Heterologous supersensitization between serotonin2 and alpha2-adrenergic receptor-mediated intracellular calcium mobilization in human platelets

Summary Recent reports suggest that serotonin (5-HT)₂ receptor-mediated second messenger systems are enhanced in platelets of affective disorders. To make the mechanism of the enhanced response clear, we investigated 5-HT₂ and alpha ()₂-adrenergic receptor-induced intracellular calcium (Ca²⁺) mobilization in platelets of healthy volunteers, using fura-2. 5-HT₂ and ₂-adrenergic receptor-mediated Ca²⁺ mobilization was enhanced by prior exposure to the other type of agonist, so called heterologous supersensitization. The supersensitization was due to the enhancement of maximal response without change in agonist affinity. Chelating extracellular Ca²⁺ did not diminish the supersensitization. This enhancement of Ca²⁺ mobilization was not inhibited by H-7, an inhibitor of protein kinase C. However, this supersensitization was inhibited by pretreatment with sodium fluoride which directly activates guanine nucleotide binding regulatory proteins (G proteins). These results suggest that the supersensitization was caused from intracellular Ca²⁺ storage sites through a G protein-coupled pathway.Abbreviations fura-2/AM 1-(2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy)-2-(2-amino-5-methylphenoxy)-ethane-N,N,N, N-tetraacetic acid, pentaacetoxymethyl ester - H-7 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride - EGTA ethylenedioxybis(ethylamine)-N,N,N,N-tetraacetic acid - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - NaF sodium fluoride - Fmax maximal fluorescence intensity - Fmin minimal fluorescence intensity