Allosteric properties of 5-HT₂ receptors in tracheal smooth muscle

Summary

5-Hydroxytryptamine (5-HT)-induced contractions were investigated in isolated tracheal smooth muscle of guinea pig and calf. In guinea-pig tracheae, ketanserin reduced to 60% the maximum response to 5-HT, but also shifted the concentration-effect curve for 5-HT to higher 5-HT concentrations, as expected from its affinity for 5-HT₂ receptors [pK _B=−log K _B=9.6, K _B in mol/l]. The concentration effect-data for the depressant effect of ketanserin are closely associated with the curve for occupancy of 5-HT₂-receptors by ketanserin. In calf tracheae, ketanserin caused surmountable antagonism of the effects of 5-HT with a pK _B of 9.5. Methysergide reduced to 25% the maximum response to 5-HT in guinea-pig tracheae and to 20% in calf tracheae. The methysergide-depressed response to 5-HT was restored by ketanserin to 60% of maximum in guinea-pig tracheae, and to 100% in calf tracheae. The results support for tracheal smooth muscle a model of an allosteric regulation of 5-HT₂-receptors which was proposed for arterial smooth muscle by Kaumann and Frenken (this journal 328:295–300, 1985). The model requires that: 1) the 5-HT₂ receptor exists in two interconvertible states R⇌R′;2) 5-HT causes its effects through R; 3) methysergide, by acting on an allosteric site near or on the 5-HT₂ receptor, shifts the equilibrium into the inactive state R′;4) ketanserin competes with 5-HT for the 5-HT₂ receptor and with methysergide for the allosteric site, thereby restoring the active state R of the 5-HT₂-receptor. All four requirements were experimentally verified in calf trachea. In guinea-pig trachea ketanscrin also appears to possess a partial ability to shift the 5-HT₂ receptor into the inactive R′ state. Thus, ketanserin is both a competitive antagonist at the 5-HT₂ receptor and also appears to be an allosteric modulator at the allosteric site.