Work

Identification of a putative binding site critical for general anesthetic activation of TRPA1

Year: 2017

Type: article

Abstract: and mouse TRPA1 channels reveal a critical role for the fifth transmembrane domain (S5) in sensing anesthetics. Interestingly, we show that anesthetics share with the antagonist A-967079 a potential binding pocket lined by residues in the S5, S6, and the first pore helix; isoflurane competitively disrupts A-967079 antagonism, and introducing these mammalian TRPA1 residues into dTRPA1 recapitulates anesthetic agonism. Furthermore, molecular modeling predicts that isoflurane and propofol bind to this pocket by forming H-bond and halogen-bond interactions with Ser-876, Met-915, and Met-956. Mutagenizing Met-915 or Met-956 selectively abolishes activation by isoflurane and propofol without affecting actions of A-967079 or the agonist, menthol. Thus, our combined experimental and computational results reveal the potential binding mode of noxious general anesthetics at TRPA1. These data may provide a structural basis for designing drugs to counter the noxious and vasorelaxant properties of general anesthetics and may prove useful in understanding effects of anesthetics on related ion channels.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1618144114

Authors: Hoai T. Ton, Thieu X. Phan, Ara M. Abramyan, Lei Shi, Gerard P. Ahern

Institutions: Vinh University, Georgetown University, National Institutes of Health, National Institute on Drug Abuse

Language: English

Topic: Ion Channels and Receptors

Subfield: Sensory Systems

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: National Institutes of Health, National Institute on Drug Abuse, National Institute of Nursing Research