G-protein-coupled receptors (GPCRs) are important drug targets and are involved in a wide variety of physiology and diseases. Crucially, there are still more than 140 orphan GPCRs, and deciphering their function remains a priority for pharmaceutical sciences. Research on orphan GPCRs has concentrated mainly on the identification of their natural ligands, whereas mounting data suggest additional ligand-independent functions for these receptors. Here we report the identification of ligand-independent (constitutive) basal activities of the orphan receptor GPRS. To analyze agonist-independent receptor activity, we generated doxycycline-inducible stable cell lines expressing the untagged wild-type receptor. Using these cell lines, we searched for receptor-dependent changes in the levels of second messengers or byproducts of G-protein signaling (cAMP and inositol phosphate IP₁, a breakdown product of IP₃). Adenylyl cyclases are primarily activated by Gαs, but can also be differentially regulated by Gβγ or Ca²⁺, so it is important to assay downstream activation of both Gαi/o and Gαq/11 pathways, respectively. For assaying Gαi/o activity, the cells were simultaneously treated with forskolin to increase basal cAMP levels. To evaluate Gαq/11 activity, we quantified IP₁ levels. We observed that the receptor was strongly induced upon doxycycline treatment. Out of the assay formats for measuring cAMP and IP₁ levels, we only detected a significant reduction of cAMP levels in induced cells. To confirm whether the observed reduction of cAMP is caused by the receptor itself, we further analyzed inducible cell lines expressing a mutant receptor that contains a point mutation at the highly conserved DRYxxV motif (a sequence considered to be required for coupling of GPCRs to the partner G-proteins). Importantly, no appreciable reduction of cAMP was detected when the mutant receptor was induced, while the increase in protein levels was similar to the wild-type receptor. We conclude that the orphan receptor GPRS has an agonist-independent basal activity that leads to the reduction of cAMP.