Zrt- and Irt-like protein 8 (ZIP8) (ZIP8)

Zrt- and Irt-like protein 8 (ZIP8), encoded by the SLC39A8 gene, is a transmembrane transporter that mediates the cellular influx of essential divalent cations, including manganese, zinc, and iron, as well as the toxic metal cadmium [1, 3, 6, 14]. It is ubiquitously expressed and plays a pivotal role in maintaining systemic manganese homeostasis, which is vital for the function of manganese-dependent enzymes such as galactosyltransferases and superoxide dismutase 2 [7, 10, 12]. Loss-of-function mutations in SLC39A8 cause a severe congenital disorder of glycosylation (SLC39A8-CDG) and Leigh-like syndrome, characterized by profound neurological and developmental deficits [5, 8, 14]. Common genetic variants, particularly the rs13107325 (Ala391Thr) polymorphism, have been linked to a wide range of complex conditions, including schizophrenia, Crohn's disease, obesity, and cardiovascular disorders [1, 9, 12]. Therapeutically, ZIP8 is an emerging target; while manganese and galactose supplementation are used to manage deficiency states, recent studies have identified small molecules like efavirenz as allosteric potentiators that can enhance its transport activity [1, 4, 7]. However, drug development must carefully navigate the risks of manganese-induced neurotoxicity and the potential for increased accumulation of toxic cadmium [5, 8, 14].

Other names

Solute carrier family 39 member 8SLC39A8Metal cation symporter ZIP8BCG induced integral membrane protein BIGM103Zinc transporter ZIP8ZRT/IRT-like protein 8

Allosteric potentiation of divalent metal ion transport and substrate supplementation