Skip to main content
SpringerLink
Log in

Kinase cascades and ligand-directed signaling at the kappa opioid receptor

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background and Rationale

The dynorphin/kappa opioid receptor (KOR) system has been implicated as a critical component of the stress response. Stress-induced activation of dynorphin-KOR is well known to produce analgesia, and more recently, it has been implicated as a mediator of stress-induced responses including anxiety, depression, and reinstatement of drug seeking.

Objective

Drugs selectively targeting specific KOR signaling pathways may prove potentially useful as therapeutic treatments for mood and addiction disorders.

Results

KOR is a member of the seven transmembrane spanning (7TM) G-protein coupled receptor (GPCR) superfamily. KOR activation of pertussis toxin-sensitive G proteins leads to Gαi/o inhibition of adenylyl cyclase production of cAMP and releases Gβγ, which modulates the conductances of Ca+2 and K+ channels. In addition, KOR agonists activate kinase cascades including G-protein coupled Receptor Kinases (GRK) and members of the mitogen-activated protein kinase (MAPK) family: ERK1/2, p38 and JNK. Recent pharmacological data suggests that GPCRs exist as dynamic, multi-conformational protein complexes that can be directed by specific ligands towards distinct signaling pathways. Ligand-induced conformations of KOR that evoke β-arrestin-dependent p38 MAPK activation result in aversion; whereas ligand-induced conformations that activate JNK without activating arrestin produce long-lasting inactivation of KOR signaling.

Conclusions

In this review, we discuss the current status of KOR signal transduction research and the data that support two novel hypotheses: (1) KOR selective partial agonists that do not efficiently activate p38 MAPK may be useful analgesics without producing the dysphoric or hallucinogenic effects of selective, highly efficacious KOR agonists and (2) KOR antagonists that do not activate JNK may be effective short-acting drugs that may promote stress-resilience.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Appleyard SM, Patterson TA, Jin W, Chavkin C (1997) Agonist-induced phosphorylation of the kappa-opioid receptor. J Neurochem 69:2012–2405

    Google Scholar 

  • Appleyard SM, Celver J, Pineda V, Kovoor A, Wayman GA, Chavkin C (1999) Agonist-dependent desensitization of the kappa opioid receptor by G protein receptor kinase and beta-arrestin. J Biol Chem 274:23802–23807

    Article  CAS  PubMed  Google Scholar 

  • Ariens EJ (1954) Affinity and intrinsic activity in the theory of competitive inhibition I Problems and theory. Arch Int Pharmacodyn Ther 99:32–49

    CAS  PubMed  Google Scholar 

  • Ashwell JD (2006) The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 6:532–540

    Article  CAS  PubMed  Google Scholar 

  • Avidor-Reiss T, Nevo I, Saya D, Bayewitch M, Vogel Z (1997) Opiate-induced adenylyl cyclase superactivation is isozyme-specific. J Biol Chem 272:5040–5047

    Article  CAS  PubMed  Google Scholar 

  • Baker SJ, Reddy EP (1998) Modulation of life and death by the TNF receptor superfamily. Oncogene 17:3261–3270

    Article  PubMed  Google Scholar 

  • Barchfeld CC, Medzihradsky F (1984) Receptor-mediated stimulation of brain GTPase by opiates in normal and dependent rats. Biochem Biophys Res Commun 121:641–648

    Article  CAS  PubMed  Google Scholar 

  • Beardsley PM, Howard JL, Shelton KL, Carroll FI (2005) Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl.) 183:118–126

    Google Scholar 

  • Belcheva MM, Vogel Z, Ignatova E, Avidor-Reiss T, Zippel R, Levy R, Young EC, Barg J, Coscia CJ (1998) Opioid modulation of extracellular signal-regulated protein kinase activity is ras-dependent and involves Gbetagamma subunits. Biochemistry 48:6898–6908

    Google Scholar 

  • Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, Coscia CJ (2005) Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes. J Biol Chem 280:27662–27669

