Interaction at end-plate receptors between different choline derivatives

Castillo, J. del; Katz, Bernard

doi:10.1098/rspb.1957.0018

Cited by 404 publications

(78 citation statements)

References 16 publications

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“…In this structural model, the receptor has five subunits with the agonist/antagonist-binding pocket located at the subunit interface (Figure 2A). In the heteromeric nAChRs, there are two binding pockets located in the two subunit interfaces [6] , typical for all heteromeric cys-loop receptors. However, homomeric receptors have potentially 5 binding steps.…”

Section: Functional Domains Of the Cys-loop Receptorsmentioning

confidence: 99%

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Allosteric activation mechanism of the cys-loop receptors

et al. 2009

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Binding of a neurotransmitter to its ionotropic receptor opens a distantly located ion channel, a process termed allosteric activation. Here we review recent advances in the molecular mechanism by which the cys-loop receptors are activated with emphasis on the best studied nicotinic acetylcholine receptors (nAChRs). With a combination of affinity labeling, mutagenesis, electrophysiology, kinetic modeling, electron microscopy (EM), and crystal structure analysis, the allosteric activation mechanism is emerging. Specifically, the binding domain and gating domain are interconnected by an allosteric activation network. Agonist binding induces conformational changes, resulting in the rotation of a β sheet of aminoterminal domain and outward movement of loop 2, loop F, and cys-loop, which are coupled to the M2-M3 linker to pull the channel to open. However, there are still some controversies about the movement of the channel-lining domain M2. Nine angstrom resolution EM structure of a nAChR imaged in the open state suggests that channel opening is the result of rotation of the M2 domain. In contrast, recent crystal structures of bacterial homologues of the cys-loop receptor family in apparently open state have implied an M2 tilting model with pore dilation and quaternary twist of the whole pentameric receptor. An elegant study of the nAChR using protonation scanning of M2 domain supports a similar pore dilation activation mechanism with minimal rotation of M2. This remains to be validated with other approaches including high resolution structure determination of the mammalian cys-loop receptors in the open state.

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Section: Functional Domains Of the Cys-loop Receptorsmentioning

confidence: 99%

“…Activation of a ligand-gated ion channel includes binding and gating steps ( Figure 1A) [6] . The Hill slope of dose-response relationships of most heteromeric cys-loop receptors is greater than one, suggesting at least two binding steps for the receptor activation ( Figure 1B) [7] .…”

Section: Kinetic Models For Channel Activationmentioning

confidence: 99%

Allosteric activation mechanism of the cys-loop receptors

et al. 2009

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“…Determination of Agonist Efficacy in Mutants-The potency of the agonist (measured here as the EC 50 for GABA) can be influenced at either step in the simplified receptor activation pathway: agonist binding or isomerization from the closed to open state (18,19). With high efficacy agonists (E Ͼ 10), slight reductions in the ability of the agonist-bound receptor to isomerize from the closed to open state typically produce a reduction in sensitivity to agonist, but little reduction in maximal response.…”

