Allosteric Modulation of the Human 5-HT7A Receptor by Lipidic Amphipathic Compounds

摘要: Human 5-HT7A receptors positively modulated adenylyl cyclases via Gs subtypes of G proteins in human embryonic kidney 293 cells, and bound 5-hydroxytryptamine (HT) with high low affinity (K(I) values 1.5 +/- 0.3 93 4 nM). More than 60% receptors, however, displayed the high-affinity 5-HT binding no sensitivity to 5'-guanylylimidodiphosphate. In this study, we found that select amphipathic agents affected 5-HT7A. Oleic acid at concentrations (<15 microM), but not palmitic, stearic, arachidonic acids, increased maximal [3H]5-HT without affecting its K(D) value [3H]mesulergine (antagonist) binding. Fatty acid-free bovine serum albumin (FF-BSA), a scavenger fatty acids lipid metabolites, substantially reduced (no change antagonist binding) lost action upon treatment inactive stearic acid. FF-BSA oleic produced appreciable effects on analogous 5-HT1D 5-HT2C. Among various lysophospholipids, lysophosphatidyl choline (50 microM) decreased binding, similar zwitterion, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS; 0.1%), it K(D)). Functionally, 5-HT-induced guanosine-5'-O-(3-[35S]thio)triphosphate (GTPgamma35S) was enhanced by CHAPS, choline; did affect dopamine-induced GTPgamma35S D1, prototypic Gs-coupled receptor. At 5-HT7A, acid, FF-BSA, also brought about corresponding changes half-maximal concentration for cAMP production, basal levels. We propose endogenous, metabolites may modulate allosterically promote enable couple more efficiently proteins.