Staying Hydrated

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Science  20 May 2005:
Vol. 308, Issue 5725, pp. 1088
DOI: 10.1126/science.308.5725.1088d

The peptide vasopressin (antidiuretic hormone) is critical for maintaining fluid homeostasis. Its receptor, V2R, is located at the surface of epithelial cells lining the kidney's collecting duct. Receptor activation increases water permeability through aquaporin, leading to the retention of water. Mutation of an arginine residue to histidine at position 137 of V2R blocks receptor activation, resulting in nephrogenic diabetes insipidus, in which patients suffer from severe dehydration due to excessive water excretion. The critical arginine is located within a motif that is highly conserved in the family of G protein-coupled receptors.

Feldman et al. find that if the arginine is mutated to either cysteine or leucine, the opposite condition occurs—excessive water retention—and they refer to this condition as nephrogenic syndrome of inappropriate antidiuresis. The mutations were identified in two infants who displayed the abnormal water overload characteristic of hyperactivated V2R, even though both patients lacked detectable vasopressin. It remains to be determined how mutations at the same position either activate or inactivate the receptor, causing genetic disorders of opposite character. — LDC

N. Engl. J. Med. 352, 1884 (2005).

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