COEXPRESSION OF 5-HT2A AND 5-HT4 RECEPTORS COUPLED TO DISTINCT SIGNALING PATHWAYS IN HUMAN INTESTINAL MUSCLE-CELLS

Background & Aims: The type and function of 5-hydroxytryptamine (5-HT) receptors on intestinal muscle cells in humans are not known. 5-HT re ceptors were characterized pharmacologically and by radioligand bindin g. Methods: Contraction, relaxation, inositol 1,4,5-triphosphate (IP3) and adenosine 3',5'-cyclic monophosphate (cAMP) formation, and 5-HT b inding were measured in dispersed muscle cells and in cells in which o nly one receptor type was preserved by selective receptor protection. Results: 5-HT binding was completely inhibited by 5-HT and partially b y 5-HT2A (ketanserin), 5HT(4) (SDZ-205,557), and 5HT(1p) (N-acetyl-5-h ydroxytryptophyl-5-hydroxytryptophan amide; 5-HTP-DP) receptor antagon ists. 5-HT caused contraction that was inhibited by ketanserin and aug mented by SDZ-205,557 and 5-HTP-DP. In the presence of ketanserin, 5-H T caused relaxation of cholecystokinin-contracted cells that was inhib ited by SDZ-205,557 and 5-HTP-DP. 5HT increased IP3, which was inhibit ed by ketanserin, and cAMP, which was inhibited by SDZ-205,557 and 5-H TP-DP. In cells with only 5-HT2A receptors, 5-HT caused contraction on ly, and residual binding was inhibited by ketanserin. In cells with on ly 5-HT4/5-HT1p receptors, 5-HT caused only relaxation and residual bi nding was inhibited by SDZ-205,557 and 5-HTP-DP. Conclusions: 5-HT2A r eceptors mediating contraction and 5-HT4 receptors mediating relaxatio n coexist on human intestinal muscle cells. The 5HT(4) receptors are c losely similar or identical to 5HT(1p) receptors.