Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis
Megan R. Beggs, Kennedi Young, Wanling Pan, Debbie O’Neill, Matthew Saurette, Allein Plain, Juraj Rievaj, Michael R. Doschak, Emmanuelle Cordat, Henrik Dimke, R. Todd Alexander
Abstract
Significance Significant calcium absorption across renal and intestinal epithelia occurs via the paracellular pathway. However, the identity of the paracellular pore involved is unknown. Claudin-2 and claudin-12 contribute paracellular calcium permeability in cell models, but single knockout animals don’t have altered serum calcium or bone mineralization. To investigate this, Cldn2/12 double knockout mice were generated. They display decreased intestinal calcium absorption and renal calcium wasting, resulting in hypocalcemia and markedly reduced bone mineralization. Claudin-2 and claudin-12 don’t physically interact in vitro, and coexpression has an additive effect on calcium permeability. Our work identifies claudin-2 and claudin-12 as important constituents of the paracellular Ca 2+ pathway in intestine and kidney enabling calcium transport and highlights their important complementary roles in maintaining calcium homeostasis.