1.A.7.1.5
The purinergic receptor, P2X4, is sensitive to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating (Samways et al., 2012). The secondary structure and gating rearrangements of TMSs in rat P2X4 receptor channels have been proposed (Silberberg et al. 2005). Bile acids inhibit the human P2X4 (Ilyaskin et al. 2019). The gating mechanism has been discussed (Du et al., 2012) and considered to be determined by the conformation of the transmembrane domain (Minato et al. 2016; Pierdominici-Sottile et al. 2016). The crystal structure of the ATP-gated P2X4 ion channel in the closed state has been reported (Kawate et al., 2009). Unobstructed lateral portals are preferentially used as access routes to the pores of P2X receptors (Samways et al., 2011).  Activation is ATP-dependent and rapid, but desensitization occurs within seconds and is ATP-independent (Stojilkovic et al. 2010). Ectodomain cysteines play roles in agonist binding and channel gating (Rokic et al. 2010).  Evermectin has distinct effects on opening and dilation of the channel pore, the first accounting for increased peak current amplitude, and the latter correlating with changes in the kinetics of receptor deactivation (Zemkova et al. 2014). Conserved amino acids within the regions linking the ectodomain with the pore-forming transmembrane domain may contribute to signal transduction and channel gating (Gao et al. 2015; Jelínkova et al. 2008). Binding of ATP produces distortions in the chains that eliminate restrictions on the interchain displacements, leading to the opening of the pore (Pierdominici-Sottile et al. 2016). The purinergic receptors, P2RX4 and P2RX7, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017). P2X4 modulators are used for the treatment of alcohol use disorders (Reyes-Espinosa et al. 2020). Lithocholic acid inhibits P2X2 and potentiates P2X4 receptor channel gating (Sivcev et al. 2020). Therapeutic targeting of the P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma modelshas been achieved (Rupert et al. 2023). A role for K_ATP channels in cytotoxicity of cells that are primed for a rapid immune response has been reported (Feske et al. 2024).