Diuresis following blood-gorging in Rhodnius prolixus is the major process leading to the transmission of Chagas' disease. We have cloned the cDNA of the first receptor known to be involved in an antidiuretic strategy in insects, a strategy that prevents diuresis. This receptor belongs to the insect CAPA receptor family known in other insects to be activated by peptides encoded within the capability gene. We characterize the expression profile in fifthinstars and find expression is localized to the alimentary canal. Highest transcript levels are found in Malpighian tubules and the anterior midgut, which are known targets of the antidiuretic hormone, RhoprCAPA-α2. Two transcripts were identified, capa-r1 and capa-r2; however, the latter encodes an atypical G proteincoupled receptor lacking a region ranging between the first and second transmembrane domain. Our heterologous expression assay revealed the expressed capa-r1 receptor is activated by Rhopr-CAPA-α2 (EC 50 = 385nM) but not by RhoprCAPA-α1. Structural analogs of the inactive RhoprCAPA-α1 were capable of activating the expressed capa-r1 receptor, confirming the importance of the C-terminal consensus sequence common to CAPA-related peptides. In addition, this receptor has some sensitivity to the pyrokininrelated peptide, RhoprCAPA-αPK1, but with an efficacy ≈40-fold less than RhoprCAPA-α2. Other peptides belonging to the PRXamide superfamily were inactive on the capa-r1 receptor. Taken together, the neuroendocrinological relevance of this receptor in facilitating the antidiuretic strategy in R. prolixus may make this receptor a useful target for development of agonists or antagonists that could help influence the transmission of Chagas' disease that occurs during diuresis in this medically important insectdisease vector.CAPA | Chagas' | G protein-coupled receptor | neurohormone | neuropeptide A major physiological process that allows insects to adopt a variety of feeding strategies and environmental niches is their ability to regulate water and ion composition in their hemolymph. This process involves control over primary urine production via the insect kidney equivalent, the Malpighian (renal) tubules (MTs) and, in a number of insects, the reabsorption of essential salts and water from the hindgut before the final excretae is voided. Insect neurohormones, including peptides and biogenic amines, together with their cognate receptors, carry out an essential role in these and related physiological processes, and numerous neuroendocrine factors regulating fluid and ion balance in insects have been described (see ref.