Characterization and localization of a peripheral neural 5- hydroxytryptamine receptor subtype (5-HT1P) with a selective agonist, 3H-5-hydroxyindalpine

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Abstract
Peripheral neural 5-hydroxytryptamine (5-HT) receptors are different from both classes 5-HT1 and 5-HT2, which have been described from studies of 5-HT receptors in the brain. Recently, it has been shown that, as in the CNS, there is more than a single type of neural receptor for 5-HT in the enteric nervous system. One of these, called 5- HT1P, has a high affinity for 3H-5-HT, initiates a long-lasting depolarization of enteric neurons associated with an increase in membrane resistance, and is the physiological receptor through which enteric serotoninergic neurons mediate slow EPSPs. The other receptor, called 5-HT3 (5-HT2P), does not bind 3H-5-HT with high affinity, and initiates a brief depolarization of enteric neurons with decreased input resistance, but a physiological action of 5-HT mediated by these receptors has not yet been identified. Hydroxylated indalpines have been found to be agonists at 5-HT1P receptors. We have now examined 5- HT1P receptors using 5-hydroxyindalpine (5-OHIP) as a probe. The action of 5-OHIP on enteric neurons was determined electrophysiologically and compared with that of 5-HT; the binding of 3H-5-OHIP to isolated enteric membranes was studied by rapid filtration, and to frozen sections of tissue by radioautography. 3H-5-OHIP binding was compared with that of 3H-5-HT. 5-OHIP, like 5-HT, induced a triphasic response in most enteric neurons: an initial short-lived depolarization, during which input resistance fell, followed by recovery, and then a long- lasting depolarization, during which the input resistance increased. 5- OHIP bound saturably, reversibly, and with high affinity to enteric membranes (Kd = 7.6 +/- 0.7 nM; Bmax = 76 +/- 14 fmol/mg protein). Binding of 3H-5-OHIP was not inhibited by agents that bind to alpha- or beta-adrenoceptors, nicotinic or muscarinic receptors, histamine H1 or H2 receptors, or 5-HT1(A,B,C, or D), 5-HT2, or 5-HT3 receptors, but was displaced by substances, such as hydroxylated indoles and a dipeptide of 5-hydroxytryptophan (5-HTP-DP), that antagonize the binding of 3H-5- HT to enteric membranes or tissue sections. It is concluded that 5-OHIP is an agonist at peripheral neural 5-HT1P receptors and can be used to label these receptors selectively outside the brain. Radioautographs demonstrated enteric 5-HT1P receptors in the lamina propria of the intestinal mucosa and in the submucosal and myenteric plexuses. Extraenteric 5-HT1P receptors were also found in the skin and heart. It is suggested that 5-HT1P receptors may be found on subtypes of primary afferent nerve fibers.

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