Ca2+-Permeable Channels/Ca2+ Signaling in the Regulation of Ileal Na+/Gln Co-Transport in Mice

Oral glutamine (Gln) has been widely used in gastrointestinal (GI) clinical practice, but it is unclear if Ca²⁺ regulates intestinal Gln transport, although both of them are essential nutrients for mammals. Chambers were used to determine Gln (25 mM)-induced I _sc through Na⁺/Gln co-transporters in the small intestine in the absence or the presence of selective activators or blockers of ion channels and transporters. Luminal but not serosal application of Gln induced marked intestinal I _sc , especially in the distal ileum. Lowering luminal Na⁺ almost abolished the Gln-induced ileal I _sc , in which the calcium-sensitive receptor (CaSR) activation were not involved. Ca²⁺ removal from both luminal and serosal sides of the ileum significantly reduced Gln- I _sc . Blocking either luminal Ca²⁺ entry via the voltage-gated calcium channels (VGCC) or endoplasmic reticulum (ER) release via inositol 1,4,5-triphosphate receptor (IP₃R) and ryanodine receptor (RyR) attenuated the Gln-induced ileal I _sc , Likewise, blocking serosal Ca²⁺ entry via the store-operated Ca²⁺ entry (SOCE), TRPV1/2 channels, and Na⁺/Ca²⁺ exchangers (NCX) attenuated the Gln-induced ileal I _sc . In contrast, activating TRPV1/2 channels enhanced the Gln-induced ileal I _sc . We concluded that Ca²⁺ signaling is critical for intestinal Gln transport, and multiple plasma membrane Ca²⁺-permeable channels and transporters play roles in this process. The Ca²⁺ regulation of ileal Na⁺/Gln transport expands our understanding of intestinal nutrient uptake and may be significant in GI health and disease.