Ca2+-Guanine Nucleotide Interactions in Brain Membranes. I. Modulation of Central 5-Hydroxytryptamine Receptors in the Rat

Abstract: The present study indicates that central 5-hydroxytryptamine (5-HT; serotonin) receptors can be modulated in opposite directions by Ca²⁺ and guanine nucleotides guanosine triphosphate (GTP), β, γ-imidoguanosine 5′-triphosphate (GppNHp)]. Thus CaCl₂ (≥0.5 mm ) inhibited whereas GTP and GppNHp (10 μm ) stimulated the 5-HT-sensitive adenylate cyclase in the hippocampus of newborn rats. Both the affinity (K_d ^?1) and the number (B_max) of ³H]5-HT binding sites in hippocampal membranes from adult rats were increased in the presence of Ca²⁺ (≥0.25 mm ); GTP (≥0.1 mm ) and GppNHp (≥0.3; μm ) produced reverse effects. The efficacy of guanine nucleotides in inhibiting specific ³H]5-HT binding was counteracted by Ca²⁺: the addition of this cation (5mm -CaCl₂) to the assay mixture resulted in a 40-fold increase in the IC₅₀ for GTP; the IC₅₀ for GppNHp increased five-fold under the same condition. The examination of the respective effects of Ca²⁺ and of GTP on the specific binding of ³H]5-HT to various hippocampal membrane preparations (from developing rats, from subcellular fractions of adult tissues, and from adult rats after the selective degeneration of serotoninergic innervation in the forebrain) indicated that the amplitudes of the Ca²⁺-induced increase and of the GTP-induced decrease were generally correlated. This conclusion did not apply to striatal membranes of kainic acid-treated rats because ³H]5-HT binding sites persisting after the intrastriatal injection of kainic acid (i.e., half of the total number in striatal membranes from control rats) were markedly less affected by GTP but at least as responsive as control membranes to the Ca²⁺-induced increase. These data are compatible with the hypothesis of a possible coupling of some–but not all–³H]5-HT binding sites to adenylate cyclase in the rat brain.