Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity (PubMed:15863613, PubMed:16950869, PubMed:18270315, PubMed:19179618, PubMed:21653899, PubMed:28673968). Functions as an energy-dependent symporter, transporting through the membranes an electroneutral complex composed of a divalent metal cation and two bicarbonate anions (PubMed:18270315). Beside these endogenous cellular substrates, can also import cadmium a non-essential metal which is cytotoxic and carcinogenic (PubMed:18270315). Controls the cellular uptake by the intestinal epithelium of systemic zinc, which is in turn required to maintain tight junctions and the intestinal permeability (PubMed:25428902). Modifies the activity of zinc-dependent phosphodiesterases, thereby indirectly regulating G protein-coupled receptor signaling pathways important for gluconeogenesis and chondrocyte differentiation (PubMed:21445361). Regulates insulin receptor signaling, glucose uptake, glycogen synthesis and gluconeogenesis in hepatocytes through the zinc-dependent intracellular catabolism of insulin (PubMed:27703010). Through zinc cellular uptake also plays a role in the adaptation of cells to endoplasmic reticulum stress (PubMed:28673968). Major manganese transporter of the basolateral membrane of intestinal epithelial cells, it plays a central role in manganese systemic homeostasis through intestinal manganese uptake (PubMed:31028174). Also involved in manganese extracellular uptake by cells of the blood-brain barrier (By similarity). May also play a role in manganese and zinc homeostasis participating in their elimination from the blood through the hepatobiliary excretion (PubMed:28536273). Also functions in the extracellular uptake of free iron (PubMed:16950869, PubMed:19179618, PubMed:21653899, PubMed:23110240, PubMed:26028554). May also function intracellularly and mediate the transport from endosomes to cytosol of iron endocytosed by transferrin (PubMed:20682781). Plays a role in innate immunity by regulating the expression of cytokines by activated macrophages (By similarity). 2 hydrogencarbonate(out) + Zn(2+)(out) = 2 hydrogencarbonate(in) + Zn(2+)(in) 2 hydrogencarbonate(out) + Mn(2+)(out) = 2 hydrogencarbonate(in) + Mn(2+)(in) Fe(2+)(out) + 2 hydrogencarbonate(out) = Fe(2+)(in) + 2 hydrogencarbonate(in) Cd(2+)(out) + 2 hydrogencarbonate(out) = Cd(2+)(in) + 2 hydrogencarbonate(in) Inhibited by cyanide and therefore dependent of an energy source (PubMed:18270315). Inhibited by DIDS/4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, an inhibitor hydrogencarbonate-dependent transporters (PubMed:18270315). Optimum pH is 7.5. Optimum temperature is 37 degrees Celsius. Optimum pH is 7.5. Optimum temperature is 37 degrees Celsius. Optimum pH is 7.5 (PubMed:18270315). Optimum temperature is 37 degrees Celsius (PubMed:18270315). Homotrimer. Localized at the basolateral membrane of enterocytes (PubMed:25428902, PubMed:28536273). Enriched at the plasma membrane upon glucose uptake (By similarity). Localized and functional at both apical and basolateral membranes of microvascular capillary endothelial cells that constitute the blood-brain barrier (By similarity). Widely expressed (PubMed:18270315). Highly and transiently expressed during the early stage of adipocyte differentiation. Strongly expressed in liver, preadipocyte, duodenum and jejunum, moderately in brain, heart, skeletal muscle, spleen, pancreas, kidney and white adipose cells. Expression is almost undetectable in lung, testis and brown adipose cells (PubMed:15794747, PubMed:15863613, PubMed:16950869, PubMed:17065364, PubMed:25428902). Expressed by chondrocytes and pituitary cells (PubMed:21445361). More strongly expressed in brain. More strongly expressed in liver, kidney and duodenum. In the KS483 cell model for osteoblast differentiation, expression levels peaks during the mineralization phase (days 18-21 of differentiation). Up-regulated during the lipopolysaccharide/LPS-induced inflammatory response (at protein level) (PubMed:16950869). Up-regulated by IL6 (PubMed:15863613, PubMed:16950869, PubMed:17065364). Up-regulated by interleukin-1/IL1 via nitric oxide (PubMed:19179618). Up-regulated upon endoplasmic reticulum stress induced by tunicamycin or high-fat diet (at protein level) (PubMed:28673968). Up-regulated into hepatocytes upon glucose uptake (at protein level) (PubMed:27703010). Up-regulated by iron in retina (at protein level) (PubMed:28057442). Ubiquitinated. Ubiquitination occurs upon iron depletion. The ubiquitinated form undergoes proteasomal degradation. N-glycosylated (PubMed:18270315, PubMed:21445361). N-glycosylation at Asn-100 is required for iron-regulated extraction of the transporter from membranes and subsequent proteasomal degradation (By similarity). Homozygous knockout mice exhibit growth retardation and dwarfism, visible even in neonates (PubMed:21445361). They exhibit moderate osteoporotic phenotypes associated with decreased bone volume and trabecular number, and increased trabecular separation (PubMed:21445361). The length of the long bones is also significantly reduced (PubMed:21445361). The decrease in bone mass is associated with increased bone resorption (PubMed:29632817). The metabolism of these mice is also affected and they constitute a model of metabolic endotoxemia with high body fat, hypoglycemia and hyperinsulinemia (PubMed:23110240, PubMed:27703010). The knockout of the gene also results in less effective blood manganese elimination and accumulation in the brain where it alters motor functions (PubMed:28536273). Knockout mice also display increased iron absorption and decreased lipopolysaccharide/LPS-induced IL-6 production (PubMed:23110240, PubMed:26028554). The permeability of the intestinal barrier is also compromised (PubMed:25428902). Conditional intestinal-specific knockout of the gene results in increased manganese levels in brain and liver while the liver-specific knockout reduces manganese levels only in liver (PubMed:31028174). Belongs to the ZIP transporter (TC 2.A.5) family. Probable cloning artifact.