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

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 Galphai/o inhibition of adenylyl cyclase production of cAMP and releases Gbetagamma, 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 beta-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.

Figure 1. KOR-mediated Signal Transduction

Cartoon depicting the current status of Kappa-opioid receptor (κ) signal transduction pathways. Receptor activation by a variety of KOR-selective ligands, can result in activation of several kinase cascades. Arrows refer to activation steps, T lines refer to blockers or inhibition of function. Abbreviations are as follows: α = G-protein alphai subunit, arrestin = phosphorylation dependent GPCR scaffold, βγ = G-protein beta-gamma subunit, cAMP = cyclic adenosine monophosphate, ERK 1/2 = extra-cellular signal regulated kinase, GRK3 = G-protein coupled receptor kinase3, JAM = JNK Activity Modifier, JNK = c-Jun N-terminal Kinase, p38 = p38 MAPK, P = phosphorylation, pCREB = phospho-cyclic AMP response element binding protein, PI3K = phosphoinositol 3-kinase, PKCζ = protein kinase C zeta, PTX = pertussis toxin, Src = short for sarcoma, member of the src family tyrosine kinases, zif268 = transcription factor, also called Egr-1.

Figure 2. Conceptualization of Collateral Efficacy at Opioid Receptors

Simplified Venn diagram depicting the potential divergence and overlap of various kappa opioid receptor ligand-directed outputs. Depending on the ligand type or bioassay used for detection, opioid receptor ligand interactions can cause the receptor to engage a number of different outputs. For example, the activation of the receptor G-protein might lead to coupling to an ion channel, while also initiating the desensitization machinery. Other ligands may initiate MAPK activation if the ligand causes sufficient receptor phosphorylation, and arrestin recruitment. Finally, some ligands may act on the receptor, not cause activation, but might recruit scaffolds which block the receptor’s ability to couple to G-proteins.