    Article  CAS  PubMed  Google Scholar 

  • Bhargava HN, Gulati A, Ramarao P (1989) Effect of chronic administration of U-50, 488H on tolerance to its pharmacological actions and on multiple opioid receptors in rat brain regions and spinal cord. J Pharmacol Exp Ther 251:21–26

    CAS  PubMed  Google Scholar 

  • Blake AD, Bot G, Freeman JC, Reisine T (1997) Differential opioid agonist regulation of the mouse mu opioid receptor. J Biol Chem 272:782–790

    Article  CAS  PubMed  Google Scholar 

  • Bruchas MR, Macey TA, Lowe JD, Chavkin C (2006) Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. J Biol Chem 281:18081–18089

    Article  CAS  PubMed  Google Scholar 

  • Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C (2007a) Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci 27:11614–11623

    Article  CAS  PubMed  Google Scholar 

  • Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C (2007b) Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase. J Biol Chem 282:29803–29811

    Article  CAS  PubMed  Google Scholar 

  • Bruchas MR, Xu M, Chavkin C (2008) Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2. Neuroreport 19:1417–1422

    Article  CAS  PubMed  Google Scholar 

  • Bruchas MR, Land BB, Lemos J, Chavkin C (2009a) CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS One 4(12):e8528

    Article  PubMed  Google Scholar 

  • Bruchas MR, Land BB, Chavkin C (2009b) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314C:44–55

    Google Scholar 

  • Carlezon WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (1998) Regulation of cocaine reward by CREB. Science 282:2272–2275

    Google Scholar 

  • Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445

    Article  CAS  PubMed  Google Scholar 

  • Carroll I, Thomas JB, Dykstra LA, Granger AL, Allen RM, Howard JL, Pollard GT, Aceto MD, Harris LS (2004) Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist. Eur J Pharmacol 501:111–119

    Article  CAS  PubMed  Google Scholar 

  • Chan AS, Yeung WW, Wong YH (2005) Integration of G protein signals by extracellular signal-regulated protein kinases in SK-N-MC neuroepithelioma cells. Cell Mol Life Sci 55:1230–1254

    Google Scholar 

  • Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215:413–415

    Google Scholar 

  • Chavkin C, Sud S, Jin W, Stewart J, Zjawiony JK, Siebert DJ, Toth BA, Hufeisen SJ, Roth BL (2004) Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. J Pharmacol Exp Ther 308:1197–1203

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Chen C, Liu-Chen LY (2007) Dynorphin peptides differentially regulate the human kappa opioid receptor. Life Sci 80:1439–1448

    Article  CAS  PubMed  Google Scholar 

  • Cheng ZJ, Yu QM, Wu YL, Ma L, Pei G (1998) Selective interference of beta-arrestin 1 with kappa and delta but not mu opioid receptor/G protein coupling. J Biol Chem 273:24328–24333

    Article  CAS  PubMed  Google Scholar 

  • Childers SR, Snyder SH (1978) Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors. Life Sci 23:759–761

    Article  CAS  PubMed  Google Scholar 

  • Clark AJ (1926) The reaction between acetyl choline and muscle cells. J Physiol 61:530–546

    CAS  PubMed  Google Scholar 

  • Clayton CC, Xu M, Chavkin C (2009) Tyrosine phosphorylation of Kir3 following kappa-opioid receptor activation of p38 MAPK causes heterologous desensitization. J Biol Chem 284:31872–31881

    Article  CAS  PubMed  Google Scholar 

  • Crain SM, Shen KF (1990) Opioids can evoke direct receptor-mediated excitatory as well as inhibitory effects on sensory neuron action potentials. NIDA Res Monogr 105:34–39

    CAS  PubMed  Google Scholar 

  • Della Rocca GJ, Maudsley S, Daaka Y, Lefkowitz RJ, Luttrell LM (1999) Pleiotropic coupling of G protein-coupled receptors to the mitogen-activated protein kinase cascade Role of focal adhesions and receptor tyrosine kinases. J Biol Chem 274:13978–13984

