title: The natriuretic peptide uroguanylin elicits physiologic actions through 2 distinct topoisomers.
abstract: The peptide uroguanylin regulates electrolyte transport in the intestine and kidney. Human uroguanylin has 2 conformations that can be stably isolated because of their slow interconversion rate. The A isomer potently activates the guanylate cyclase C receptor found primarily in the intestine. The B isomer, by contrast, is a very weak agonist of this receptor, leading to a widely held assumption that it is physiologically irrelevant. We show here, however, that human uroguanylin B has potent natriuretic activity in the kidney. Interestingly, uroguanylin A and B both induce saluretic responses, but the activity profiles for the 2 peptides differ markedly. The uroguanylin B dose-response curve is sigmoidal with a threshold dose of approximately 10 nmol/kg of body weight, whereas uroguanylin A has a comparable threshold but a bell-shaped dose-response curve. In addition, our study indicates a unique interplay between the A and B isoforms, such that the A form at high concentrations antagonizes the natriuretic action of the B form. These data show that the kidney contains a uroguanylin receptor of which the pharmacological profile does not match that of the well-defined intestinal uroguanylin receptor (guanylate cyclase C), an observation consistent with previous studies showing that the kidney of the guanylate cyclase C knockout mouse remains responsive to uroguanylin. The results presented here also support the unconventional notion that distinct conformations of a single endocrine peptide can elicit different responses in different tissues.
authors.affiliation: University of North Carolina at Chapel Hill, Department of Cell and Molecular Physiology, 111 Mason Farm Rd, Chapel Hill, NC 27599, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Moss
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Riguera
authors.forename: Robert M
authors.initials: RM
authors.lastname: Solinga
authors.forename: Marco M
authors.initials: MM
authors.lastname: Kessler
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Zimmer
authors.forename: William J
authors.initials: WJ
authors.lastname: Arendshorst
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
authors.forename: Michael F
authors.initials: MF
authors.lastname: Goy
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D008297:Male; D045265:Natriuretic Peptides / Q000494:pharmacology*; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine
chemical_list: D045265:Natriuretic Peptides; D020033:Protein Isoforms; C084362:uroguanylin; D012964:Sodium; D006162:Guanylate Cyclase