Depending upon the cofactors Mg2+ or Mn2+, ATP stimulates or inhibits the signal transduction activities of the natriuretic factor receptor guanylate cyclases, ANF-RGC and CNP-RGC: there is stimulation in the presence of Mg2+ and inhibition in the presence of Mn2+. A defined core ATP-regulated modulatory (ARM) sequence motif within the intracellular ‘kinase-like’ domain of the cyclases is critical for stimulation, but the mechanism of the inhibitory transduction process is not known. In addition, ATP inhibits the basal cyclase activity of a rod outer segment membrane guanylate cyclase (ROS-GC). The mechanism of this inhibitory transduction process is also not known. These issues have been addressed in the present investigation through a program of deletion mutagenesis/expression studies of the cyclases. The study shows that the ATP-mediated inhibitory transduction processes of the natriuretic factor receptor cyclases and of ROS-GC are identical. The ATP-regulated inhibitory domain of all these cyclases resides within the C-terminal segment of the cyclase. This domain is in a different location from the one representing the ATP-stimulatory ARM. The identification of the inhibitory domain in the C-terminal segment of the cyclase indicates that this segment is composed of two separate domains: one representing a catalytic cyclase domain and the other an ATP-regulated inhibitory (ARMi) domain. These findings establish a novel ATP-mediated inhibitory transduction mechanism of the membrane guanylate cyclases which is distinct from that of its counterpart, the stimulatory ATP-mediated hormonal signal transduction mechanism. Thus, they define a new paradigm of guanylate cyclase-linked signal transduction pathways.
Research Article| October 01 1996
Distinct inhibitory ATP-regulated modulatory domain (ARMi) in membrane guanylate cyclases
Rameshwar K SHARMA
Rameshwar K SHARMA *
1The Unit of Regulatory and Molecular Biology, Department of Cell Biology, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, U.S.A.
*To whom correspondence and reprint requests should be addressed.
Search for other works by this author on:
- Views Icon Views
- Share Icon Share
- Cite Icon Cite
Teresa DUDA, Rafal GORACZNIAK, Rameshwar K SHARMA; Distinct inhibitory ATP-regulated modulatory domain (ARMi) in membrane guanylate cyclases. Biochem J 1 October 1996; 319 (1): 279–283. doi: https://doi.org/10.1042/bj3190279
Download citation file: