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Both guanosine 5'-triphosphate (GTP) and 5'-guanylylimidodiphosphate (GMP-PNP) inhibited the specific binding of ¹²⁵I-labelled calcitonin to tubular membranes purified from rat renal cortex. The number of receptor sites was reduced but the affinity of calcitonin for its receptors remained unchanged. Guanosine 5'-triphosphate and GMP-PNP were active at much lower concentrations (10 µmol/l) than other nucleotides. Their inhibitory effects could not be explained by chelation and persisted after the washing of pre-incubated membranes. Neither of these guanyl nucleotides was able to modify the rate of degradation of ¹²⁵I-labelled calcitonin.

Guanosine 5'-triphosphate and GMP-PNP also activated adenylate cyclase under basal conditions and in the presence of calcitonin, the maximum effect being obtained at a concentration of 100 µmol/l, but did not modify fluoride-sensitive adenylate cyclase. The affinity of calcitonin for the enzyme was higher in the presence of these guanyl nucleotides, particularly with GMP-PNP. The concentrations of calcitonin corresponding to 50% maximum adenylate cyclase activation (K_m) for the reaction without guanyl nucleotides, with GTP and with GMP-PNP were 1·9, 0·67 and 0·06 nmol/l respectively.

The relationship between the number of receptors occupied and adenylate cyclase activity was calculated from Hill equations derived from binding experiments and enzyme assays after incubation for 25 min. The values obtained with and without guanyl nucleotides were clearly different since the occupancy of the same percentage of receptors corresponded to much greater activation of adenylate cyclase when guanyl nucleotides were present. These data show that at the concentration at which it is found in the plasma, calcitonin can activate renal adenylate cyclase only in the presence of guanyl nucleotides.

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