The zinc-activated channel (ZAC) is a cationic ion channel belonging to the superfamily of Cys-loop receptors, which consists of pentameric ligand-gated ion channels ^[1].

The 1.2 MDa C4-symmetric assembly consists of an ER-embedded transmembrane domain (TMD) in a domain-swapped 6 transmembrane (6TM) cation channel fold that is capped by a large cytosolic domain (CD). In this manner, IP3Rs share significant homology with the much larger and distantly-related RyRs ^[2]. The CD contains all known ligand binding sites, including the IP3 binding site, two Ca²⁺ binding sites, an adenine nucleotide binding site, and a C₂H₂ Zn²⁺ finger fold. A comprehensive Ca²⁺-dependent conformational landscape has been defined by cryo-EM ^[3].

Not only zinc (Zn²⁺) but also copper (Cu²⁺) and protons (H⁺) are agonists of ZAC, displaying potencies and efficacies in the rank orders of H⁺>Cu²⁺>Zn²⁺ and H⁺>Zn²⁺>Cu²⁺, respectively ^[4].