Activation of ion channels in the frog end‐plate by high concentrations of acetylcholine.

Colquhoun, David; Ogden, David

doi:10.1113/jphysiol.1988.sp016912

Cited by 214 publications

(233 citation statements)

References 49 publications

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“…Interestingly, these two values are quite similar to the two affinities estimated from [ 3 H]nicotine binding to high affinity sites in brain (Lippiello et al, 1987;see below). The activatable, low affinity resting state R has a dissociation constant for ACh of about 50 -100 M (Changeux et al, 1984; see also e.g., Colquhoun and Ogden, 1988). Assuming diffusion-limited agonist binding (10 8 -10 9 M Ϫ1 s Ϫ1 ), the estimated rate of ACh dissociation from the D state would be Ϸ1 s Ϫ1 .…”

Section: Generalized Mechanistic Models Of Desensitizationmentioning

confidence: 99%

“…1(A); Katz and Thesleff, 1957]. At the microscopic level, this process reflects the time-dependent accumulation of receptors in longlived nonconducting states (e.g., Sakmann et al, 1980;Colquhoun and Ogden, 1988). Moreover, because purified nAChRs reconstituted in lipid bilayers can undergo desensitization, this process must be intrinsic to the receptor protein (see Ochoa et al, 1989)-although, as we will discuss, it can be modified by a variety of other cellular agents and exogenous signals (Huganir and Greengard, 1990).…”

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confidence: 99%

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Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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Section: Generalized Mechanistic Models Of Desensitizationmentioning

confidence: 99%

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confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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“…1 b,c). Such channel kinetics for other receptors have been interpreted as being a reflection of channel cycling through closed, open, and desensitized states [19]. It is possible that prolonged handling of the proteins during extensive purification schemes renders the channel-forming proteins more likely to assume a state that leads to a desensitized channel.…”

Section: Activation Of Ion Channels In Reconstituted Preparationsmentioning

confidence: 99%

Ion channel properties of a protein complex with characteristics of a glutamate/N‐methyl‐d‐aspartate receptor

Aistrup¹,

Szentirmay²,

Kumar³

et al. 1996

FEBS Letters

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“…In the case of AP5, assuming similar pKa values measured for AP7, the corrected value for kon would be 7.4 x 10UM-s-1, close to the diffusion limit of 108M-15s1 expected for low molecular weight ligands (Gutfreund, 1972). A comparable estimate has been obtained for the binding of acetylcholine to the nicotinic receptor at the frog neuromuscular junction, 9 x 10oM-1s-1 (Colquhoun & Ogden, 1988 Kinetic and equilibrium experments for D-CPP-ene were reanalysed with this model. The goodness of fit of responses to concentration jump application of D-CPP-ene was similar to that obtained for the 2 agonist-2 antagonist binding site model described earlier, but yielded a 3.5 fold faster association rate constant (1.7 x 10iM-1s-'); the dissociation rate constant, 0.62s-' was similar for both models (cf.…”

Section: Comparison Ofantagonist Binding Kinetics With Equilibrium Pomentioning

confidence: 99%

Structure‐activity analysis of binding kinetics for NMDA receptor competitive antagonists: the influence of conformational restriction

Benveniste

Mayer

1991

British J Pharmacology

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1 The kinetics of action of 17 structurally related NMDA receptor competitive antagonists were measured under voltage clamp in mouse hippocampal neurones. Analysis of the response to rapid changes in antagonist concentration during constant application of agonist was used to estimate microscopic association (k0.) and dissociation (k0ff) rate constants for antagonist binding, assuming a two-equivalent site model for competitive antagonism. Dose-inhibition curves were analysed to estimate antagonist equilibrium dissociation constants.2 For a series of 11 co-phosphono, a-amino acids k03 and k0ff varied 26 and 107 fold respectively. Rapid association and dissociation rate constants were obtained for flexible antagonist molecules such as D-2-amino-7-phosphonoheptanoic acid (D-AP7): k03 1.4 x 17 M-1 -I 1; kff 20.3 s -. For conformationally restrained molecules such as 3S,4aR,6S,8aR-6-phosphonomethyl-decahydroisoquinoline-3-carboxylic acid (LY 235959), association and dissociation rate constants were much slower: k01 1.1 x 106M-1s-1; koff 0.2 s'-. For the D-and L-isomers of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) estimates for k0. were similar, but for the L-isomer koff was 10 fold faster than for the D-isomer.3 For 2-amino-5-phosphonopentanoic acid (AP5) and its piperidine derivative cis-44phosphonomethyl) piperidine-2-carboxylic acid (CGS 19755), an increase in chain length of two methylene groups between the co-phosphono and oc-carboxylate moieties caused a 1.6 to 1.8 fold decrease in k0. with little change in koffI In contrast, for AP5, CPP and its co-carboxylate analogue, addition of a double bond close to the phosphonate moiety caused a 1.3 to 1.6 fold increase in k0.. 0 4 For antagonists with an co-tetrazole moiety, k0. and koff were 2.8-4.6 times faster than for the parent co-phosphono compounds. A similar, but smaller increase in k0. and k0ff was observed for antagonists with an co-carboxylate moiety. S The slow kinetics of action of potent NMDA receptor antagonists were not an artefact of buffered diffusion. In neurones equilibrated with 200piM D-AP7, 2puM LY 235959 and 10pM NMDA, a transient agonist response was recorded following a rapid switch to D-AP7-free solution. This can only be explained by differences in the binding kinetics of AP7 and LY 235959, since at equilibrium, with these concentrations, either antagonist essentially eliminates the agonist response to 10puM NMDA. 6 For all antagonists studied, the ratio koff/k0. was agonist binding assays showed only 1.4 fold higher affinity. 7 The insights gained from our experiments may be of use for predicting the structural features required to generate more potent NMDA receptor antagonists, and suggest that novel acyclic compounds will have greater potential for high potency than derivatives of conformationally rigid compounds with piperazine, piperidine or bicyclic ring structures.

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Activation of ion channels in the frog end‐plate by high concentrations of acetylcholine.

Cited by 214 publications

References 49 publications

Desensitization of neuronal nicotinic receptors

Desensitization of neuronal nicotinic receptors

Ion channel properties of a protein complex with characteristics of a glutamate/N‐methyl‐d‐aspartate receptor

Structure‐activity analysis of binding kinetics for NMDA receptor competitive antagonists: the influence of conformational restriction

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