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Abstract
The effects of tagetone on flunitrazepam (FNTZ) binding to synaptosomal membranes from chick brains in the presence and absence of allosteric modulations induced by gamma-aminobutyric acid (GABA) were investigated. Tagetone, at 50 mu g/ml (final concentration), decreased the binding affinity of [3H]FNTZ to synaptosomal membranes form chick brain (Kd=3.34 +/- 0.36 nM without tagetone and Kd,t=5.86 +/- 0.86 nM with tagetone; p<0.05, two tailed Student's t-test) without affecting maximal binding (Bmax=488 +/- 24 fmoles/mg protein, and Bmax,t=500 +/- 25 fmoles/ mg protein in the absence and in the presence of tagetone respectively). The potency of GABA to stimulate [3H]FNTZ binding increased in the presence of tagetone (EC50 values were 2.78 and 1.12 mu M with and without tagetone respectively). GABA was able to decrease merocyanine Delta A570-610 values in a concentration dependent manner; half maximal effect was attained at a GABA concentration of 34 +/- 13 mu M. Tagetone, at a concentration of 50 mu g/ml and in the presence of GABA 30 mu M or 60 mu M, enhanced the ability of GABA alone on decreasing Delta A570-610. Tagetone alone did not change Delta A570-610 values. FNTZ, a well known GABA modulator, could also potentiate the effect of GABA. Theoretical calculations indicate that the effects on merocyanine Delta A value are mainly exerted at the membrane potential level (Delta Psim). The present results strongly suggest that tagetone affected the function of GABAA receptor in a complex way: on the one hand it impaired FNTZ binding; on the other hand tagetone improved both the coupling between FNTZ and GABA binding sites and it enhanced GABA-induced chloride permeability. Changes in the geometrical and electrostatic properties of the self-organized membrane structure may account for these effects of tagetone.