Title

The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily.

Journal

The Journal of biological chemistry

Volume

287

Issue

None

Pages

40207-15

Date

2012-11-23

Authors

Changeux JP

The method was subsequently improved upon with the synthesis of 4-(N-maleimido)phenyltrimethyl- ammonium iodide, whereby the diazonium is substituted with a maleimide group

As anticipated, TDF interacted covalently with E. electricus electroplaque as an irreversible competitive antagonist, and curare protected against this cova- lent attachment

One group of modulators includes Ca2+􏰆, which potentiates most neuronal nAChRs (99, 100) and binds to the extracellular domain below the ACh site at residues contributed from both sides of the subunit interface (96). Another includes Zn2 􏰆 .

In receptor-rich mem- branes from T. marmorata, chlorpromazine labeled the four types of subunits of the nAChR (67), and precise quantitative measurements demonstrated that it bound to just one high affinity site per 2alpha􏰀1beta􏰂1gamma􏰃1delta􏰄1 oligomer (68).

It took more than a year to demonstrate that chlorpromazine labels serine 262, within the second transmembrane segment (TM2) of the delta􏰄-subunit

It was now possible to follow reversible binding to these purified membranes using the nicotinic agonist decamethonium as the radioactive ligand (by the method of equilibrium dialysis that Gilbert and Müller-Hill (9) used to identify the lac repressor)

The detergent deoxycholate gently extracted the binding protein without denaturing it, and bound decamethonium was displaced by var- ious nicotinic agonists and antagonists, including curare and Flaxedil in the order of their physiological effects

General anesthetics (both intravenous and volatile) negatively modulate excitatory nAChRs but posi- tively enhance inhibitory GABA receptors.

Third, Chen-Yuan Lee, a Taiwanese pharmacologist, had found that a snake venom toxin, 􏰂-bungarotoxin (􏰂-BGT), spe- cifically blocks in vivo neuromuscular transmission in high ver- tebrates at the postsynaptic level without interacting with AChE

alpha􏰂-BGT blocked the electroplaque’s electrical response in vivo and the microsac’s ion flux response to nicotinic agonists in vitro; alpha􏰂-BGT also blocked the binding of radioactive decamethonium to the detergent extract

A second important group consists of modulators, such as galantamine, that bind at “non-agonist” interfaces, which, in heteropentameric nAChRs, differ from the neurotransmitter- binding site and appear to be homologs of the benzodiazepine site on GABAA receptors

The antihelminthic ivermectin was originally discovered to behave as a strong positive modulator of alpha􏰀7-nAChR

The cytoplasmic domain of the alpha􏰀4-nAChR subunit also binds a variety of scaffold proteins that interact with cytoskeletal proteins and with G protein systems that are involved in intracellular signaling pathways

The kinetics of access of chlorpromazine to this site increased by 100-fold when rap- idly mixed with ACh under conditions expected to generate functional ion channels

In nAChRs, several phosphorylation sites (104) that control desensitization in mus- cle and 􏰀7-nAChR also contribute to end plate localization by agrin-induced tyrosine phosphorylation of the cytoskeletal protein 43K-rapsyn

Its action was altered by mutations within the TM2 domain

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