The Involvement of PACAP/VIP System in the Synaptic Transmission in the Hippocampus

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two closely related peptides, which can activate protein kinase A (PKA). At least three receptors for PACAP and VIP have been identified. The PACAP-specific receptor, PAC1 receptor, exhibits a higher affinity for PACAP than VIP, whereas VIP receptors, VPAC1-R and VPAC2-R, have similar affinities for PACAP and VIP. Both PACAP/VIP and their cognate receptors are highly expressed in the brain, including the hippocampus. Recently, their roles in the regulation of synaptic transmission have begun to emerge. PACAP/VIP can signal through different pathways to regulate N-methyl-d-aspartate (NMDA) receptors in CA1 pyramidal cells. The activation of VPAC1/2-Rs increases evoked NMDA currents via the cyclic AMP/PKA pathway. However, the activation of PAC1-R stimulates a PLC/PKC/Pyk2/Src signaling pathway to enhance NMDA receptor function in hippocampal neurons. Furthermore, different concentrations of PACAP induce different effects on the both α-amino-3-hydroxy-5-isoxazole-propionic acid-evoked current and basal synaptic transmission by activating different receptors. Their roles in learning and memory are also demonstrated using transgenic mice and pharmacological methods.

[1]  I. Gozes,et al.  Learning and sexual deficiencies in transgenic mice carrying a chimeric vasoactive intestinal peptide gene , 2007, Journal of Molecular Neuroscience.

[2]  J. Roder,et al.  Co-stimulation of mGluR5 and N-Methyl-D-aspartate Receptors Is Required for Potentiation of Excitatory Synaptic Transmission in Hippocampal Neurons* , 2003, Journal of Biological Chemistry.

[3]  P. Marin,et al.  PACAP type I receptor transactivation is essential for IGF‐1 receptor signalling and antiapoptotic activity in neurons , 2007, The EMBO journal.

[4]  Angus C Nairn,et al.  DARPP-32: an integrator of neurotransmission. , 2004, Annual review of pharmacology and toxicology.

[5]  W. Quinn,et al.  A neuropeptide gene defined by the Drosophila memory mutant amnesiac. , 1995, Science.

[6]  J. Vilardaga,et al.  Pharmacological properties of two recombinant splice variants of the PACAP type I receptor, transfected and stably expressed in CHO cells. , 1995, European journal of pharmacology.

[7]  D. Purpura,et al.  NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders , 2007, Nature Reviews Neuroscience.

[8]  L. Panlilio,et al.  Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist , 1992, Brain Research.

[9]  T. Iijima,et al.  Differential alteration of hippocampal synaptic strength induced by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) , 1997, Neuroscience Letters.

[10]  Benjamin D. Philpot,et al.  Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity , 2008, Neuropharmacology.

[11]  M. Bennett,et al.  Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. , 2009, Biochemical Society transactions.

[12]  H. Hashimoto,et al.  Desensitization, surface expression, and glycosylation of a functional, epitope-tagged type I PACAP (PAC(1)) receptor. , 2000, Biochimica et biophysica acta.

[13]  J. Mcculloch,et al.  A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology , 2006, Neuropharmacology.

[14]  M. Brunelli,et al.  PACAP-38 enhances excitatory synaptic transmission in the rat hippocampal CA1 region. , 2000, Learning & memory.

[15]  S. Said.  The discovery of VIP: Initially looked for in the lung, isolated from intestine, and identified as a neuropeptide , 2007, Peptides.

[16]  Michael W. Salter,et al.  Src kinases: a hub for NMDA receptor regulation , 2004, Nature Reviews Neuroscience.

[17]  G. Volsi,et al.  Modulation of AMPA receptor‐mediated ion current by pituitary adenylate cyclase‐activating polypeptide (PACAP) in CA1 pyramidal neurons from rat hippocampus , 2009, Hippocampus.

[18]  S. Cavallaro,et al.  Opposing effects by pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide on hippocampal synaptic transmission , 2003, Experimental Neurology.

[19]  J. Macdonald,et al.  Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMDA receptors and synaptic transmission , 2009, Hippocampus.

[20]  R. Hauger,et al.  G-protein-coupled receptor kinase 3- and protein kinase C-mediated desensitization of the PACAP receptor type 1 in human Y-79 retinoblastoma cells , 2001, Neuropharmacology.

[21]  M. Bear,et al.  LTP and LTD An Embarrassment of Riches , 2004, Neuron.

[22]  H. Daniel,et al.  Epac mediates PACAP‐dependent long‐term depression in the hippocampus , 2009, The Journal of physiology.

[23]  B. Orser,et al.  In CA1 Pyramidal Neurons of the Hippocampus Protein Kinase C Regulates Calcium-Dependent Inactivation of NMDA Receptors , 2000, The Journal of Neuroscience.

[24]  渡辺 潤.  Pituitary adenylate cyclase-activating polypeptide(PACAP)の神経幹細胞に対するアストロサイト分化誘導作用の解析 , 2008 .

[25]  S. Rawlings,et al.  International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. , 1998, Pharmacological reviews.

[26]  N. Dun,et al.  Potentiation of NMDA currents by pituitary adenylate cyclase activating polypeptide in neonatal rat sympathetic preganglionic neurons. , 1997, Journal of neurophysiology.