    Article  CAS  PubMed  Google Scholar 

  • Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M (1996) International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev 48:567–592

    Google Scholar 

  • Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spurney RF, Luttrell LM, Lefkowitz RJ (2006) Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem 281:10856–10864

    Article  CAS  PubMed  Google Scholar 

  • Grudt TJ, Williams JT (1995) Opioid receptors and the regulation of ion conductances. Rev Neurosci 6:279–286

    CAS  PubMed  Google Scholar 

  • Gurwell JA, Duncan MJ, Maderspach K, Stiene-Martin A, Elde RP, Hauser KF (1996) Kappa-opioid receptor expression defines a phenotypically distinct subpopulation of astroglia: relationship to Ca2+ mobilization, development, and the antiproliferative effect of opioids. Brain Res 737:175–187

    Article  CAS  PubMed  Google Scholar 

  • Horan P, Taylor J, Yamamura HI, Porreca F (1992) Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. J Pharmacol Exp Ther 260:1237–1243

    Google Scholar 

  • Hsia JA, Moss J, Hewlett EL, Vaughan M (1984) ADP-ribosylation of adenylate cyclase by pertussis toxin: effects on inhibitory agonist binding. J Biol Chem 25:1086–1090

    Google Scholar 

  • Hudmon A, Choi JS, Tyrrell L, Black JA, Rush AM, Waxman SG, Dib-Hajj SD (2008) Phosphorylation of sodium channel Na(v)18 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. J Neurosci 28:3190–3201

    Article  CAS  PubMed  Google Scholar 

  • Hunton DL, Barnes WG, Kim J, Ren XR, Violin JD, Reiter E, Milligan G, Patel DD, Lefkowitz RJ (2005) Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis. Mol Pharmacol 67:1229–1236

    Article  CAS  PubMed  Google Scholar 

  • Jordan BA, Cvejic S, Devi LA (2000) Kappa opioid receptor endocytosis by dynorphin peptides. DNA Cell Biol 19:19–27

    Article  CAS  PubMed  Google Scholar 

  • Kam AY, Chan AS, Wong YH (2004) Phosphatidylinositol-3 kinase is distinctively required for mu-, but not kappa-opioid receptor-induced activation of c-Jun N-terminal kinase. J Neurochem 89:391–402

    Article  CAS  PubMed  Google Scholar 

  • Karandikar M, Cobb MH (1999) Scaffolding and protein interactions in MAP kinase modules. Cell Calcium 26:219–226

    Article  CAS  PubMed  Google Scholar 

  • Kenakin T (2003) Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci 24:346–354

    Article  CAS  PubMed  Google Scholar 

  • Kenakin T (2007) Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol Sci 28:407–415

    Article  CAS  PubMed  Google Scholar 

  • Kim E, Clark AL, Kiss A, Hahn JW, Wesselschmidt R, Coscia CJ, Belcheva MM (2006) Mu- and kappa-opioids induce the differentiation of embryonic stem cells to neural progenitors. J Biol Chem 281:33749–33760

    Google Scholar 

  • Knoll AT, Carlezon WA (2010) Dynorphin, stress, and depression. Brain Res 1314:56–73

    Google Scholar 

  • Kohout TA, Lefkowitz RJ (2003) Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol 63:9–18

    Article  CAS  PubMed  Google Scholar 

  • Kreek MJ, Koob GF (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23–47

    Google Scholar 

  • Kreek MJ, Zhou Y, Butelman ER, Levran O (2009) Opiate and cocaine addiction: from bench to clinic and back to the bench. Curr Opin Pharmacol 9(1):74–80

    Article  CAS  PubMed  Google Scholar 

  • Kreibich AS, Blendy JA (2004) cAMP response element-binding protein is required for stress but not cocaine-induced reinstatement. J Neurosci 24:6686–6692

