Selective blocking effects of tropisetron and atropine on recombinant glycine receptors

Some serotonin 5-MH3 receptor ligands of tropeine structure have been recen tly shown to modulate ionophore function and binding of glycine receptors. This led us to study the effects of the tropeines tropisetron and atropine on recombinant human glycine receptors transiently expressed in Xenopus ooc ytes by using whole-cell voltage-clamp electrophysiology, Glycine currents were inhibited by atropine in an apparently competitive manner and with con siderable selectivity of the tropeines for alpha(2) versus alpha(1) subunit s. Coexpression of beta with alpha subunits and replacement of the N-termin al region of the alpha(1) subunits by the corresponding beta segment result ed in similar increases in the inhibitory potencies. Our data suggest commo n sites of the tropeines for inhibition on the N-terminal region of glycine receptors, The point mutations R271K and R271L of the alpha(1) subunit dec reased, whereas a T112A substitution increased, the inhibition constants (K -i) of the tropeines, These changes in the K-i values of the tropeines were associated with opposite changes in the EC50 of glycine, Selectivities for the tropeines versus glycine (EC50/K-i) varied within three orders of magn itude. These results, when expressed in terms of free energy changes, can b e interpreted according to a two-state receptor model.