Molecular Pharmacology, Vol 18, 193-198, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

The Effects of Thyroid Status on the Modulation of Fat Cell -Adrenergic Receptor Agonist Affinity by Guanine Nucleotides

¹ Department of Pharmacological Sciences, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794

The influence of thyroid status in vivo on the ability of guanine nucleotides to affect the affinity of fat cell -adrenergic receptors for an (-)agonist is explored in the present study. In euthyroid rat fat cell membranes, 100 µM GTP or Gpp(NH)p induces a reduction in the affinity of specific (-)[³H]dihydroalprenolol binding sites for isoproterenol, but not propranolol. The kinetics of the effect of 100 µM Gpp(NH)p were rapid, achieving near-steady-state levels within 10 mm at 22°C. One micromolar Gpp(NH)p or 5 µM GTP (in the presence of a nucleotide regenerating system) induced half-maximal reduction in the affinity of specific (-)[³H]dihydroalprenolol binding sites for isoproterenol. One hundred micromolar concentrations of either guanine nucleotide produced a maximal effect. The ability of Gpp(NH)p to reduce agonist affinity of the binding sites was shown to be readily reversed by simple washing of the membranes. The affinity of specific (-)[³H]dihydroalprenolol binding sites of fat cell membranes for (-)isoproterenol was reduced in the hypothyroid state. Half-maximal inhibition of specific (-)[³H]dihydroalprenolol binding (at 10 nM radioligand) occurred at 7 µM isoproterenol in hypothyroid, as compared to 1 µM isoproterenol in euthryoid, rat fat cell membranes. In hyperthyroid rat fat cell membranes, only 0.4 µM isoproterenol was required to half-maximally inhibit the specific binding of (-)[³H]dihydroalprenolol. In the presence of 50 µM Gpp(NH)p the concentration of isoproterenol required for half-maximal inhibition of specific binding in euthyroid rat fat cell membranes was increased from 1 to 7 µM. Neither 100 µM GTP nor Gpp(NH)p influenced the affinity of specific (-)[³H]dihydroalprenolol binding sites for isoproterenol in fat cell membranes obtained from hypo-or hyperthyroid rats. These data suggest that thyroid hormones can modulate -adrenergic receptor affinity for agonists (but not antagonists) and the ability of guanine nucleotides to regulate agonist (but not antagonist) affinity in fat cells.

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ACKNOWLEDGMENT The invaluable assistance of Mr. David Herzog is gratefully acknowledged.