Molecular pharmacology of the nicotinic acetylcholine receptor

Karlin, Arthur; Kao, Peter N.; DiPaola, Mario

doi:10.1016/0165-6147(86)90366-4

Cited by 60 publications

(23 citation statements)

References 18 publications

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“…The report by Karlin et al [14] that "the site on c~ which is specifically labeled by [3H]quinacrine azide is within a CNBr fragment containing MI" thus appears challenging. Indeed, [3H]quinacrine azide specific labeling is inhibited by histrionicotoxin and thus is expected to take place at the level of a site overlapping, if not identical, to the high-affinity NCB site studied here [31].…”

Section: Discussionmentioning

confidence: 99%

The noncompetitive blocker [³H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

et al. 1989

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The membrane bound acetylcholine receptor from Torpedo marmorata was photolabeled by the noncompetitive channel blocker [~H]chlorpromazine under equilibrium conditions in the presence of the agonist carbamoylcholine. The radioactivity incorporated into the AChR subunits was reduced by addition of phencyclidine, a specific ligand for the high-affinity site for noncompetitive blockers. The ~t-subunit was purified and digested with trypsin and/or CNBr and the resulting fragments fractionated by HPLC. Sequence analysis resulted in the identification of Ser-248 as a major residue labeled by pH]chlorpromazine in a phencyclidine-sensitive manner. This residue is located in the hydrophobic and putative transmembrane segment M2 of the ~t-subunit, a region homologous to that containing the chlorpromazine-labeled Ser-262 in the Nchain [1] and the Ser-254 and Leu-257 in the//-chain [2]. Extended sequence analysis of the hydrophobic segment M 1 further showed that no labeling.occurred in this region.

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Section: Discussionmentioning

confidence: 99%

The noncompetitive blocker [³H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

et al. 1989

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“…Electrical recordings of AcCho-induced currents have measured the permeability properties of the channel and have given details of the kinetics of receptor activation (for reviews, see refs. [1][2][3][4][5]. The cDNA sequences for each of the four subunits of AcChoR from Torpedo californica (6)(7)(8) and several other species have been obtained (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

Stable expression of transfected Torpedo acetylcholine receptor alpha subunits in mouse fibroblast L cells.

Claudio¹

1987

Proc. Natl. Acad. Sci. U.S.A.

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Torpedo californica electric organ cDNA libraries were constructed in XgtlO and Xgtll. Four acetylcholine receptor (AcChoR) subunit cDNA clones were isolated and shown to contain the entire coding region for each of the subunits. When in vitro synthesized AcChoR mRNA was microinjected into Xenopus laevis oocytes, functional cell surface AcChoRs were expressed. A very simple and fast 22Na-uptake experiment was performed on batches of microinjected oocytes to identify oocytes that were expressing large quantities of functional cell surface AcChoRs for use in single-channel recordings. In addition to the transient expression system, DNA-mediated cotransformation is described, which is a method for stably introducing AcChoR cDNAs into the chromosomes of tissue culture cells. Because the AcChoR is composed of four different subunits, it is necessary to integrate four cDNAs into the chromosomes of the same cell before stable expression of a completely functional receptor complex can be established. We show that 80% of the cells that integrated the selectable marker gene into their chromosomes also integrated all four AcChoR cDNAs. When Torpedo asubunit cDNA inserted into an appropriate expression vector was introduced into cells by transfection, a-subunit protein was synthesized that migrated on NaDodSO4/polyacrylamide gels with the same molecular mass as native Torpedo a subunits and expressed antigenic determinants similar to those of native Torpedo a subunits.The nicotinic acetylcholine receptor (AcChoR) is the postsynaptic receptor at skeletal neuromuscular junctions and is the best characterized ionic-channel protein in vertebrates. It is an oligomeric, intrinsic membrane glycoprotein consisting of four subunits (a, /3, y, 8) with the stoichiometry a2Py5. The

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“…In contrast, Ml peptides do not form channels. Ml was also considered to be a component of the AChR channel [24]. Of course, channel formation by amphipathic peptides may as well channel forming [26,27].…”

Section: The Helix-m2 Modelmentioning

confidence: 99%

The selectivity filter of a ligand‐gated ion channel

Hucho

Hilgenfeld

1989

FEBS Letters

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Evidence from electrophysiology and biochemistry supports the hypothesis that the ion channel of the nicotinic acetylcholine receptor is formed by homologous amino acid sequences of all receptor subunits, called hel,ices M2. A model of the ion channel is proposed and the selectivity filter is described as a ring of negatively-charged amino acid side chains [(1988) Nature 335, 6456481 which may undergo conformational changes upon permeation of the cation.

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Molecular pharmacology of the nicotinic acetylcholine receptor

Cited by 60 publications

References 18 publications

The noncompetitive blocker [³H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

The noncompetitive blocker [³H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

Stable expression of transfected Torpedo acetylcholine receptor alpha subunits in mouse fibroblast L cells.

The selectivity filter of a ligand‐gated ion channel

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Molecular pharmacology of the nicotinic acetylcholine receptor

Cited by 60 publications

References 18 publications

The noncompetitive blocker [3H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

The noncompetitive blocker [3H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

Stable expression of transfected Torpedo acetylcholine receptor alpha subunits in mouse fibroblast L cells.

The selectivity filter of a ligand‐gated ion channel

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The noncompetitive blocker [³H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit

The noncompetitive blocker [³H]chlorpromazine labels segment M2 but not segment M 1 of the nicotinic acetylcholine receptor α‐subunit