Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.
Classically, there is a direct correlation between the lipophilic nature of a molecule and its rate of permeation across a biological membrane, so cell membranes should be more permeable to small, neutral molecules than they are to charged molecular species of similar size. Consequently, the distribution of NH+4 in biological systems is generally believed to be due to the rapid diffusion and equilibration of lipophilic NH3 across cell membranes and the accumulation of NH+4 to be governed by pH differences between compartments. Here we report that renal tubule cells from the medullary thick ascending limb of Henle have an apical membrane which is not only virtually impermeable to NH3, but is also highly permeable to NH+4. These remarkable properties have been incorporated into a model which explains how this renal epithelium can mediate vectorial movement of NH+4 between compartments of equal pH.
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