Opioid Receptors

Author: Gianpiero Pescarmona
Date: 14/06/2010


Opioid Receptors

Sigma1 and Sigma2 non-opioid receptors

Tesi sigma1 e sigma2


In the quest of sigma2



1. FUNCTION: Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration.
2. SUBUNIT: Forms a ternary complex with ANK2 and ITPR3. The complex is disrupted by agonists. Interacts with KCNA4 (By similarity).
3. SUBCELLULAR LOCATION: Nucleus inner membrane. Nucleus outer membrane. Endoplasmic reticulum membrane. Lipid droplet. Cell junction. Cell membrane. Cell projection, growth cone. Note=Targeted to lipid droplets, cholesterol and galactosylceramide-enriched domains of the endoplasmic reticulum. Enriched at cell-cell communication regions, growth cone and postsynaptic structures. Localization is modulated by ligand- binding.
4. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=5; Name=1; IsoId=Q99720-1; Sequence=Displayed; Name=2; IsoId=Q99720-2; Sequence=VSP_021982; Name=3; Synonyms=Sigma-R1A; IsoId=Q99720-3; Sequence=VSP_021986; Name=4; IsoId=Q99720-4; Sequence=VSP_021984, VSP_021985; Name=5; IsoId=Q99720-5; Sequence=VSP_021981, VSP_021983; Note=No experimental confirmation available;
5. TISSUE SPECIFICITY: Widely expressed with higher expression in liver, colon, prostate, placenta, small intestine, heart and pancreas. Expressed in the retina by retinal pigment epithelial cells.
6. MISCELLANEOUS: Depletion by RNAi inhibits growth and survival signaling cascades and induces cell death. The antagonist rimcazole produces the same effect.
7. SIMILARITY: Belongs to the ERG2 family.
8. WEB RESOURCE: Name=Wikipedia; Note= Sigma-1 receptor entry

Cent Nerv Syst Agents Med Chem. 2009 Sep;9(3):184-9.
Sigma-1 receptor chaperones and diseases.
Tsai SY, Hayashi T, Mori T, Su TP.

Cellular Pathobiology Section, Cellular Neurobiology Research Branch, IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Baltimore, MD 21224, USA.
Chaperones are proteins that assist the correct folding of other protein clients either when the clients are being synthesized or at their functional localities. Chaperones are responsible for certain diseases. The sigma-1 receptor is recently identified as a receptor chaperone whose activity can be activated/deactivated by specific ligands. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca(2+) signaling from endoplasmic reticulum into mitochondrion. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca(2+) homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. The sigma-1 receptor has been implicated in many diseases including addiction, pain, depression, stroke, and cancer. Whether the chaperone activity of the sigma-1 receptor attributes to those diseases awaits further investigation.

Papers sigma 1 receptor calcium


1. FUNCTION: Receptor for bile acid. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids.
2. SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
3. TISSUE SPECIFICITY: Ubiquitously expressed. Expressed at higher level in spleen and placenta. Expressed at lower level in other tissues. In digestive tissues, it is expressed in stomach, duodenum, ileocecum, ileum, jejunum, ascending colon, transverse colon, descending colon, cecum and liver, but not in esophagus and rectum.
4. SIMILARITY: Belongs to the G-protein coupled receptor 1 family.

Papers tgr5 or gpbar1

Papers tgr5 expression

Novel interaction of bile acid and neural signaling in the regulation of cholangiocyte function. 2007

Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts. 2006

UDCA and TUDCA enhanced intracellular Ca2+ and IP3 levels, together with increased phosphorylation of protein kinase C-alpha. Parallel changes were observed regarding the activation of the MAPK and PI3K pathways, changes that were abolished by addition of BAPTA/AM or Gö6976. (a Ca2+-dependent protein kinase C-alpha inhibitor).

Bile acids induce Ca2+ release from both the endoplasmic reticulum and acidic intracellular calcium stores through activation of inositol trisphosphate receptors and ryanodine receptors. 2006

Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance. 2000


1. INTERACTION: P00519:ABL1; NbExp=1; IntAct=EBI-954396, EBI-375543;
2. SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor (Potential).
4. CAUTION: There seems to be two proteins encoded by the FAM127A gene, one with a C-terminal CAAX box (the sequence shown here) and a smaller protein (AC A6ZKI3).


SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein (Potential).

Brain Res. 1995 Mar 27;675(1-2):110-20.
Distinct neuroprotective profiles for sigma ligands against N-methyl-D-aspartate (NMDA), and hypoxia-mediated neurotoxicity in neuronal culture toxicity studies. 1995

Lockhart BP, Soulard P, Benicourt C, Privat A, Junien JL.

INSERM U-336, Développement, Plastieité et Vieillissement du Système Nerveux, Ecole Nationale Supérieure de Chimie, Montpellier, France.

Substantiating evidence has raised the possibility that sigma ligands may have therapeutic potential as neuroprotective agents in brain ischemia. It has been suggested that the neuroprotective capacity of sigma ligands is related primarily to their affinity for the NMDA receptor complex and not to any selective action at the sigma binding site. However, sigma specific ligands, devoid of significant affinity for the NMDA receptor, are also neuroprotective via an inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. In the present study, we have investigated the potential neuroprotective effect of a comprehensive series of sigma ligands, with either significant (sigma/PCP) or negligible (sigma) affinity for the PCP site of the NMDA receptor, in order to delineate a selective sigma site-dependent neuroprotective effect. For this aim, we have employed two different neuronal culture toxicity paradigms implicating either postsynaptic-mediated neurotoxicity, (brief exposure of cultures to a low concentration of NMDA or Kainate) or pre- and postsynaptic mechanisms (exposure to hypoxic/hypoglycemic conditions). Only sigma ligands with affinity for the NMDA receptor [(+) and (-) cyclazocine, (+) pentazocine, (+) SKF-10047, ifenprodil and haloperidol] were capable of attenuating NMDA-induced toxicity whereas the sigma [(+)BMY-14802, DTG, JO1784, JO1783, and (+)3-PPP] and kappa-opioid [CI-977, U-50488H] ligands, with very low affinity for the NMDA receptor, were inactive. The rank order of potency, based on the 50% protective concentration (PC50) value, of sigma/PCP ligands against NMDA-mediated neurotoxicity correlates with their affinity for the PCP site of the NMDA receptor, and not with their affinity for the sigma site. In addition sigma/PCP, sigma or kappa-opioid ligands failed to attenuate kainate-mediated neurotoxicity. On the other hand, sigma/PCP, sigma and kappa-opioid ligands were potent inhibitors of hypoxia/hypoglycemia-induced neurotoxicity, although their neuroprotective potency did not correlate with their affinity for either the sigma or PCP binding sites. In conclusion, the ability of sigma and kappa-opioid ligands to attenuate hypoxia/hypoglycemia, but not NMDA or kainate-induced toxicity, suggests that these drugs exert their neuroprotective role by a predominantly presynaptic mechanism possibly by inhibiting ischemic-mediated glutamate release.

2012-07-11T15:31:15 - Eleonora Bonfanti

Opioid receptors are prototypical G-protein coupled receptors belonging to the subfamily of rhodopsin receptors and consist of approximately 400 amino acids. On a molecular basis, they possess 7 α-helical transmembrane domains and an extracellular N-terminus with multiple glycosylation sites. MOR, DOR, and KOR are highly homologous to each other at the sequence and post-translational levels, with particularly high conservation in the regions spanning the transmembrane domains and intracellular loops. Divergence can be found at the N- and C-termini as well as the extracellular loops, accounting for the unique pharmacological properties of these receptors. Opioid receptors can couple to both pertussis toxin-sensitive and insensitive G-proteins, with coupling characteristics differing slightly between the receptor types. A series of studies describing biphasic effects of low and high concentrations of opioids on enkephalin release from the guinea-pig myenteric plexus illustrates the potential for diversity of opioid actions. Low concentrations (<10 nM) of mu, delta, or kappa agonists enhanced stimulated release, whereas higher concentrations (>10 nM) inhibit the stimulated release of enkephalin. Importantly, the inhibitory and enhancing effects could be dissociated based on the class of G protein coupled to the respective effects. Pertussis toxin, which inactivates Gi and Go classes of G proteins, could block the inhibitory effects of high opioid concentrations, leaving the enhancement by low concentrations uneffected. The converse was true when cholera toxin treatment was used to decrease Gs activity. Enhancement of release by low concentrations of opioids was blocked by cholera toxin, whereas the inhibitory effects of higher opioid concentrations was unaffected.
G-protein coupling of opioid receptors to their effectors can be direct or involve intermediate or other indirect effector pathways. Activation of inwardly rectifying K+ channels (GIRK+), inhibition of voltage-dependent Ca2+ channels as well as inhibition of adenylyl cyclase are direct G-protein-coupled effects of opioid receptor activation. In addition to the well-known inhibition of adenylate cyclase, some evidence has indicated that an opioid-mediated enhancement of this activity can also be demonstrated at low agonist concentrations. Evidence describing opioid regulation of additional second messenger systems has also been reported. In particular, kappa agonists affect the turnover of phosphatidylinositol (PI). Both positive and inhibitory effects on PI turnover have been reported in the hippocampus and cerebellum, respectively. Infact, opioid receptors can activate phospholipase C (PLC), the mitogen-activated protein kinase (MAPK) cascade, and large conductance Ca2+-activated K+ channels by utilising other intermediary messenger systems. Modification of Ca2+ and K+ conductance by opioid receptors can lead to a decrease in neuronal excitability, a decrease in neuronal firing rate, and inhibition of neurotransmitter release. Functionally, opioid receptors have been implicated in regulation of pain, reinforcement, reward, neuroendocrine modulation, and alteration in neuro-transmitter release. The consequence of opioid receptor activation appears to be correlated closely with the anatomical location as well as expression levels of the opioid receptor subtypes.

Opioid receptor expression and function in the central nervous system
Opioid receptors are widely and differentially distributed in the CNS.
MOR, in particular, is widely distributed throughout the forebrain, midbrain, and hindbrain with greatest expression apparent in the neocortex, caudateputamen, nucleus accumbens, thalamus, hippocampus, amygdala, and nucleus tractus solitarius.
This distribution of the MOR is consistent with its suggested role in pain perception as well as sensorimotor integration.
Conversely, KOR has been found to be expressed in moderate amounts in many brain areas, with greatest expression in the caudate putamen, nucleus accumbens, hypothalamus, amygdala, and neural lobe of the pituitary. KOR has been implicated to be involved in feeding, pain perception, and neuroendocrine function.
DOR is particularly highly expressed in olfactory related neural areas, the neocortex, caudate-putamen, nucleus accumbens, and amygdala while exhibiting limited binding in the thalamus, hypothalamus, and brainstem. This distribution corresponds with the suggested involvement of DOR in motor as well as olfactory and cognitive functioning.

Opioid receptor expression and function in the spinal cord and peripheral nervous system
Opioid-mediated analgesia is mediated by modulation of ascending and descending pain pathways. Accordingly, MOR, DOR, and KOR expression has been confirmed in dorsal root ganglia, the spinal cord, and trigeminal nucleus of the ascending pain pathway as well as the central Gray area, pontine, gigantocellulare, and intermediate reticular nuclei of the descending pain pathway, with predominantly MOR and KOR expression in the median raphe and raphe magnus. In the periaqueductal gray region and the nucleus locus coeruleus, opioid receptor agonists produce analgesia by disinhibiting descending fibres through inhibition of Gamma-Aminobutyric acid (GABA)-ergic neuronal inputs, which modulates other descending pathways in turn, such as noradrenergic neurons, to produce analgesia. In addition to spinal and centrally mediated opioid analgesia, opioid receptors expressed on peripheral neurons can also contribute to antinociception.
MOR and KOR have been found to be expressed in the stomach, duodenum, jejunum, ileum as well as proximal and distal colon, where their function is thought to include control of visceral pain, regulation of transit time of luminal contents, and mucosal transport of fluids and electrolytes.
Accordingly, the adverse effect of systemic administration of opioid agonists on GI function is thought to arise primarily from modulation of the enteric pathways governing peristalsis by opioid receptor agonists. The effect of opioid receptor agonists on gut motility and secretion has been utilised clinically in the symptomatic management of diarrhea. Furthermore, opioid receptors may be involved in the modification of GI inflammation, possibly through the protein kinase C-mediated desensitization of chemokine receptors.

Opioid receptor expression and function in nonneuronal tissues
Opioid receptor protein and mRNA have also been described in several nonneuronal tissues such as vascular and cardiac epithelia as well as keratinocytes, although the significance of opioid receptor expression in these nonnociceptive tissues is less clear. MOR, DOR, and KOR are also expressed on various immune cells including lymphocytes and macrophages. Activation of the receptors have been reported to modulate immune function including the macrophage oxidative burst and cytokine production.

Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control

Neuropharmacology of Endogenous Opioid Peptides

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