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

J Cell Sci. 2005 Nov 1;118(Pt 21):5109-18. doi: 10.1242/jcs.02631. Epub 2005 Oct 18.


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+.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cations, Divalent / metabolism
  • Cell Line
  • Cell Membrane Permeability / genetics
  • Cell Membrane Permeability / physiology*
  • Claudins
  • Codon, Initiator / genetics
  • Dogs
  • Humans
  • LLC-PK1 Cells
  • Magnesium / metabolism
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Molecular Sequence Data
  • Mutation, Missense
  • Point Mutation
  • Protein Biosynthesis
  • Subcellular Fractions / metabolism
  • Swine
  • Tight Junctions / genetics
  • Tight Junctions / metabolism*


  • Cations, Divalent
  • Claudins
  • Codon, Initiator
  • Membrane Proteins
  • claudin 16
  • Magnesium