title: Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases.
abstract: Cyclic GMP is a ubiquitous second messenger that regulates a wide array of physiologic processes such as blood pressure, long bone growth, intestinal fluid secretion, phototransduction and lipolysis. Soluble and single-membrane-spanning enzymes called guanylyl cyclases (GC) synthesize cGMP. In humans, the latter group consists of GC-A, GC-B, GC-C, GC-E and GC-F, which are also known as NPR-A, NPR-B, StaR, Ret1-GC and Ret2-GC, respectively. Membrane GCs are activated by peptide ligands such as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), guanylin, uroguanylin, heat stable enterotoxin and GC-activating proteins. Nesiritide and carperitide are clinically approved peptide-based drugs that activate GC-A. CD-NP is an experimental heart failure drug that primarily activates GC-B but also activates GC-A at high concentrations and is resistant to degradation. Inactivating mutations in GC-B cause acromesomelic dysplasia type Maroteaux dwarfism and chromosomal mutations that increase CNP concentrations are associated with Marfanoid-like skeletal overgrowth. Pump-based CNP infusions increase skeletal growth in a mouse model of the most common type of human dwarfism, which supports CNP/GC-B-based therapies for short stature diseases. Linaclotide is a peptide activator of GC-C that stimulates intestinal motility and is in late-stage clinical trials for the treatment of chronic constipation. This review discusses the discovery of cGMP, guanylyl cyclases, the general characteristics and therapeutic applications of GC-A, GC-B and GC-C, and emphasizes the regulation of transmembrane guanylyl cyclases by phosphorylation and ATP.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA. potter@umn.edu
authors.forename: Lincoln R
authors.initials: LR
authors.lastname: Potter
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D001846:Bone Development; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*
chemical_list: D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C414616:guanyl cyclase-B receptor; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP