The mechanism by which high concentrations of cAMP selectively destabilize the gp80 mRNA in Dictyostelium discoideum was investigated. This treatment which leads to down-regulation of the cAMP receptor was also found to cause an increase in calcium uptake. Given this observation, we sought a role for calcium as a second messenger in the degradation of the gp80 mRNA. Changes in the mRNA levels were examined after treating cells with compounds known to alter their intracellular Ca2+ concentrations. This included the use of A23187, Ca2+, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate HC1 (TMB-8), LiCl and 8-p-chlorophenylthioadenosine 3',5'-cyclic monophosphate (ClPhS-Ado-3':5'-P). The sum of the data suggest that it is the cAMP-induced influx of Ca2+ across the plasma membrane, as apposed to a cAMP-mediated release of Ca2+ from intracellular stores, that initiates gp80 mRNA degradation. Treatment of cells with Concanavalin A (ConA) to induce cAMP receptor down-regulation, also causes a reduction in gp80 mRNA levels and an increase in calcium uptake.