title: p38 MAP kinase mediates both short-term and long-term synaptic depression in aplysia.
abstract: At Aplysia sensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers. We find that FMRFa leads to the phosphorylation and activation of p38 mitogen-activated protein (MAP) kinase. Short-term depression and the release of arachidonate are blocked by the specific p38 kinase inhibitor SB 203580. Both the inhibitor and an affinity-purified antibody raised against recombinant Aplysia p38 kinase injected into sensory neurons prevented long-term depression, which depends on the phosphorylation of translation factors cAMP response element-binding protein 2 (CREB2) and activating transcription factor 2. Facilitation produced by 5-HT, on the other hand, inactivates p38 kinase. Chromatin immunoprecipitation assays indicate that p38 kinase activates CREB2. p38 kinase also is pivotal in the bidirectional regulation of synaptic plasticity: when the kinase is inhibited, brief treatment with 5-HT that normally produces only short-term facilitation now results in long-term facilitation. Conversely, in sensory neurons injected with the activated kinase, long-term facilitation is blocked, and brief exposure to FMRFa, which normally results in short-term depression, results in long-term depression. We conclude that p38 kinase, which itself is bidirectionally regulated by FMRFa and 5-HT, acts as a modulator of synaptic plasticity by positively regulating depression and serving as an inhibitory constraint for facilitation.
authors.affiliation: Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Guan
authors.forename: Joung-Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Stavros
authors.initials: S
authors.lastname: Lomvardas
authors.forename: Kerri
authors.initials: K
authors.lastname: Holick
authors.forename: Shiqin
authors.initials: S
authors.lastname: Xu
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
authors.forename: James H
authors.initials: JH
authors.lastname: Schwartz
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D001048:Aplysia; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019835:FMRFamide / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051698:Activating Transcription Factor 2; C097204:ApCREB2 protein, Aplysia californica; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016718:Arachidonic Acid; D012701:Serotonin; D019835:FMRFamide; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D006655:Histone Deacetylases