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Probing Nicotinic Acetylcholine Receptor Function in Mouse Brain Slices via Laser Flash Photolysis of Photoactivatable Nicotine
Published on: January 25, 2019
Conformational changes in the nicotinic acetylcholine receptor during gating and desensitization
Innocent H Yamodo1, David C Chiara, Jonathan B Cohen
1Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Biochemistry
|December 8, 2009
Summary
Structural changes in nicotinic acetylcholine receptors (nAChRs) during desensitization were monitored. Fast desensitization involves conformational changes in the channel lumen, while slow desensitization affects other regions.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Nicotinic acetylcholine receptors (nAChRs) are crucial Cys-loop ligand-gated ion channels modulating neuronal excitability.
- Receptor desensitization (fast and slow) is key to regulating neuronal activity duration.
Purpose of the Study:
- To investigate structural rearrangements in the transmembrane domain of Torpedo nAChR during fast and slow desensitization.
- To differentiate conformational changes associated with channel opening versus desensitization.
Main Methods:
- Time-resolved photolabeling using 3-(trifluoromethyl)-3-(m-iodophenyl)diazirine (TID), a hydrophobic probe.
- Monitoring photolabeling extent in specific regions (delta-subunit M2-M3 loop, deltaM1/M2 pocket, M2-9' leucines) across different functional states.
Main Results:
- Photolabeling of the open state pocket (delta-subunit M2-M3 loop and deltaM1/M2) persisted during fast desensitization, decreasing only in slow desensitization.
- Photolabeling at the M2-9' leucines in the channel lumen decreased during resting to open and open to fast desensitized state transitions.
- These findings suggest distinct conformational states and potentially separate gates for channel opening and desensitization.
Conclusions:
- Fast desensitization involves conformational changes within the M2-9' channel lumen.
- Regions of the delta-subunit M2-M3 loop and M1-M4 helix bundle remain conformationally stable until slow desensitization occurs.
- The study supports a model with separate gating mechanisms for channel opening and desensitization in nAChRs.
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