Paracellin-1 and the modulation of ion selectivity of tight junctions

被引:191
作者
Hou, JH
Paul, DL
Goodenough, DA
机构
[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA
关键词
paracellin-1; ion selectivity; tight junction; hypomagnesemia;
D O I
10.1242/jcs.02631
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tight junctions play a key selectivity role in the paracellular conductance of ions. Paracellin-1 is a member of the tight junction claudin protein family and mutations in the paracellin-1 gene cause a human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe renal Mg2+ wasting. The mechanism of paracellin-1 function and its role in FHHNC are not known. Here, we report that in LLC-PK1 epithelial cells paracellin-1 modulated the ion selectivity of the tight junction by selectively and significantly increasing the permeability of Na+ (with no effects on Cl-) and generated a high permeability ratio of Na+ to Cl-. Mutagenesis studies identified a locus of amino acids in paracellin-1 critical for this function. Mg 2, flux across cell monolayers showed a far less-pronounced change (compared to monovalent alkali cations) following exogenous protein expression, suggesting that paracellin-1 did not form Mg2+-selective paracellular channels. We hypothesize that in the thick ascending limb of the nephron, paracellin-1 dysfunction, with a concomitant loss of cation selectivity, could contribute to the dissipation of the lumen-positive potential that is the driving force for the reabsorption of Mg2+.
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页码:5109 / 5118
页数:10
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