Arrestin-Mediated Activation of p38 MAPK: Molecular Mechanisms and Behavioral Consequences
Studies of kappa opioid receptor signaling mechanisms during the last decade have demonstrated that agonist activation of the receptor results in Gβγ-dependent signaling and distinct arrestin-dependent signaling events. Gβγ-dependent signaling results in
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Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Kappa Opioid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Stress-Induced Release of Dynorphin Increases Phospho-p38 MAPK in a GRK3and Arrestin-3-Dependent Manner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Astrocyte Activation by Dynorphin Occurs Through an Arrestin/p38 MAPK Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Kappa Receptor Activation of Arrestin/p38 MAPK Regulates the Potassium Channel Kir3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Kappa Receptor Activation of Arrestin/p38 MAPK Activates the Serotonin Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Studies of kappa opioid receptor signaling mechanisms during the last decade have demonstrated that agonist activation of the receptor results in Gβγ-dependent signaling and distinct arrestin-dependent signaling events. Gβγ-dependent signaling results in ion channel regulation causing neuronal inhibition, inhibition of transmitter release, and subsequent analgesic responses. In contrast, arrestin-dependent signaling events result in p38 MAPK activation and subsequent dysphoric and proaddictive behavioral responses. Resolution of these two branches of signaling cascades has enabled strategies designed to identify pathway-selective drugs that may have unique therapeutic utilities. Keywords Kappa opioid receptor • Dynorphin • Arrestin • p38 MAPK
C. Chavkin (*) • S.S. Schattauer • J.R. Levin Department of Pharmacology, University of Washington, Seattle, WA 98195, USA e-mail: [email protected] V.V. Gurevich (ed.), Arrestins - Pharmacology and Therapeutic Potential, Handbook of Experimental Pharmacology 219, DOI 10.1007/978-3-642-41199-1_14, © Springer-Verlag Berlin Heidelberg 2014
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Abbreviations ASK1 β2AR CRF JNK ERK1/2 GRK GPCRs GIRK, Kir3 GFAP KOR rKOR hKOR MAPK MAP3K5 PKC 5HT
Apoptosis signal-regulating kinase 1 β2-Adrenergic receptor Corticotropin-releasing factor c-Jun N-terminal Kinase Extracellular signal-regulated kinase G-protein receptor kinase G-protein-coupled receptors G-protein-gated inwardly rectifying potassium channel Glial fibrillary a
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