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).
3. TISSUE SPECIFICITY: Ubiquitous.
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.