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Further investigation into the signal transduction mechanism of the 5‐HT 4 ‐like receptor in the circular smooth muscle of human colon
Author(s) -
McLean Peter G.,
Coupar Ian M.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15506.x
Subject(s) - adenylyl cyclase , methysergide , chemistry , ibmx , agonist , 5 ht receptor , endocrinology , receptor , phosphodiesterase , muscle relaxation , medicine , rolipram , biophysics , antagonist , forskolin , serotonin , biochemistry , biology , enzyme
1 The nature of the receptor coupling mechanism of the 5‐hydroxytryptamine 4 (5‐HT 4 ) receptor in the circular smooth muscle of the human colon has been further investigated. 2 5‐HT stimulated cyclic AMP generation and caused a relaxation in a concentration‐dependent fashion, with EC 50 values of 175.5 and 274.9 nM respectively. DAU 6236 increased cyclic AMP formation and caused a relaxant effect but was a partial agonist relative to 5‐HT. 3 The 5‐HT 4 receptor antagonist, GR 113808, inhibited cyclic AMP formation and relaxation induced by 5‐HT with ‐log K i values of 9.1 (cyclic AMP) and 8.9 (relaxation) and apparent pA 2 values of 9.2 (cyclic AMP) and 9.5 (relaxation). 4 Ondansetron and methysergide failed to inhibit cyclic AMP formation or the relaxation induced by 5‐HT. 5 The phosphodiesterase inhibitor, IBMX, produced a concentration‐dependent relaxation (EC 50 = 30 μ m ) and at 1 μ m it enhanced the 5‐HT‐induced relaxation producing a leftward shift of the 5‐HT concentration‐effect curve with a concentration‐ratio of 4.1. Rolipram caused a concentration‐dependent relaxation (EC 50 = 564.8 nM) and at 200 nM caused a leftward shift of the concentration‐effect curve to 5‐HT with a concentration‐ratio of 5.5. 6 Application of the adenylyl cyclase inhibitor, SQ 22536 (0.1 mM), and the protein kinase inhibitors, H7 (100 nM) and H89 (200 nM), inhibited the relaxant effect of 5‐HT inducing a rightward shift of the concentration‐effect curve with concentration‐ratios of 10.1, 2.7 and 4.2 respectively. 7 Forskolin stimulated cyclic AMP production and caused a relaxation. The maximum relaxant effect of forskolin (6 μ m , 13.8±1.9 cm.s) was not significantly different from the maximum relaxant effect of 5‐HT (10 μ m , 12.7±4.9 cm.s). However, the cyclic AMP levels stimulated by forskolin (6 μ m , 49.3±6.6 pmol mg −1 ) were markedly greater than those stimulated by 5‐HT (10 μ m , 7.6±2.0 pmol mg −1 ). 8 In conclusion, these results indicate that the 5‐HT 4 receptors of the circular smooth muscle of human colon mediate relaxation and inhibition of spontaneous contractions via activation of adenylyl cyclase, formation of cyclic AMP and activation of protein kinase A.