| |
[摘要]：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 beta-sheet trigger channel activation. Homology modeling reveals that the beta 4-beta 5 linker physically connects the neurotransmitter binding site to the inner beta-sheet. Inserting 1, 2, 4, and 8 glycines in this region of the GABA(A) receptor beta-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 alpha- and gamma-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. |
|
