Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP 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 -phosphate of ATP enables channel activation by ATP-divalent complex, cooperatively stabilizes the nucleotide on the receptor to slow ATP unbinding and recovery from desensitization, a key mechanism for limiting channel activity. These findings reveal how P2X3 receptors recognize and are activated by divalent-bound ATP, aiding future physiological investigations and drug development.
| Li, Mufeng; Toombes, Gilman E S; Silberberg, Shai D et al. (2015) Physical basis of apparent pore dilation of ATP-activated P2X receptor channels. Nat Neurosci 18:1577-83 |
| Heymann, Gabriel; Dai, Jian; Li, Mufeng et al. (2013) Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels. Proc Natl Acad Sci U S A 110:E4045-54 |
| Li, Mufeng; Silberberg, Shai D; Swartz, Kenton J (2013) Subtype-specific control of P2X receptor channel signaling by ATP and Mg2+. Proc Natl Acad Sci U S A 110:E3455-63 |
| Kawate, Toshimitsu; Robertson, Janice L; Li, Mufeng et al. (2011) Ion access pathway to the transmembrane pore in P2X receptor channels. J Gen Physiol 137:579-90 |
| Silberberg, Shai D; Swartz, Kenton J (2009) Structural biology: Trimeric ion-channel design. Nature 460:580-1 |
| Li, Mufeng; Chang, Tsg-Hui; Silberberg, Shai D et al. (2008) Gating the pore of P2X receptor channels. Nat Neurosci 11:883-7 |
| Silberberg, Shai D; Li, Mufeng; Swartz, Kenton J (2007) Ivermectin Interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels. Neuron 54:263-74 |
