Endomorphin-1 and endomorphin-2 are partial agonists at the human μ-opioid receptor

Hosohata, Keiko; Burkey, Thomas H.; Alfaro-Lopez, Josue; Varga, Éva; Hruby, Victor J.; Roeske, William R.; Yamamura, Henry I.

doi:10.1016/s0014-2999(98)00117-4

Cited by 53 publications

(31 citation statements)

References 13 publications

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“…The endomorphins were reported to be partial agonists at MOPr in some cases, such as in GTP␥S binding assays with spinal cord and thalamus (Hosohata et al, 1998;Narita et al, 1998;Sim et al, 1998;Xie et al, 2008) and in inhibition of neuronal Ca 2ϩ currents (Connor et al, 1999), whereas the endomorphins behaved as full agonists in other cases, such as inhibition of contraction of mouse vas deferens (Al-Khrasani et al, 2001;Rónai et al, 2006); such differences are likely to depend in part on the receptor reserve in each tissue. In the present study with LC neurons, we found endomorphin-2 to be a full agonist for activation of GIRK current.…”

Section: Discussionmentioning

confidence: 99%

“…35 S]GTP␥S binding assays revealed the endomorphins to have low efficacy values close to those of morphine (Hosohata et al, 1998;Narita et al, 1998;Sim et al, 1998;Xie et al, 2008) but the endomorphins were able to induce efficient trafficking of MOPr under conditions where morphine was ineffective (Burford et al, 1998;McConalogue et al, 1999;Trafton et al, 2000). The advantages of quantifying efficacy with full concentration-response curves and of examining occupancy-response relationships are that such differences can be observed more clearly and can be quantified.…”

Section: Discussionmentioning

confidence: 99%

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Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

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Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the -opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [DAla 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K ϩ current in a concentrationdependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K ϩ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

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“…The first saturable transport system across the BBB to be shown for a peptide was for Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH 2 ) (Banks and Kastin 1984). Endomorphin-1 (EM-1) and endomorphin-2 (EM-2), are two endogenous peptides selectively activating mu-opiate receptors (Zadina et al 1997;Goldberg et al 1998;Gong et al 1998;Hosohata et al 1998). The endormorphins are structurally similar to Tyr-MIF-1.…”

Section: Introductionmentioning

confidence: 99%

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Vı́gh

Kastin

Liao

et al. 2004

Experimental Brain Research

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Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two highly selective mu-opiate receptor agonists. We recently demonstrated that EM-1 and EM-2 have a saturable transport system from brain-to-blood in vivo. Since the endothelial cells are the main component of the non-fenestrated microvessels of the blood-brain barrier (BBB), we examined whether these endogenous tetrapeptides have a saturable transport system in cultured cerebral endothelial cells. EM-1 and EM-2 binding and transport were studied in a transwell system in which primary mouse endothelial cells were co-cultured with rat glioma cells. We found that binding of both endomorphins was greater on the basolateral than the apical cell surface. Flux of EM-1 and EM-2 occurred predominantly in the basolateral to apical direction, each showing self-inhibition with an excess of the respective endomorphin. Transport was not influenced by the addition of the Pglycoprotein inhibitor, cyclosporin A. Neither the mu-opiate receptor agonist DAMGO nor the delta-opiate receptor agonist DPDPE had any effect on the transport. Thus, the results show that a saturable transport system for EM-1 and EM-2 occurs at the level of endothelial cells of the BBB, and unlike β-endorphin and morphine, P-glycoprotein is not needed for the brain-to-blood transport. Cross-inhibition of the transport of each endomorphin by the other suggests a shared transport system that is different from mu-or delta-opiate receptors. As endormorphins are mainly produced in the CNS, the presence of the efflux system at the BBB could play an important role in pain modulation and neuroendocrine control.

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“…The first one concerns the different influences of the two endomorphins on the MOP-R (11, 13, 14, 42, 53 -56). The second one is that the endomorphin peptides are found to be partial agonists of the MOP-R (57,58). The third question is that the distribution of the MOP-R is similar but not identical to that of two endomorphins.…”

Section: The Morphological Relationships Between Endomorphins and Mop-rmentioning

confidence: 99%

Recent Advances in the Search for the N-Opioidergic System: Morphological Studies of the Endomorphinergic Neurons in the Central Nervous System

Wang

Zadina

Guan

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-Endomorphins (EMs) are newly found endogenous opioid peptides. Both endomorphin-1 (EM-1) and -2 (EM-2) are composed of four amino acids. Their high affinity and specificity for m-opioid receptors have been confirmed by many physiological and pharmacological studies. In the present minireview, we discuss the distribution and localization of these peptides. While EM-2 is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. We also discuss the possible coexistence of EM with other neurotransmitters. Finally, we introduce some new results regarding the ultrastructure and synaptic relationships of EM-2 obtained by the immunoelectron microscopic method.Keywords: Endomorphin, Distribution, Coexistence, Ultrastructure, SynapseEndomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2) are endogenous agonists for the m-opioid receptors (MOP-R) first isolated from bovine (1) and then from human brain cortex (2). Endomorphins (EMs) activate G-proteins (3 -6) and inhibit calcium (7,8) and activate potassium (9) channels. The peptides have been reported to be involved in many physiological phenomena, including pain modulation (1, 10 -14), feeding responses (15), oxygen consumption (16), blood pressure regulation (17 -19) and modulation of endocrine function (20,21). EMs are the only endogenous peptides that exhibit high affinity and selectivity for MOP-R. In addition, EM-1 is the first agonist for MOP-R shown to produce profound potent analgesia in the absence of reward behavior, indicating significant clinical potential (22). For these reasons, the morphological study of the endomorphinergic neurons in the central nervous system is of extraordinary interest. EM-1 has been shown to be the predominant form in the brain, while EM-2 is predominant in the spinal cord (23). We discuss them separately and then discuss the relationship to MOP-R. We also report some recent findings concerning the ultrastructure and synaptic relationships of the EM-2-like immunoreactive (EM2-LI) neuronal processes in the dorsal horn of the spinal cord. The distribution of the EM2-LI neurons in the central nervous systemThe first paper on the distribution of the EM2-LI neurons was published in 1997 (24) soon after the discovery of this peptide (1). In the first paper, the EM2-LI varicose fibers were reported in a long, narrow region, extending from the open medulla oblongata to the lowest level of the sacral spinal cord. Most of these immunoreactive fibers were distributed in the superficial laminae of the spinal dorsal horn and the entire region of the spinal trigeminal tract. The nucleus of the solitary tract, the parasolitary nucleus, the lateral reticular nucleus, and the nucleus ambiguus were also reported as containing EM2-LI fibers (24). Subsequently, the distribution of the EM2-LI fibers in the spinal cord was confirmed many times and by different laboratories (23, 25 -30). Similarly, many studies contributed data concerning the a...

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Endomorphin-1 and endomorphin-2 are partial agonists at the human μ-opioid receptor

Cited by 53 publications

References 13 publications

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Recent Advances in the Search for the N-Opioidergic System: Morphological Studies of the Endomorphinergic Neurons in the Central Nervous System

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