Structural link between γ-aminobutyric acid type A (GABAA) receptor agonist binding site and inner β-sheet governs channel activation and allosteric drug modulation.
Rapid opening and closing of pentameric ligand-gated ion channels (pLGICs) regulate information flow throughout the brain. For pLGICs, it is postulated that neurotransmitter-induced movements in the extracellular inner β-sheet trigger channel activation. Homology modeling reveals that the β4-β5 linker physically connects the neurotransmitter binding site to the inner β-sheet. Inserting 1, 2, 4, and 8 glycines in this region of the GABA(A) receptor β-subunit progressively decreases GABA activation and converts the competitive antagonist SR-95531 into a partial agonist, demonstrating that this linker is a key element whose length and flexibility are optimized for efficient signal propagation. Insertions in the α- and γ-subunits have little effect on GABA or SR-95531 actions, suggesting that asymmetric motions in the extracellular domain power pLGIC gating. The effects of insertions on allosteric modulator actions, pentobarbital, and benzodiazepines, have different subunit dependences, indicating that modulator-induced signaling is distinct from agonist gating.
Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
Srinivasan P
SP
Venkatachalan
Cynthia
C
Czajkowski
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D018755:GABA Agonists / Q000737:chemistry* / Q000494:pharmacology*; D018756:GABA Antagonists / Q000737:chemistry / Q000494:pharmacology; D018757:GABA Modulators / Q000737:chemistry / Q000494:pharmacology; D005998:Glycine / Q000737:chemistry; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D010424:Pentobarbital / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000494:pharmacology
D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D011724:Pyridazines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C049853:gabazine; D010424:Pentobarbital; D005998:Glycine