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Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine7 receptors

, : Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine7 receptors. Biochemical Pharmacology 58(11): 1807-1813, Dec 1

Oleamide belongs to a family of amidated lipids with diverse biological activities, including sleep induction and signaling modulation of several 5-hydroxytryptamine (5-HT) receptor subtypes, including 5-HT1A, 5-HT2A/2C, and 5-HT7. The 5-HT7 receptor, predominantly localized in the hypothalamus, hippocampus, and frontal cortex, stimulates cyclic AMP formation and is thought to be involved in the regulation of sleep-wake cycles. Recently, it was proposed that oleamide acts at an allosteric site on the 5-HT7 receptor to regulate cyclic AMP formation. We have further investigated the interaction between oleamide and 5-HT7 receptors by performing radioligand binding assays with HeLa cells transfected with the 5-HT7 receptor. Methiothepin, clozapine, and 5-HT all displaced specific (3H)5-HT (100 nM) binding, with pKD values of 7.55, 7.85, and 8.39, respectively. Oleamide also displaced (3H)5-HT binding, but the maximum inhibition was only 40% of the binding. Taking allost eric (see below) cooperativity into account, a KD of 2.69 nM was calculated for oleamide. In saturation binding experiments, oleamide caused a 3-fold decrease in the affinity of (3H)5-HT for the 5-HT7 receptor, without affecting the number of binding sites. A Schild analysis showed that the induced shift in affinity of (3H)5-HT reached a plateau, unlike that of a competitive inhibitor, illustrating the allosteric nature of the interaction between oleamide and the 5-HT7 receptor. Oleic acid, the product of oleamide hydrolysis, had a similar effect on (3H)5-HT binding, whereas structural analogs of oleamide, trans-9,10-octadecenamide, cis-8,9-octadecenamide, and erucamide, did not alter (3H)5-HT binding significantly. The findings support the hypothesis that oleamide acts via an allosteric site on the 5-HT7 receptor regulating receptor affinity.


PMID: 10571256

DOI: 10.1016/s0006-2952(99)00274-9

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