Guanyl Nucleotide and Divalent Cation Regulation of Cortical S 2 Serotonin Receptors

Computer‐assisted quantitative analysis of radioligand binding to rat cortical S 2 serotonin receptors indicates the existence of two affinity states of the same receptor population. Monophasic antagonist competition curves for [ 3 H]ketanserin‐labelled sites suggest a uniform population of receptors with one affinity state for antagonists. Biphasic competition curves of agonists suggest that agonists discriminate high‐and low‐agonist‐affinity forms of the S 2 receptors. The affinities of agonists for the high‐and low‐affinity states, and the apparent percentages of high agonist‐affinity forms varies with different agonists. The guanine nucleotides GTP and guanyl‐5′‐imido‐diphosphate [Gpp(NH)p], as well as divalent cations, modulate the proportion of the sites with high affinity for agonists as evidenced by their ability to shift the agonist competition curves for [ 3 H]ketanserin‐labelled S 2 receptors. GTP and Gpp(NH)p effects appear to be agonist‐specific, as they do not affect antagonist competition for [ 3 H]ketanserin‐labelled S 2 receptors, or [ 3 H]ketanserin binding to S 2 receptors. ATP and ADP have little or no effect on the binding properties of S 2 serotonin receptors, whereas GDP is less potent than GTP. The presence of these specific nucleotide effects are the first evidence suggesting involvement of a guanine nucleotide‐binding protein in the mechanism of agonist interaction with the S, serotonin receptor. In general, the binding properties of [ 3 H]ketanserin‐labelled S 2 serotonin receptors strongly resemble those of adenylate‐cyclase coupled receptors such as the β‐adrenergic, the α 2 ‐receptor, and the D‐2 dopamine receptor. This may indicate the S 2 serotonin receptor is coupled to adenylate cyclase activity, through a GTP binding protein.