Cross-talk of opioid peptide receptor and ?-adrenergic receptor signalling in the heart

Abstract

Opioid peptide receptor (OPR) and beta-adrenergic receptor (beta-AR) are well-established members of G-protein-coupled receptor (GPCR) superfamily and are involved in regulating cardiac contractility, energy metabolism, myocyte survival or death. OPRs are typical Gi/Go-coupled receptors and activated by opioid peptides derived from the endorphin, dynorphin and enkephalin families, whereas beta-AR stimulated by catecholamines is the model system for Gs-coupled receptors. While it is widely accepted that beta-AR stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise, we have only begun to appreciate functional roles of OPR stimulation in regulating cardiovascular performance. Cardiovascular regulatory effects of endogenous opioids were initially considered to originate from the central nervous system and involved the pre-synaptic co-release of norepinephrine with enkephalin from sympathetic neuronal terminals in the heart. However, opioid peptides of myocardial origin have been shown to play important roles in local regulation of the heart. Notably, OPR stimulation not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury via activation of Gi-mediated signalling pathways. Further, OPRs functionally and physically cross-talk with beta-ARs via multiple hierarchical mechanisms, including heterodimerization of these receptors, counterbalance of functional opposing G protein signalling, and interface at downstream signalling events. As a result, the beta-AR-mediated positive inotropic effect and increase in cAMP are markedly attenuated by OPR activation in isolated cardiomyocytes as well as sympathectomized intact rat hearts. This brief review will focus on the interaction between beta-AR and OPR and its potential physiological and pathophysiological relevance in the heart.

Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

“…For example, both ␦-OPR and -OPR have been found to associate with ␤ 2 AR (Jordan et al, 2001;McVey et al, 2001;Ramsay et al, 2002), with an important functional consequence being cross-internalization between ␤ 2 AR and ␦-OPR (Jordan et al, 2001). Such heterodimerization between OPRs and ARs may help to explain reports of unusual cross talk between opioid peptides and ␤-adrenergic agonists in various tissues (Pepe et al, , 2004Xiao et al, 1997). The -OPR subtype does not demonstrate any associations with ␤-adrenergic receptors but has been shown to interact with the ␣ 2A -adrenergic receptor (Jordan et al, 2003), the SSTR2A somatostatin receptor (Pfeiffer et al, 2002), and the NK1 substance P receptor (Pfeiffer et al, 2003).…”

Cellular localization and adaptive changes of the cardiac delta opioid receptor system in an experimental model of heart failure in rats

“…Previously, stimulation of cardiac opioid receptors has been shown to be cardioprotective during myocardial infarction possibly by triggering intracellular signaling events similar to ischemic preconditioning [7]. Activation of cardiac G-protein coupled delta opioid receptors (DOR) induces an intracellular kinase pathway in which activation of mitochondrial ATP-sensitive K + -channels seem to play an important role [8][9][10].…”

‘Opioidergic postconditioning’ of heart muscle during ischemia/reperfusion injury

“…Moreover, ORs appear to dimerize with other GRCRs, e.g. a 2 -and b 2 -adrenergic receptors [37] or somatostatin receptors [38]. Thus, the OR dimerization results in altered pharmacological characteristics especially associated with ligand binding.…”