Biochemical Aspects of Cholinergic Excitation

Maelicke, Alfred

doi:10.1002/anie.198401951

Cited by 59 publications

(20 citation statements)

References 338 publications

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“…Resorcarenes are specially mentioned as the hosts for quaternary ammonium compounds and appear to be the strongest known complexing agents for methyl ammonium derivatives [6]. An excellent example of this is their binding of acetylcholine, a neurotransmitter substance at the muscle synapse [7,8]. In addition to methyl ammonium derivatives, resorcarenes also bind several other guests; the forces that affect the complex formation of resorcarenes are purely noncovalent, such as hydrogen bonding, cation-and CH-interactions [9].…”

mentioning

confidence: 99%

Ammonium ion mediated resorcarene capsules: ESI-FTICRMS study on gas-phase structure and ammonium ion affinity of tetraethyl resorcarene and its per-methylated derivative

Mäkinen

Vainiotalo

Nissinen

2003

J. Am. Soc. Mass Spectrom.

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The ammonium ion binding affinities of tetraethyl resorcarene (1) and its per-methylated derivative (2) were studied by electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry. Ten different ammonium ions were tested as guests for the resorcarenes. A strong tendency for complex formation was observed with all ammonium ions of size and charge distribution suitable for noncovalent interactions with the cavities of the resorcarene hosts 1 and 2. Although differences in ammonium ion affinities were observed between 1 and 2 due to the dissimilar conformations, the overall tendency was that increase in the degree of substitution and the length of carbon chain of the ammonium cation facilitated the complex formation until the sterical hindrance impeded the complexation. Dimeric as well as monomeric ammonium ion complexes were formed with resorcarene 1, but resorcarene 2 was unable to form the dimeric capsules because of the lack of H-bond donor possibilities. The nature of binding of the guest was further investigated with ion-molecule reactions and by determination of the single crystal X-ray structure of host 1 complexed with tetramethyl ammonium bromide.

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confidence: 99%

Ammonium ion mediated resorcarene capsules: ESI-FTICRMS study on gas-phase structure and ammonium ion affinity of tetraethyl resorcarene and its per-methylated derivative

Mäkinen

Vainiotalo

Nissinen

2003

J. Am. Soc. Mass Spectrom.

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“…WF6, see [15]) are particularly well suited for these experiments as the half.lives of their complexes with the receptor are of the order of many hours [20,21], In con. trast, the complexes of the receptor with acetylcholine (and its low molecular weight agonists and antagonists) have half-lives in ~he subsccond to second time range [5,7,20,22]. It may therefore be argued that the channel.activating effect of eseriLne under the experimental conditions of Fig, 2 could be due to displace.…”

Section: Discussionmentioning

confidence: 99%

Desensitization is a property of the cholinergic binding region of the nicotinic acetylcholine receptor, not of the receptor‐integral ion channel

Kuhlmann¹,

Okonjo²,

Maelicke³

1991

FEBS Letters

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The reversible acctylchollne esternse inhibitor (-}.physostiilmine (¢serine) is th© prolotypc of a new class of nie~tinlc ucetylcholinc receptor (nAChR) activating liga,ds: it induces cation fluxes into nAChR.rich membrane vesicl~s from 7~r#eda marmoeata cle~:tric tissue even under condl.lions of antalionist blocked :tcctylcholin~ binding sil~s (Okonjo, Kuhlm~mn. Maelicke. Neuron, in press). This su~tlest's that escrine exerts it~ than. nel.activating proi'~rty via binding sites at the nAChR separate from those of tile natural transmitter. We now report thllt eserine e'-m activate the channel wen when the receptor has t~en preincub~ttcd (des©nsitiz©d) with elevated concentrations of acetylcholi~e, Titus the confornudional state Of the receptor corresponding to de~nsitixation is confined to the transmitter bindinB rclli0n, leaving the ch=tr'4nel fully activatable ,-albeit only from other than the tr~msmitter bindin~ site(s),

