The family of guanylyl cyclase receptors and their ligands

Abstract

IN 1963, shortly after the discovery of cAMP (1–5), Ashman et al. (6) identified cyclic-GMP (cGMP) in rat urine. Reports soon followed showing that various agents including neurotransmitters and hormones elevated cGMP concentrations in many different cells (for review see Ref. 7). In 1969, three laboratories discovered the enzyme, guanylyl cyclase (8–11). Initial expectations that the enzyme would be regulated in much the same manner as its already exciting sibling, adenylyl cyclase, met with immediate problems. These included the localization of guanylyl cyclase to both the particulate and soluble fractions of cell homogenates, and multiple experimental failures to activate the enzyme in broken cell preparations by agents known to elevate cGMP levels in intact cells. As a consequence, much of the earliest work on guanylyl cyclase concentrated on descriptive features of the soluble and particulate forms. In the mid-1970s, three studies (12–14) provided the first evidence that guanylyl cyclase activities present in the soluble and particulate fractions of cell homogenates appeared to be due to different proteins.