Yeast mat α2 mutants express both mating pheromones and both mating pheromone receptors. They show modest signaling in the pheromone response pathway, as revealed by increased levels of FUS1 transcript, yet are resistant to pheromone treatment. Together, these phenotypes suggest that α2- cells undergo autocrine activation of the pheromone response pathway, which is subsequently attenuated. We constructed a regulatable version of the α2 gene (GALα2) and showed that, upon loss of α2 activity, cells exhibit an initial robust response to pheromone that is attenuated within 3 h. We reasoned that the viability of α2- cells might be due to attenuation, and therefore performed a genome-wide synthetic lethal screen to identify potential adaptation components. We identified two genes, SST2 and ASG7. Loss of either of these attenuation components results in activation of the pheromone pathway in α2- cells. Loss of both proteins causes a more severe phenotype. Sst2 functions as a GTPase activating protein (GAP) for the G α subunit of the trimeric G protein. Asg7 is an a -cell specific protein that acts in concert with the α-cell specific a -factor receptor, Ste3, to inhibit signaling by Gβγ. Hence, our results suggest that mat α2 mutants mimic the intracellular signaling events that occur in newly fused zygotes.