    Article  CAS  PubMed  Google Scholar 

  • Kukkonen JP, Näsman J, Rinken A, Dementjev A, Akerman KE (1998) Pseudo-noncompetitive antagonism of M1, M3, and M5 muscarinic receptor-mediated Ca2+ mobilization by muscarinic antagonists. Biochem Biophys Res Commun 243:41–46

    Article  CAS  PubMed  Google Scholar 

  • Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci 28:407–414

    Article  CAS  PubMed  Google Scholar 

  • Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, Hnasko TS, Palmiter RD, Chavkin C (2009) Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci USA 106:19168–19173

    Article  CAS  PubMed  Google Scholar 

  • Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517

    Article  CAS  PubMed  Google Scholar 

  • Li JG, Luo LY, Krupnick JG, Benovic JL, Liu-Chen LY (1999) U50, 488H-induced internalization of the human kappa opioid receptor involves a beta-arrestin- and dynamin-dependent mechanism Kappa receptor internalization is not required for mitogen-activated protein kinase activation. J Biol Chem 274:12087–12094

    Article  CAS  PubMed  Google Scholar 

  • Li J, Li JG, Chen C, Zhang F, Liu-Chen LY (2002) Molecular basis of differences in (-)(trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclohexyl]benzeneacetamide-induced desensitization and phosphorylation between human and rat kappa-opioid receptors expressed in Chinese hamster ovary cells. Mol Pharmacol 61:73–84

    Article  CAS  PubMed  Google Scholar 

  • Li JG, Zhang F, Jin XL, Liu-Chen LY (2003) Differential regulation of the human kappa opioid receptor by agonists: etorphine and levorphanol reduced dynorphin A- and U50, 488H-induced internalization and phosphorylation. J Pharmacol Exp Ther 305:531–540

    Article  CAS  PubMed  Google Scholar 

  • Liu-Chen LY (2004) Agonist-induced regulation and trafficking of kappa opioid receptors. Life Sci 75:511–536

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Ilasaca M (1998) Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol 56:269–277

    Article  CAS  PubMed  Google Scholar 

  • Lozama A, Prisinzano TE (2009) Chemical methods for the synthesis and modification of neoclerodane diterpenes. Bioorg Med Chem Lett 19:5490–5495

    Article  CAS  PubMed  Google Scholar 

  • Marinissen MJ, Gutkind JS (2001) G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22:368–376

    Article  CAS  PubMed  Google Scholar 

  • McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:1574–1577

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin JP, Marton-Popovici M, Chavkin C (2003a) Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 23:5674–5683

    CAS  PubMed  Google Scholar 

  • McLaughlin JP, Xu M, Mackie K, Chavkin C (2003b) Phosphorylation of a carboxyl-terminal serine within the kappa-opioid receptor produces desensitization and internalization. J Biol Chem 278:34631–34640

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin JP, Myers LC, Zarek PE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Chavkin C (2004) Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance. J Biol Chem 279:1810–1818

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C (2006) Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacology 31:1241–1248

    Google Scholar 

  • McLennan GP, Kiss A, Miyatake M, Belcheva MM, Chambers KT, Pozek JJ, Mohabbat Y, Moyer RA, Bohn LM, Coscia CJ (2008) Kappa opioids promote the proliferation of astrocytes via Gbetagamma and beta-arrestin 2-dependent MAPK-mediated pathways. J Neurochem 107:1753–1765

    Article  CAS  PubMed  Google Scholar 

  • Minden A, Karin M (1998) Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta 1333:F85–F104

    Google Scholar 

  • Minneman KP, Iversen IL (1976) Enkephalin and opiate narcotics increase cyclic GMP accumulation in slices of rat neostriatum. Nature 262:313–314

    Article  CAS  PubMed  Google Scholar 

  • Negus SS, Mello NK, Linsenmayer DC, Jones RM, Portoghese PS (2002) Kappa opioid antagonist effects of the novel kappa antagonist 5′-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys. Psychopharmacology (Berl) 163:412–419

    Article  CAS  Google Scholar 

  • Nobes C, Hall A (1994) Regulation and function of the Rho subfamily of small GTPases. Curr Opin Genet Dev 4:77–81

    Article  CAS  PubMed  Google Scholar 

  • Pan ZZ (2003) Kappa-opioid receptor-mediated enhancement of the hyperpolarization-activated current (I(h)) through mobilization of intracellular calcium in rat nucleus raphe magnus. J Physiol 548:765–775

    Article  CAS  PubMed  Google Scholar 

  • Perez DM, Karnik SS (2005) Multiple signaling states of G-protein-coupled receptors. Pharmacol Rev 57:147–161

    Article  CAS  PubMed  Google Scholar 

  • Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776

    Article  CAS  PubMed  Google Scholar 

  • Pierce KL, Lefkowitz RJ (2001) Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci 2:727–733

    Article  CAS  PubMed  Google Scholar 

  • Pierce KL, Tohgo A, Ahn S, Field ME, Luttrell LM, Lefkowitz RJ (2001) Epidermal growth factor (EGF) receptor-dependent ERK activation by G protein-coupled receptors: a co-culture system for identifying intermediates upstream and downstream of heparin-binding EGF shedding. J Biol Chem 276:23155–23160

    Article  CAS  PubMed  Google Scholar 

  • Piñeyro G (2009) Membrane signalling complexes: implications for development of functionally selective ligands modulating heptahelical receptor signalling. Cell Signal 21:179–185

    Article  PubMed  Google Scholar 

  • Prasad HC, Zhu CB, McCauley JL, Samuvel DJ, Ramamoorthy S, Shelton RC, Hewlett WA, Sutcliffe JS, Blakely RD (2005) Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A 102:11545–11550

    Article  CAS  PubMed  Google Scholar 

  • Raman M, Chen W, Cobb MH (2007) Differential regulation and properties of MAPKs. Oncogene 26:3100–3112

    Article  CAS  PubMed  Google Scholar 

  • Raynor K, Kong H, Hines J, Kong G, Benovic J, Yasuda K, Bell GI, Reisine T (1994) Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappa opioid receptor. J Pharmacol Exp Ther 270:1381–1386

    CAS  PubMed  Google Scholar 

  • Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology (Berl.) 200:59–70

    Google Scholar 

  • Rockman MV, Hahn MW, Soranzo N, Zimprich F, Goldstein DB, Wray G (2005) Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol 3:e387

    Article  PubMed  Google Scholar 

  • Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci U S A 99:11934–11939

    Article  CAS  PubMed  Google Scholar 

  • Rumbaugh G, Adams JP, Kim JH (2006) Huganir RL (2006) SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci U S A 103:4344–4351

    Article  CAS  PubMed  Google Scholar 

  • Rusin KI, Giovannucci DR, Stuenkel EL, Moises HC (1997) Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. J Neurosci 17:6565–6574

    CAS  PubMed  Google Scholar 

  • Sadja R, Alagem N, Reuveny E (2003) Gating of GIRK channels: details of an intricate, membrane-delimited signaling complex. Neuron 39:9–12

    Article  CAS  PubMed  Google Scholar 

  • Samuvel DJ, Jayanthi LD, Bhat NR, Ramamoorthy S (2005) A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression. J Neurosci 25:29–41

    Article  CAS  PubMed  Google Scholar 

  • Shahabi NA, McAllen K, Sharp BM (2006) delta opioid receptors stimulate Akt-dependent phosphorylation of c-jun in T cells. J Pharmacol Exp Ther 316:933–939

    Article  CAS  PubMed  Google Scholar 

  • Smith C, Rahman T, Toohey N, Mazurkiewicz J, Herrick-Davis K, Teitler M (2006) Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor. Mol Pharmacol 70:1264–1270

