CLONING AND EXPRESSION OF AN ATP-REGULATED HUMAN RETINA C-TYPE NATRIURETIC FACTOR RECEPTOR GUANYLATE-CYCLASE

The natriuretic factors are structurally related polypeptide hormones that regulate the hemodynamics of the physiological processes of diuresis, water balance, and blood pressure. Presumably, these hormones act through the activation of guanylate cyclases which are also the specific receptors of these hormones. Two such structurally similar cell surface receptors are known; the ligand for one is atrial natriuretic factor (ANF) and for the other is C-type natriuretic peptide (CNP). Studies with ANF receptor guanylate cyclase (ANF-RGC) have indicated that its ligand binding site is extracellular and the catalytic site is intracellular, but the mere ligand binding to the receptor domain does not activate the cytosolic catalytic domain. An intervening ATP-mediated event is obligatory: ATP binds to a defined ATP-regulated module (ARM) sequence and bridges the events of ligand binding and signal transduction. The mechanism of CNP signaling is not known, although CNP in intact cells transfected with CNP receptor guanylate cyclase (CNP-RGC) stimulates the formation of cyclic GMP. Furthermore, there is no prior evidence of the presence of CNP signal transduction system in retina, although the presence of ANF-RGC has been documented. We now report the molecular cloning and expression of CNP-RGC from human retina and show that ATP is obligatory in CNP signaling also. Compared to the previously published sequence of CNP-RGC cDNA isolated from human brain, the sequence of retinal cDNA reveals three new structural aspects at the noncoding regions: (1) it contains an additional stretch of 367 nucleotides at the 5' region; (2) this stretch is followed by a 37-nucleotide sequence that is different from the corresponding brain sequence; and (3) the 3' region contains an additional sequence of 20 nucleotides. The presence of signal transducers for both ANF and CNP peptides in retina suggests that these peptides, in addition to their traditional roles as regulators of the hemodynamic processes of cardiovasculature, have additional modulatory roles in the neural retina also.