Distinct inhibitory ATP-regulated modulatory domain (ARMi) in membrane guanylate cyclases.
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.
Duda
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T
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, Stratford 08084, USA.
Goraczniak
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Sharma
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RK
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D008345:Manganese / Q000378:metabolism; D017354:Point Mutation; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000737:chemistry / Q000378:metabolism; D015183:Restriction Mapping; D012374:Rod Cell Outer Segment / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D014162:Transfection
D008345:Manganese; D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; C073616:atrial natriuretic factor receptor C; D008274:Magnesium