    Article  CAS  PubMed  Google Scholar 

  • Song X, Coffa S, Fu H, Gurevich VV (2009) How does arrestin assemble MAPKs into a signaling complex? J Biol Chem 284:685–695

    Article  CAS  PubMed  Google Scholar 

  • Spencer RJ, Jin W, Thayer SA, Chakrabarti S, Law PY, Loh HH (1997) Mobilization of Ca2+ from intracellular stores in transfected neuro2a cells by activation of multiple opioid receptor subtypes. Biochem Pharmacol 7:809–818

    Article  Google Scholar 

  • Steiner JA, Carneiro AM, Blakely RD (2008) Going with the flow: trafficking-dependent and -independent regulation of serotonin transport. Traffic 9:1393–1402

    Article  CAS  PubMed  Google Scholar 

  • Stephenson RP (1956) A modification of receptor theory. Br J Pharmacol 11:379–393

    CAS  Google Scholar 

  • Stiene-Martin A, Mattson MP, Hauser KF (1993) Opiates selectively increase intracellular calcium in developing type-1 astrocytes: role of calcium in morphine-induced morphologic differentiation. Brain Res Dev Brain Res 76:189–196

    Article  CAS  PubMed  Google Scholar 

  • Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317

    Article  CAS  PubMed  Google Scholar 

  • Taussig R, Iñiguez-Lluhi JA, Gilman AG (1993) Inhibition of adenylyl cyclase by Gi alpha. Science 261:218–221

    Article  CAS  PubMed  Google Scholar 

  • Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183

    Article  CAS  PubMed  Google Scholar 

  • Tibbles LA, Woodgett JR (1999) The stress-activated protein kinase pathways. Trends Neurosci 28:436–445

    Google Scholar 

  • Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320:1–13

    Article  CAS  PubMed  Google Scholar 

  • Violin JD, Lefkowitz RJ (2007) Beta-arrestin-biased ligands at seven transmembrane receptors. Trends Pharmacol Sci 28:416–422

    Article  CAS  PubMed  Google Scholar 

  • Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology 33:643–652

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Tang K, Inan S, Siebert D, Holzgrabe U, Lee DY, Huang P, Li JG, Cowan A, Liu-Chen LY (2005) Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. J Pharmacol Exp Ther 312:220–230

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (2008) 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A. J Pharmacol Exp Ther 324:1073–1083

    Article  CAS  PubMed  Google Scholar 

  • Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455

    Article  CAS  PubMed  Google Scholar 

  • Wickman KD, Clapham DE (1995) G-protein regulation of ion channels. Curr Opin Neurobiol 5(3):278–285

    Article  CAS  PubMed  Google Scholar 

  • Xu M, Bruchas MR, Ippolito DL, Gendron L, Chavkin C (2007) Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase J Neurosci 27:2570–2581

    Article  CAS  PubMed  Google Scholar 

  • Yan F, Bikbulatov RV, Mocanu V, Dicheva N, Parker CE, Wetsel WC, Mosier PD, Westkaemper RB, Allen JA, Zjawiony JK, Roth BL (2009) Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor. Biochemistry 48:6898–6908

    Article  CAS  PubMed  Google Scholar 

  • Zhu CB, Carneiro AM, Dostmann WR, Hewlett WA, Blakely RD (2005) p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. J Biol Chem 280:15649–15658

    Article  CAS  PubMed  Google Scholar 

  • Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (2006) A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:3551–3560

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institute on Drug Abuse U.S. Public Health Service Grants DA25970, DA20570, and DA25182 and the Hope for Depression Research Foundation.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA

    Michael R. Bruchas & Charles Chavkin

Authors
  1. Michael R. Bruchas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles Chavkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles Chavkin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bruchas, M.R., Chavkin, C. Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology 210, 137–147 (2010). https://doi.org/10.1007/s00213-010-1806-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-1806-y

Keywords

Search

Navigation