrate excitatory glutamatergic inputs originating from both cortical and subcortical areas. The latter include the mediodorsal thalamus (MD) nuclei, which project densely to the medial PFC (mPFC) and are part of the neuronal network underlying executive control and working memory (2-4). Disruption of this network has been involved in cognitive symptoms of psychiatric disorders, such as schizophrenia (3, 5). These symptoms severely compromise the quality of life of patients and remain poorly controlled by currently available antipsychotics (3, 6).The PFC is densely innervated by serotonin (5-hydroxytryptamine, 5-HT) neurons originating from the dorsal and median raphe nuclei and numerous lines of evidence indicate a critical role of 5-HT in the control of emotional and cognitive functions depending on PFC activity (7,8). The modulatory action of 5-HT reflects its complex pattern of effects on cortical network activity, depending on the 5-HT receptor subtypes involved, and on receptor localization in pyramidal neurons, GABAergic interneurons or nerve terminals of afferent neurons.Among the 14 5-HT receptor subtypes, the 5-HT 2A receptor is a Gq protein-coupled receptor (9, 10) particularly enriched in the mPFC, with a predominant expression in apical dendrites of layer V pyramidal neurons (11)(12)(13)(14). Moreover, a low proportion of 5-HT 2A receptors was detected presynaptically on thalamocortical fibers (12,(15)(16)(17).Activation of 5-HT 2A receptors exerts complex effects upon the activity of the PFC network (18). The most prominent one is an increase in p...

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G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors

Cited by 350 publications

References 35 publications

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

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