Intestinal Ca²⁺ absorption. At high luminal Ca²⁺ levels (mM range), Ca²⁺ will be absorbed predominantly via the paracellular route. At low luminal levels, Ca²⁺ is being absorbed via the transcellular route as follows: (1) luminal Ca²⁺ is first absorbed via TRPV6 expressed in the brush border membrane; (2) transport of Ca²⁺ to basolateral membrane is facilitated by calbindin-D_9K (calbindin also acts as an intracellular buffer, preventing second messenger signaling during the Ca²⁺ absorptive process); and (3) basolateral exit occurs mostly via the plasma Ca²⁺-pump PMCA1b. During periods of hypocalcemia, 1,25-vitamin D₃ [1,25(OH)₂D₃] upregulates the expression of TRPV6 and calbindin via the nuclear vitamin D receptor (VDR/NR1I1) to stimulate intestinal Ca²⁺ absorption.