[27]  P. Paoletti,et al.  Relating NMDA Receptor Function to Receptor Subunit Composition: Limitations of the Pharmacological Approach , 2006, The Journal of Neuroscience.

[28]  R. Lefkowitz,et al.  Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Konnerth,et al.  Impairment of Mossy Fiber Long-Term Potentiation and Associative Learning in Pituitary Adenylate Cyclase Activating Polypeptide Type I Receptor-Deficient Mice , 2001, The Journal of Neuroscience.

[30]  A. Arimura.  PACAP: The road to discovery , 2007, Peptides.

[31]  K. Joo,et al.  Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain , 2004, The Journal of comparative neurology.

[32]  M. Sheng,et al.  Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity , 2004, Science.

[33]  A. Harmar,et al.  Desensitization of the Human Vasoactive Intestinal Peptide Receptor (hVIP2/PACAP R): Evidence for Agonist‐Induced Receptor Phosphorylation and Internalization a , 1998, Annals of the New York Academy of Sciences.

[34]  J. Ribeiro,et al.  VIP enhances synaptic transmission to hippocampal CA1 pyramidal cells through activation of both VPAC1 and VPAC2 receptors , 2005, Brain Research.

[35]  J. Roder,et al.  Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires Gαq, Protein Kinase C, and Activation of Src , 2005, The Journal of Neuroscience.

[36]  Aurel O. Iuga,et al.  Maxadilan, a PAC1 receptor agonist from sand flies , 2007, Peptides.

[37]  M. Bear,et al.  Metaplasticity: the plasticity of synaptic plasticity , 1996, Trends in Neurosciences.

[38]  J. Macdonald,et al.  Convergence of PKC-dependent kinase signal cascades on NMDA receptors. , 2001, Current drug targets.

[39]  W. Abraham.  Metaplasticity: tuning synapses and networks for plasticity , 2008, Nature Reviews Neuroscience.

[40]  V. Pawlak,et al.  Lack of NMDA Receptor Subtype Selectivity for Hippocampal Long-Term Potentiation , 2005, The Journal of Neuroscience.

[41]  S. Cull-Candy,et al.  Role of Distinct NMDA Receptor Subtypes at Central Synapses , 2004, Science's STKE.

[42]  J. Ribeiro,et al.  Tonic adenosine A1 and A2A receptor activation is required for the excitatory action of VIP on synaptic transmission in the CA1 area of the hippocampus , 2007, Neuropharmacology.

[43]  G. Collingridge,et al.  Differential Roles of NR2A and NR2B-Containing NMDA Receptors in Cortical Long-Term Potentiation and Long-Term Depression , 2004, The Journal of Neuroscience.

[44]  M. Brunelli,et al.  Differential effects of PACAP-38 on synaptic responses in rat hippocampal CA1 region. , 2001, Learning & memory.

[45]  C. Colwell,et al.  Regulation of glutamatergic signalling by PACAP in the mammalian suprachiasmatic nucleus , 2006, BMC Neuroscience.

[46]  E. Baldi,et al.  Pituitary Adenylate Cyclase-Activating Polypeptide Hormone (PACAP) at Very Low Dosages Improves Memory in the Rat , 2001, Neurobiology of Learning and Memory.

[47]  K. Finlayson,et al.  VPAC and PAC receptors: From ligands to function. , 2009, Pharmacology & therapeutics.

[48]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[49]  D. Choquet,et al.  NMDA receptor surface mobility depends on NR2A-2B subunits , 2006, Proceedings of the National Academy of Sciences.

[50]  J. Macdonald,et al.  Signaling molecules and receptor transduction cascades that regulate NMDA receptor-mediated synaptic transmission. , 2003, International review of neurobiology.

[51]  Rafael Yuste,et al.  Protein kinase A regulates calcium permeability of NMDA receptors , 2006, Nature Neuroscience.

[52]  M. Bear,et al.  Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression , 2007, Neuropharmacology.

[53]  M. Johnson,et al.  Differential Activation of Phospholipase D by VPAC and PAC1 Receptors , 2000, Annals of the New York Academy of Sciences.

[54]  R. Malenka,et al.  AMPA receptor trafficking and synaptic plasticity. , 2002, Annual review of neuroscience.

[55]  D. Lovinger,et al.  Activation of NR2A-Containing NMDA Receptors Is Not Obligatory for NMDA Receptor-Dependent Long-Term Potentiation , 2005, The Journal of Neuroscience.

[56]  I. Gozes,et al.  Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[57]  A. Couvineau,et al.  Stable expression of the recombinant human VIP1 receptor in clonal Chinese hamster ovary cells: pharmacological, functional and molecular properties. , 1996, European journal of pharmacology.

[58]  J. Vilardaga,et al.  Properties of the VIP-PACAP type II receptor stably expressed in CHO cells , 1994, Regulatory Peptides.

[59]  P. Illés,et al.  VIP enhances both pre‐ and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells , 2004, British journal of pharmacology.

[60]  B. Madsen,et al.  PACAP38 modulates activity of NMDA receptors in cultured chick cortical neurons. , 1997, Journal of neurophysiology.