Altered allostery of the left flipper domain underlies the weak ATP response of rat P2X5 receptors.

摘要: Although the extracellular ATP-gated cation channel purinergic receptor P2X5 is widely expressed in heart, skeletal muscle, and immune nervous systems mammals, little known about its functions channel-gating activities. This lack of knowledge due to P2X5's weak ATP responses several mammalian species, such as humans, rats, mice. WT human (hP2X5Δ328-349) does not respond ATP, whereas a full-length variant, hP2X5 (hP2X5-FL), containing exon 10 encoding second transmembrane domain (TM2), does. However, although rat (rP2X5) has TM2, induces only currents rP2X5, which prompted us investigate mechanism underlying this small response. Here, we show that single replacements specific rP2X5 residues with corresponding (S191F or F195H) significantly enhance current amplitude rP2X5. Using combination engineered disulfide cross-linking, single-channel recording, molecular modeling, interrogated effects S191F F195H substitutions on allostery left flipper (LF) domain. On basis our findings, propose bound ATP-induced distinct LF other functional subtypes caused response receptors. The findings study provide prerequisite for future transgenic studies physiological pathological