Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis.

Megan R Beggs, Kennedi Young, Wanling Pan, Debbie D O'Neill, Matthew Saurette, Allein Plain, Juraj Rievaj, Michael R Doschak, Emmanuelle Cordat, Henrik Dimke, R Todd Alexander

Proceedings of the National Academy of Sciences of the United States of America 2021 Nov 30

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Calcium (Ca2+) homeostasis is maintained through coordination between intestinal absorption, renal reabsorption, and bone remodeling. Intestinal and renal (re)absorption occurs via transcellular and paracellular pathways. The latter contributes the bulk of (re)absorption under conditions of adequate intake. Epithelial paracellular permeability is conferred by tight-junction proteins called claudins. However, the molecular identity of the paracellular Ca2+ pore remains to be delineated. Claudins (Cldn)-2 and -12 confer Ca2+ permeability, but deletion of either claudin does not result in a negative Ca2+ balance or increased calciotropic hormone levels, suggesting the existence of additional transport pathways or parallel roles for the two claudins. To test this, we generated a Cldn2/12 double knockout mouse (DKO). These animals have reduced intestinal Ca2+ absorption. Colonic Ca2+ permeability is also reduced in DKO mice and significantly lower than single-null animals, while small intestine Ca2+ permeability is unaltered. The DKO mice display significantly greater urinary Ca2+ wasting than Cldn2 null animals. These perturbations lead to hypocalcemia and reduced bone mineral density, which was not observed in single-KO animals. Both claudins were localized to colonic epithelial crypts and renal proximal tubule cells, but they do not physically interact in vitro. Overexpression of either claudin increased Ca2+ permeability in cell models with endogenous expression of the other claudin. We find claudin-2 and claudin-12 form partially redundant, independent Ca2+ permeable pores in renal and colonic epithelia that enable paracellular Ca2+ (re)absorption in these segments, with either one sufficient to maintain Ca2+ balance. Copyright © 2021 the Author(s). Published by PNAS.

Citation

Megan R Beggs, Kennedi Young, Wanling Pan, Debbie D O'Neill, Matthew Saurette, Allein Plain, Juraj Rievaj, Michael R Doschak, Emmanuelle Cordat, Henrik Dimke, R Todd Alexander. Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2021 Nov 30;118(48)