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“…Collagen (I and 111) appears to be involved in AChR aggregation [79]. [18]. The exobilayer portion of the AChR model consists of a pentagonal arrangement of strands carrying a substantial number of charged groups within the pentagon ('cup' or 'flower').…”

Section: Models Of the Cytoplasmic Portions Of The Achrmentioning

confidence: 99%

“…One of the striking properties of the AChR is the conversion to an inactive ('desensitized') form after activation by agonist [18] even for pure receptor in vesicles [138- the closed form of the cup. A summary of these steps is outlined in the scheme in Fig.…”

Section: Desensitization and Resensitizationmentioning

confidence: 99%

A structural and dynamic model for the nicotinic acetylcholine receptor

Kosower

1987

European Journal of Biochemistry

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Folding of the five polypeptide subunits (azpy6) of the nicotinic acetylcholine receptor (AChR) into a functional structural model is described. The principles used to arrange the sequences into a structure include: (1) hydrophobicity --f membrane-crossing segments; (2) amphipathic character + ion-carrying segments (ion channel with single group rotations); (3) molecular shape (elongated, pentagonal cylinder) + folding dimensions of exobilayer portion; (4) choice of acetylcholine binding sites + specific folding of exobilayer segments; (5) location of reducible disulfides (near agonist binding site) -+ additional specification of exobilayer arrangement; (6) genetic homology + consistency of functional group choices; (7) noncompetitive antagonist labeling + arrangement of bilayer helices. The AChR model is divided into three parts: (a) exobilayer consisting of 11 antiparallel p-strands from each subunit; (b) bilayer consisting of four hydrophobic and one amphiphilic a-helix from each subunit; (c) cytoplasmic consisting of one (folded) loop from each subunit.The exobilayer strands can form a closed 'flower' (the 'resting state') which is opened ('activated') by agonists bound perpendicular to the strands. Rearrangement of the agonists to a strand-parallel position and partial closing of the 'flower' leads to a desensitized receptor. The actions of acetylcholine and succinoyl and suberoyl bis-cholines are clarified by the model. The opening and closing of the exobilayer 'flower' controls access to the ion channel which is composed of the five amphiphilic bilayer helices. A molecular mechanism for ion flow in the channel is given. Openings interrupted by short duration closings (50 ps) depend upon channel group motions.The unusual photolabeling of intrabilayer serines in a, p and 6 subunits but not in y subunits near the binding site for non-competitive antagonists is explained along with a mechanism for the action of these antagonists such as phencyclidine. The unusual a 192Cys-193Cys disulfide may have a special peptide arrangement, such as a cispeptide bond to a following proline (G.A. Petsko and E.M. Kosower, unpublished results). The position of phosphorylatable sites and proline-rich segments are noted for the cytoplasmic loops.The dynamic behavior of the AChR channel and many different experimental results can be interpreted in terms of the model. An example is the lowering of ionic conductivity on substitution of bovine for Torpedo 6 M2 segment. The model represents a useful construct for the design of experiments onAChR. perimenter into a better understanding of current information and to the formulation of new approaches to the problem. In the absence of a definitive structural determination, the structure and dynamic properties of a large molecular complex like the acetylcholine receptor (AChR) must be inferred from a great variety of facts aided by physical and chemical theory. Even if the elusive crystal structure for AChR were obtained, theories for the dynamic behavior would still be necessary. I have...

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Biochemical Aspects of Cholinergic Excitation

Cited by 59 publications

References 338 publications

Ammonium ion mediated resorcarene capsules: ESI-FTICRMS study on gas-phase structure and ammonium ion affinity of tetraethyl resorcarene and its per-methylated derivative

Ammonium ion mediated resorcarene capsules: ESI-FTICRMS study on gas-phase structure and ammonium ion affinity of tetraethyl resorcarene and its per-methylated derivative

Desensitization is a property of the cholinergic binding region of the nicotinic acetylcholine receptor, not of the receptor‐integral ion channel

A structural and dynamic model for the nicotinic acetylcholine receptor

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