Section: Characterization Of Mutations In the Tm2-tm3mentioning

confidence: 99%

Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation

Kash¹,

Dizon

Trudell

et al. 2004

Journal of Biological Chemistry

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Fast synaptic inhibition in the mammalian central nervous system is mediated primarily via activation of the ␥-aminobutyric acid type A receptor (GABA A -R). Upon agonist binding, the receptor undergoes a structural transition from the closed to the open state. This transition, known as gating, is thought to be associated with a sequence of conformational changes originating at the agonist-binding site, ultimately resulting in opening of the channel. Using site-directed mutagenesis and several different GABA A -R agonists, we identified a number of highly conserved charged residues in the GABA A -R ␤ 2 subunit that appear to be involved in receptor activation. We then used charge reversal double mutants and disulfide trapping to investigate the interactions between these flexible loops within the ␤ 2 subunit. The results suggest that interactions between an acidic residue in loop 7 (Asp 146 ) and a basic residue in pretransmembrane domain-1 (Lys 215 ) are involved in coupling agonist binding to channel gating.Fast synaptic inhibition is a major determinant of network dynamics in the central nervous system (1). In the mammalian brain, this is mediated primarily via activation of the ␥-aminobutyric acid type A receptor (GABA A -R) 1 (2, 3). Each GABA A -R is composed of five subunits arranged around a central ion-conducting pore (4), with each subunit consisting of a large intracellular domain, four transmembrane domains (TM1-TM4), and a larger N-terminal extracellular domain (2). Experimental evidence suggests that the GABA-binding site lies within an asymmetric pocket formed at the interface between the ␣ and ␤ receptor subunits (5-8). The channel "gate" in the GABA A -R is believed to be formed by charged residues in the TM1-TM2 loop (9 -11). The binding of agonist triggers a complex structural transition that results in the opening of the gate, allowing ions to flow through the channel. The mechanisms by which this occurs remain poorly defined.The nature of the coupling between binding and channel opening in this receptor family has been recently investigated in several laboratories. Interactions between charged residues in the flexible loops 2 and 7 in the extracellular domain and those in the short linker between the second and third transmembrane domains (TM2-3L) of the GABA A -R ␣ 1 subunit have been implicated in the process of receptor activation (12). In addition, a recent report suggests that the pre-TM1 region is critical for receptor activation in the closely related serotonin (5-HT 3 ) receptor (13). In this study, we used site-directed mutagenesis and a number of GABA A -R agonists of varying efficacies to examine the contribution of the corresponding flexible loops in the GABA A -R ␤ 2 subunit to receptor activation. Based on previous studies (12-14) and the presence of highly conserved charged residues (see Fig. 1), we hypothesized that interactions between charged residues in these domains are crucial for coupling agonist binding to channel gating. We tested this hypothesis using a charge revers...

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“…Early descriptions account for the opening in response to the receptor-ligand interaction [44] (R←→ O). This formulation was extended to account for desensitization, leading to a cyclic reaction scheme [45] (R←→O←→I ←→R).…”

Section: Circuit Level Model Of Nicotine Action In the Vtamentioning

confidence: 99%

“…Based on the observation that the receptor desensitizes most readily from the open-state and returns to the resting state without opening, a two-gate mechanism is proposed by which activation and desensitization are mediated by two distinct, but interrelated, gates in the ion permeation pathway [50] . The asymmetrical heteromeric structure of the nAChR inspired an uncoupled model [44]). C, Afferent inputs and circuitry of the ventral tegmental area.…”

Section: Circuit Level Model Of Nicotine Action In the Vtamentioning

confidence: 99%

Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms

Graupner

Gutkin

2009

Acta Pharmacol Sin

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Neuromodulator action has received increasing attention in theoretical neuroscience. Yet models involving both neuronal populations dynamics at the circuit level and detailed receptor properties are only now being developed. Here we review recent computational approaches to neuromodulation, focusing specifically on acetylcholine (ACh) and nicotine. We discuss illustrative examples of models ranging from functional top-down to neurodynamical bottom-up. In the top-down approach, a computational theory views ACh as encoding the uncertainty expected in an environment. A different line of models accounts for neural population dynamics treating ACh as toggling neuronal networks between read-in of information and recall of memory. Building on the neurodynamics idea we discuss two models of nicotine's action with increasing degree of biological realism. Both consider explicitly receptor-level mechanisms but with different scales of detail. The first is a large-scale model of nicotine-dependent modulation of dopaminergic signaling that is capable of simulating nicotine self-administration. The second is a novel approach where circuit-level neurodynamics of the ventral tegmental area (VTA) are combined with explicit models of the dynamics of specific nicotinic ACh receptor subtypes. We show how the model is constructed based on local anatomy, electrophysiology and receptor properties and provide an illustration of its potential. In particular, we show how the model can shed light on the specific mechanisms by which nicotine controls dopaminergic neurotransmission in the VTA. This model serves us to conclude that detailed accounts for neuromodulator action at the basis of behavioral and cognitive models are crucial to understand how neuromodulators mediate their functional properties.

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Interaction at end-plate receptors between different choline derivatives

Cited by 404 publications

References 16 publications

Allosteric activation mechanism of the cys-loop receptors

Allosteric activation mechanism of the cys-loop receptors

Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation

Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms

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