Paracellin-1 and the modulation of ion selectivity of tight junctions.
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. Mg2+ 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+.
Hou
Jianghui
J
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Paul
David L
DL
Goodenough
Daniel A
DA
D000595:Amino Acid Sequence; D000818:Animals; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000235:genetics / Q000502:physiology*; D057167:Claudins; D018387:Codon, Initiator / Q000235:genetics; D004285:Dogs; D006801:Humans; D018374:LLC-PK1 Cells; D008274:Magnesium / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017354:Point Mutation; D014176:Protein Biosynthesis; D013347:Subcellular Fractions / Q000378:metabolism; D013552:Swine; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism*
D002413:Cations, Divalent; D057167:Claudins; D018387:Codon, Initiator; D008565:Membrane Proteins; C502010:claudin 16; D008274:Magnesium