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1 Harry S. Truman Memorial Veterans Hospital and Departments of 2 Pharmacology, and 3 Pathology and Anatomical Sciences, School of Medicine, Missouri University, Columbia, Missouri 65212; and 4 Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
Uroguanylin,
guanylin, and lymphoguanylin are small peptides that
activate renal and intestinal receptor guanylate cyclases (GC). They
are structurally similar to bacterial heat-stable enterotoxins (ST)
that cause secretory diarrhea. Uroguanylin, guanylin, and ST elicit
natriuresis, kaliuresis, and diuresis by direct actions on kidney GC
receptors. A 3,762-bp cDNA characterizing a uroguanylin/guanylin/ST receptor was isolated from opossum kidney (OK) cell RNA/cDNA. This
kidney cDNA (OK-GC) encodes a mature protein containing 1,049 residues
sharing 72.4-75.8% identity with rat, human, and porcine forms of
intestinal GC-C receptors. COS or HEK-293 cells expressing OK-GC
receptor protein were activated by uroguanylin, guanylin, or
ST13 peptides. The 3.8-kb OK-GC
mRNA transcript is most abundant in the kidney cortex and intestinal
mucosa, with lower mRNA levels observed in urinary bladder, adrenal
gland, and myocardium and with no detectable transcripts in skin or
stomach mucosa. We propose that OK-GC receptor GC participates
in a renal mechanism of action for uroguanylin and/or
guanylin in the physiological regulation of urinary sodium, potassium,
and water excretion. This renal tubular receptor GC may be a target for
circulating uroguanylin in an endocrine link between the intestine and
kidney and/or participate in an intrarenal paracrine mechanism for
regulation of kidney function via the intracellular second messenger, cGMP.
guanosine 3',5'-cyclic monophosphate; uroguanylin; OK cells
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