Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors

Abstract Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylat...

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Bibliographic Details
Published in:Endocrine reviews 2024-09, Vol.45 (5), p.755-771
Main Author: Potter, Lincoln R
Format: Article
Language:English
Subjects:
Achondroplasia
Animals
Bone density
Bone growth
Cyclic GMP
Dephosphorylation
Enzymes
Gametocytes
Guanylate cyclase
Homology
Humans
Hypertrophy
Inactivation
Kinases
Long bone
Meiosis
Membranes
Mice
Peptides
Phosphorylation
Receptors
Receptors, Atrial Natriuretic Factor - metabolism
Receptors, Guanylate Cyclase-Coupled - metabolism
Sea urchins
Signal Transduction - physiology
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Summary:Abstract Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylated on 4 to 7 conserved serines or threonines at the beginning of their kinase homology domains. This review describes studies that demonstrate that phosphorylation and dephosphorylation are required for activation and inactivation of these enzymes, respectively. Phosphorylation sites in GC-A, GC-B, GC-E, and sea urchin receptors are discussed, as are mutant receptors that mimic the dephosphorylated inactive or phosphorylated active forms of GC-A and GC-B, respectively. A salt bridge model is described that explains why phosphorylation is required for enzyme activation. Potential kinases, phosphatases, and ATP regulation of GC receptors are also discussed. Critically, knock-in mice with glutamate substitutions for receptor phosphorylation sites are described. The inability of opposing signaling pathways to inhibit cGMP synthesis in mice where GC-A or GC-B cannot be dephosphorylated demonstrates the necessity of receptor dephosphorylation in vivo. Cardiac hypertrophy, oocyte meiosis, long-bone growth/achondroplasia, and bone density are regulated by GC phosphorylation, but additional processes are likely to be identified in the future. Graphical Abstract Graphical Abstract
ISSN:0163-769X
1945-7189
1945-7189
DOI:10.1210/endrev/bnae015