title: The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids.
abstract: The sigma1 receptor is distinguished for its ability to bind various pharmacological agents including drugs of abuse such as cocaine and methamphetamine. Some endogenous ligands have been identified as putative sigma1 receptor regulators. High affinity ligands for the sigma1 receptor contain a nitrogen atom connected to long alkyl chains. We found that long alkyl chain primary amines including endogenous amines belonging to the sphingolipid family such as D-erythro-sphingosine and sphinganine bind with considerable affinity to the sigma1 receptor but not to the sigma2 receptor. The binding of D-erythro-sphingosine to the sigma1 receptor appears to be competitive in nature as assessed against the radioligand [3H]-(+)-pentazocine. Interestingly, the well studied sphingolipid mediator sphingosine-1 phosphate did not bind to the sigma1 or the sigma2 receptor. Sphingosine is converted to sphingosine-1 phosphate by a family of sphingosine kinases that regulate the relative levels of these two bioactive lipids in the cell. The selective binding of sphingosine but not sphingosine-1 phosphate to the sigma1 receptor suggests a mechanism for regulation of sigma1 receptor activity by the sphingosine kinase. We have successfully reconstituted this hypothetical model in HEK-293 cells overexpressing both the sigma1 receptor and sphingosine kinase-1. The data presented here strongly supports sphingosine as an endogenous modulator of the sigma1 receptor.
authors.affiliation: Department of Pharmacology, University Wisconsin-Madison, School of Medicine and Public Health, 1300 University Ave., Madison, WI 53706, USA. sramachandr4@wisc.edu
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Uyen B
authors.initials: UB
authors.lastname: Chu
authors.forename: Timur A
authors.initials: TA
authors.lastname: Mavlyutov
authors.forename: Arindam
authors.initials: A
authors.lastname: Pal
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Ruoho
mesh_terms: D000588:Amines / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004347:Drug Interactions; D000939:Epitopes; D004926:Escherichia coli / Q000235:genetics; D006168:Guinea Pigs; D006639:Histidine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D008024:Ligands; D008099:Liver / Q000378:metabolism; D058619:Maltose-Binding Proteins; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010423:Pentazocine / Q000037:antagonists & inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000737:chemistry / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000588:Amines; D002352:Carrier Proteins; D000939:Epitopes; D006639:Histidine; D008024:Ligands; D058619:Maltose-Binding Proteins; D010423:Pentazocine; D017853:Phosphotransferases (Alcohol Group Acceptor); D017480:Receptors, sigma; D013107:Sphingolipids; D013110:Sphingosine; D000099157:Sphingosine Kinase; C481931:erythro-(2R,3S)-sphingosine