کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1984098 | 1539921 | 2012 | 6 صفحه PDF | دانلود رایگان |
Glycine receptor chloride channels are Cys-loop receptor proteins that isomerize between a low affinity closed state and a high affinity ion-conducting state. There is currently much interest in understanding the mechanisms that link affinity changes with conductance changes. This essentially involves an agonist binding in the glycine receptor ligand-binding site initiating local conformational changes that propagate in a wave towards the channel gate. However, it has proved difficult to convincingly distinguish those agonist-induced domain movements that are critical for triggering activation from those that are simply local deformations to accommodate ligands in the site. We employed voltage-clamp fluorometry to compare conformational changes in the ligand-binding site in response to activation by glycine, which binds locally, and ivermectin, which binds in the transmembrane domain. We reasoned that ivermectin-mediated activation should initiate a conformational wave that propagates from the pore-lining domain towards the ligand-binding domain, eliciting conformational changes in those extracellular domains that are allosterically linked to the gate. We found that ivermectin indeed elicited conformational changes in ligand-binding domain loops C, D and F. This implies that conformational changes in these domains are important for activation. This result also provides a mechanism to explain how ivermectin potentiates glycine-induced channel activation.
► Agonist-induced conformational changes initiate Cys-loop receptor activation.
► It is difficult to define which conformational changes are critical for activation.
► Ivermectin activates glycine receptors by binding in the transmembrane domain.
► We find ivermectin induces conformational changes in 3 glycine-binding domains.
► This suggests an allosteric linkage between these domains and the gate.
Journal: The International Journal of Biochemistry & Cell Biology - Volume 44, Issue 2, February 2012, Pages 335–340