Structural basis of neurosteroid anesthetic action on GABAA receptors [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 571.3 Anatomy and morphology
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: Article No. 3972 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260145
• Chủ đề: 1. 59 basic biological sciences; 2. 60 applied life sciences

Tóm tắt

 Type A ?-aminobutyric acid receptors (GABA<
 sub>
 A<
 /sub>
 Rs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABA<
 sub>
 A<
 /sub>
 R transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABA<
 sub>
 A<
 /sub>
 R structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric ?1GABA<
 sub>
 A<
 /sub>
 R (ELIC-?1GABA<
 sub>
 A<
 /sub>
 R). The chimera retains the functional and pharmacological properties of GABA<
 sub>
 A<
 /sub>
 Rs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1?TM2 linker. The study provides a framework to discover new GABA<
 sub>
 A<
 /sub>
 R modulators with therapeutic potential.