Selective interaction of bile acids with muscarinic receptors: a case of molecular mimicry.
Bile acids alter regulatory pathways in several cell types. The molecular basis for these actions is not fully elucidated, but lithocholyltaurine interacts functionally with muscarinic receptors on gastric chief cells. In the present report, we demonstrate selective interaction of bile acids with Chinese hamster ovary (CHO) cells expressing each of the five muscarinic receptors. Lithocholyltaurine decreases binding of a radioligand to muscarinic M3 receptors, but not to other muscarinic receptors. Sulfated lithocholyltaurine, the major human metabolite, inhibits radioligand binding to muscarinic M1, but not to M2 or M3 receptors. Post-receptor actions of lithocholyltaurine include modulation of acetylcholine-induced increases in inositol phosphate formation and mitogen-activated protein (MAP) kinase phosphorylation. Molecular modeling suggests that the specific and functional interaction of lithocholyltaurine with muscarinic receptors is most likely due to similar shape and surface charge distribution of portions of acetylcholine and the bile acid. We propose that bile acids are signaling molecules whose effects may be mediated by interaction with muscarinic receptors.
Raufman
Jean Pierre
JP
Division of Gastroenterology and Hepatology, VA Maryland Health Care System and the University of Maryland Medical System, 22 S. Greene Street, Room N3W62, Baltimore, MD 21201-1595, USA. jraufman@medicine.umaryland.edu
Chen
Ying
Y
Cheng
Kunrong
K
Compadre
Cesar
C
Compadre
Lilia
L
Zimniak
Piotr
P
D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D018727:Muscarinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D019832:N-Methylscopolamine / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011869:Radioligand Assay; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013658:Taurolithocholic Acid / Q000378:metabolism / Q000494:pharmacology
D001647:Bile Acids and Salts; D007295:Inositol Phosphates; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D013658:Taurolithocholic Acid; D008095:Lithocholic Acid; D020928:Mitogen-Activated Protein Kinases; D000109:Acetylcholine; C027746:glycolithocholic acid; D019832:N-Methylscopolamine