Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires Gα<sub>q</sub>, Protein Kinase C, and Activation of Src

Macdonald, D. S.; Weerapura, Manjula; Beazely, Michael A.; Martin, Loren J.; Czerwinski, Waldemar; Roder, John; Orser, BA; MacDonald, John F.

doi:10.1523/jneurosci.3871-05.2005

Cited by 106 publications

(129 citation statements)

References 66 publications

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“…Our experiments show that the PKA, Akt/PKB, and PKC pathways eventually converge on Pyk2, a scaffold tyrosine kinase known to be a key player in GPCR-mediated signaling in neurons (46), in agreement with previous studies (Refs. 21, 47, and 48 and as shown in Fig.…”

Section: Discussionsupporting

confidence: 93%

“…Given that the synaptic actions of many neurotransmitters and neuromodulators occur through activation of PKA, Akt/PKB, and PKC (for example, see Ref. 46), activation of these divergent pathways during the initial phases of the rapid response to CORT provides the cell with a high degree of plasticity, includ- ing cross-talk and cross-modulation. Involvement of other signaling cascades is conceivable if the membrane actions of CORT are indeed mediated by a GPCR that results in the assembly of a signalosome.…”

Section: Discussionmentioning

confidence: 99%

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Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Yang

Roselli

Patchev

et al. 2013

Journal of Biological Chemistry

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Background: The intracellular signaling cascades through which corticosterone rapidly alters neuronal activity are poorly defined. Results: Corticosterone alters glutamatergic transmission by activating diverse GPCR-dependent signaling pathways. Conclusion: Corticosterone-induced changes in neuronal excitability are initiated at the plasma membrane. Significance: The sequential recruitment and integration of diverse signaling cascades by corticosterone adds to the understanding of how steroids rapidly alter neuronal function.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Yang

Roselli

Patchev

et al. 2013

Journal of Biological Chemistry

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“…2c). Thus, basal NMDAR synaptic responses were not affected by NRG1β-ErbB4 signaling, consistent with evidence that synaptic NMDARs are not tonically upregulated by Src in CA1 neurons 5,47,48 . Our findings indicate that NRG1β prevents and reverses the enhancement of synaptic NMDAR currents by Src but does not affect basal NMDAR function in CA1 neurons.…”

Section: Nrg1β-erbb4 Blocks Src Enhancement Of Nmdar Epscs In Ca1supporting

confidence: 82%

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Pitcher

Kalia

et al. 2011

Nat Med

152

146

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Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

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“…6). Recent work by others has shown that PACAP is involved in the PKA-mediated activation of NMDA receptors in the hippocampus (Yaka et al, 2003;Macdonald et al, 2005). Previous work in our laboratory and by others has shown that activation of NMDA receptors is necessary for the formation of associative LTM in invertebrates [Aplysia, Murphy and Glanzman (1999); Drosophila, Xia et al (2005); Lymnaea, Jami et al (2007), Wu et al (2007), and Wan et al (2010)], and we now hypothesize that invertebrate PACAP-like peptides play a mechanistic role in the learninginduced activation of NMDA receptors similar to that previously described in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

A Homolog of the Vertebrate Pituitary Adenylate Cyclase-Activating Polypeptide Is Both Necessary and Instructive for the Rapid Formation of Associative Memory in an Invertebrate

Pirger

László²,

Kemenes³

et al. 2010

J. Neurosci.

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Similar to other invertebrate and vertebrate animals, cAMP-dependent signaling cascades are key components of long-term memory (LTM) formation in the snail Lymnaea stagnalis, an established experimental model for studying evolutionarily conserved molecular mechanisms of long-term associative memory. Although a great deal is already known about the signaling cascades activated by cAMP, the molecules involved in the learning-induced activation of adenylate cyclase (AC) in Lymnaea remained unknown.Using matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy in combination with biochemical and immunohistochemical methods, recently we have obtained evidence for the existence of a Lymnaea homolog of the vertebrate pituitary adenylate cyclaseactivating polypeptide (PACAP) and for the AC-activating effect of PACAP in the Lymnaea nervous system. Here we first tested the hypothesis that PACAP plays an important role in the formation of robust LTM after single-trial classical food-reward conditioning. Application of the PACAP receptor antagonist PACAP6-38 around the time of single-trial training with amyl acetate and sucrose blocked associative LTM, suggesting that in this "strong" food-reward conditioning paradigm the activation of AC by PACAP was necessary for LTM to form. We found that in a "weak" multitrial food-reward conditioning paradigm, lip touch paired with sucrose, memory formation was also dependent on PACAP. Significantly, systemic application of PACAP at the beginning of multitrial tactile conditioning accelerated the formation of transcriptiondependent memory.Our findings provide the first evidence to show that in the same nervous system PACAP is both necessary and instructive for fast and robust memory formation after reward classical conditioning.

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Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires Gα_q, Protein Kinase C, and Activation of Src

Cited by 106 publications

References 66 publications

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

A Homolog of the Vertebrate Pituitary Adenylate Cyclase-Activating Polypeptide Is Both Necessary and Instructive for the Rapid Formation of Associative Memory in an Invertebrate

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Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires Gαq, Protein Kinase C, and Activation of Src

Cited by 106 publications

References 66 publications

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

A Homolog of the Vertebrate Pituitary Adenylate Cyclase-Activating Polypeptide Is Both Necessary and Instructive for the Rapid Formation of Associative Memory in an Invertebrate

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Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires Gα_q, Protein Kinase C, and Activation of Src