Psychopharmacology

, Volume 210, Issue 2, pp 137–147

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

Review

DOI: 10.1007/s00213-010-1806-y

Cite this article as:
Bruchas, M.R. & Chavkin, C. Psychopharmacology (2010) 210: 137. doi:10.1007/s00213-010-1806-y

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.

Keywords

Kappa opioid receptor Dynorphin Kinase MAPK GPCR Ligand-directed signaling p38 ERK 1/2 JNK Relapse Stress Opioid Arrestin Depression Addiction Therapeutics 

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of WashingtonSeattleUSA

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