Polymer-based open-channel blockers for the acetylcholine receptor : the effect of spacer length on blockade kinetics
Blocking open ion channels provides a promising way to modulate synaptic transmission. Using the muscle-type acetylcholine receptor (AChR) as a test system, we seek to develop blockers that have blockade kinetics tunable via structural modifications. Here we investigate whether the blockade kinetics can be modulated by specifying the length of a poly(ethylene glycol) (PEG) spacer incorporated into the blocker. Single-channel electrophysiological experiments show that simple bis(trimethylammonium) compounds ( 1a- 3) both activate the AChR and block the open channel. The blockade kinetics are found to depend on spacer length: both the association and dissociation rate constants decrease with increasing spacer length. The decrease in the association rate constant can be quantitatively explained by the entropic cost of polymer confinement in the transmembrane lumen, while the decrease in the dissociation rate constant is consistent with weak, additive noncovalent interactions between the channel and the spacer. These results provide useful insights into the future design of kinetically tunable open-channel blockers for the AChR.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2008 |
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| Erschienen: |
2008 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:47 |
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| Enthalten in: |
Biochemistry - 47(2008), 35 vom: 02. Sept., Seite 9163-73 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lin, Wan-Chen [VerfasserIn] |
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| Links: |
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| Themen: |
3WJQ0SDW1A |
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| Anmerkungen: |
Date Completed 09.10.2008 Date Revised 01.12.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/bi800737j |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM181473968 |
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| 245 | 1 | 0 | |a Polymer-based open-channel blockers for the acetylcholine receptor |b the effect of spacer length on blockade kinetics |
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| 500 | |a Date Revised 01.12.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Blocking open ion channels provides a promising way to modulate synaptic transmission. Using the muscle-type acetylcholine receptor (AChR) as a test system, we seek to develop blockers that have blockade kinetics tunable via structural modifications. Here we investigate whether the blockade kinetics can be modulated by specifying the length of a poly(ethylene glycol) (PEG) spacer incorporated into the blocker. Single-channel electrophysiological experiments show that simple bis(trimethylammonium) compounds ( 1a- 3) both activate the AChR and block the open channel. The blockade kinetics are found to depend on spacer length: both the association and dissociation rate constants decrease with increasing spacer length. The decrease in the association rate constant can be quantitatively explained by the entropic cost of polymer confinement in the transmembrane lumen, while the decrease in the dissociation rate constant is consistent with weak, additive noncovalent interactions between the channel and the spacer. These results provide useful insights into the future design of kinetically tunable open-channel blockers for the AChR | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Cholinergic Antagonists |2 NLM | |
| 650 | 7 | |a Receptors, Cholinergic |2 NLM | |
| 650 | 7 | |a Trimethyl Ammonium Compounds |2 NLM | |
| 650 | 7 | |a Polyethylene Glycols |2 NLM | |
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