Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP.

ABSTRACT: P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targets. Although several P2X3 structures are known, it is unclear how physiologically abundant Ca²⁺-ATP and Mg²⁺-ATP activate the receptor, or how divalent cations regulate channel function. We used structural, computational and functional approaches to show that a crucial acidic chamber near the nucleotide-binding pocket in human P2X3 receptors accommodates divalent ions in two distinct modes in the absence and presence of nucleotide. The unusual engagement between the receptor, divalent ion and the γ-phosphate of ATP enables channel activation by ATP-divalent complex, coope

SUBMITTER: Li M 

PROVIDER: S-EPMC6590987 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature