Structure and activity of OK-GC: a kidney receptor guanylate cyclase activated by guanylin peptides

Uroguanylin, guanylin, and lymphoguanylin are small peptides that activate renal and intestinal receptor guanylate cyclases (GC). They are structurall y similar to bacterial heat-stable enterotoxins (ST) that cause secretory d iarrhea. Uroguanylin, guanylin, and ST elicit natriuresis, kaliuresis, and diuresis by direct actions on kidney GC receptors. A 3,762-bp cDNA characte rizing a uroguanylin/guanylin/ST receptor was isolated from opossum kidney (OK) cell RNA/cDNA. This kidney cDNA (OK-GC) encodes a mature protein conta ining 1,049 residues sharing 72.4-75.8% identity with rat, human, and porci ne forms of intestinal GC-C receptors. COS or HEK-293 cells expressing OK-G C receptor protein were activated by uroguanylin, guanylin, or ST13 peptide s. The 3.8-kb OK-GC mRNA transcript is most abundant in the kidney cortex a nd intestinal mucosa, with lower mRNA levels observed in urinary bladder, a drenal gland, and myocardium and with no detectable transcripts in skin or stomach mucosa. We propose that OK-GC receptor GC participates in a renal m echanism of action for uroguanylin and/or guanylin in the physiological reg ulation of urinary sodium, potassium, and water excretion. This renal tubul ar receptor GC may be a target for circulating uroguanylin in an endocrine link between the intestine and kidney and/or participate in an intrarenal p aracrine mechanism for regulation of kidney function via the intracellular second messenger, cGMP.