التفاصيل البيبلوغرافية
| العنوان: |
The ryanodine receptor pore blocker neomycin also inhibits channel activity via a previously undescribed high-affinity Ca²⁺ binding site |
| المؤلفون: |
Laver, Derek R., Hamada, Tomoyo, Fessenden, James D., Ikemoto, Noriaki |
| المساهمون: |
The University of Newcastle. Faculty of Health, School of Biomedical Sciences and Pharmacy |
| بيانات النشر: |
Springer |
| سنة النشر: |
2007 |
| المجموعة: |
NOVA: The University of Newcastle Research Online (Australia) |
| مصطلحات موضوعية: |
ryanodine receptor, neomycin-ryanodine binding, bilayer, single channel recording |
| الوصف: |
In this study, we present evidence for the mechanism of neomycin inhibition of skeletal ryanodine receptors (RyRs). In single-channel recordings, neomycin produced monophasic inhibition of RyR open probability and biphasic inhibition of [3H]ryanodine binding. The half maximal inhibitory concentration (IC₅0) for channel blockade by neomycin was dependent on membrane potential and cytoplasmic [Ca²⁺], suggesting that neomycin acts both as a pore plug and as a competitive antagonist at a cytoplasmic Ca²⁺ binding site that causes allosteric inhibition. This novel Ca²⁺/neomycin binding site had a neomycin affinity of 100 nM and a Ca²⁺ affinity of 35 nM, which is 30-fold higher than that of the well-described cytoplasmic Ca²⁺ activation site. Therefore, a new high affinity class of Ca²⁺ binding site(s) on the RyR exists that mediates neomycin inhibition. Neomycin plugging of the channel pore induced brief (1-2 ms) conductance substates at 30% of the fully open conductance, whereas allosteric inhibition caused complete channel closure with durations that depended on the neomycin concentration. We quantitatively account for these results using a dual inhibition model for neomycin that incorporates voltage-dependent pore plugging and Ca²⁺-dependent allosteric inhibition. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| تدمد: |
0022-2631 |
| Relation: |
Journal of Membrane Biology Vol. 220, Issue 1-3, p. 11-20; http://hdl.handle.net/1959.13/44499; uon:5776 |
| الاتاحة: |
http://hdl.handle.net/1959.13/44499 |
| رقم الانضمام: |
edsbas.8E0C2FEA |
| قاعدة البيانات: |
BASE |