Allosteric receptors after 30 years

Changeux, Jean‐Pierre; Edelstein, Stuart J.

doi:10.1007/bf02904502

Cited by 69 publications

(87 citation statements)

References 255 publications

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“…4). As MDL is an established competitive NR1 glycine site antagonist, we propose that Zn 2ϩ potentiates NR1/NR3A receptors via an allosteric binding site (27). Consistent with this interpretation, MDL drastically reduces the apparent affinity of glycine but not of Zn 2ϩ (ref .…”

Section: Discussionsupporting

confidence: 65%

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn ²⁺ and NR1 antagonist

Madry

Betz

Geiger

et al. 2008

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

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Coassembly of the glycine-binding NMDA receptor subunits NR1 and NR3A results in excitatory glycine receptors of low efficacy. Here, we report that micromolar concentrations of the divalent cation Zn 2؉ produce a 10-fold potentiation of NR1/NR3A receptor responses, which resembles that seen upon antagonizing glycine binding to the NR1 subunit. Coapplication of both Zn 2؉ and NR1 antagonist caused a supralinear potentiation, resulting in a >120-fold increase of glycine-activated currents. At concentrations >50 M, Zn 2؉ alone generated receptor currents with similar efficacy as glycine, implying that NR1/NR3A receptors can be activated by different agonists. Point mutations in the NR1 and NR3A glycinebinding sites revealed that both the potentiating and agonistic effects of Zn 2؉ are mediated by the ligand-binding domain of the NR1 subunit. In conclusion, Zn 2؉ acts as a potent positive modulator and agonist at the NR1 subunit of NR1/NR3A receptors. Our results suggest that this unconventional member of the NMDA receptor family may in vivo be gated by the combined action of glycine and Zn 2؉ or a yet unknown second ligand.binding site ͉ ligand-gated ion channel ͉ NMDA receptor ͉ zinc N -methyl-D-aspartate receptors represent a complex family of the tetrameric ionotropic glutamate receptors that have attracted substantial interest because of their unique pharmacology and role in synaptic plasticity and memory formation (1, 2). The diversity of NMDA receptor subtypes derives from a multitude of receptor subunits, which are encoded by seven different genes that have been classified into three subfamilies (NR1, NR2A-D, and NR3A and NR3B) (3). Each subunit shares a common modular design characterized by the extracellular (i) N-terminal domain (NTD), (ii) the S1S2 ligand binding domain (LBD), (iii) an intramembrane region that forms the ion channel, and (iv) an extended intracellular C-terminal tail (4).Conventional NMDA receptors are composed of two glycinebinding NR1 subunits and two glutamate-binding NR2 subunits each (5) and are efficiently activated upon simultaneous binding of both glutamate and glycine (6). Coexpression of the glycinebinding NR3A or NR3B subunit with NR1 and NR2 subunits generates heteromeric receptors composed of NR1, NR2, and NR3 subunits, which also require glutamate and glycine for gating but exhibit altered biophysical properties (7-10). In contrast, recombinant NMDA receptors assembled from two NR1 and two NR3 subunits (11) do not respond to glutamate but are exclusively activated by glycine (''excitatory glycine receptors''; ref. 12). The glycine currents produced by these NR1/NR3 receptors are, however, rather small, although assembly and surface insertion occur with similar efficiency as that of conventional NR1/NR2 receptors (13). Recently, antagonists of the NR1 glycine-binding site were found to markedly enhance the glycine responses of NR1/NR3 receptors (13,14), presumably by preventing rapid receptor desensitization caused by glycine binding to the NR1 subunit.An important endogenou...

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Section: Discussionsupporting

confidence: 65%

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn ²⁺ and NR1 antagonist

Madry

Betz

Geiger

et al. 2008

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

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“…Thus, channel gating involves global conformational changes from the binding pocket to the gating machinery. This phenomenon can be well described by Monod-Wyman-Changeux allosteric activation (MWC) model [1,14,15] (Figure 1C). Excellent agreement of experimental data to the MWC model further strengthens this conclusion [13] .…”

Section: Kinetic Models For Channel Activationmentioning

confidence: 66%

“…This family includes nicotinic receptors (nAChRs), serotonin receptor type 3 (5-HT 3 R), γ-aminobutyric acid receptors type A and C (GABA A/C ), glycine receptors, zinc-activated cation channel, and invertebrate glutamate/ serotonin-activated anionic channels or GABA-gated cation channels [1][2][3] . Recently, prokaryotic proton-gated ion channels are also considered to be in the same family although they are devoid of the signature cysteine loop [4] .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, prokaryotic proton-gated ion channels are also considered to be in the same family although they are devoid of the signature cysteine loop [4] . All cysloop receptors are allosteric proteins, in which binding of agonist to the binding pocket in the subunit interface of the extracellular amino-terminal domain controls the distantly located channel domain to open the pore [1] . This long range coupling between binding pocket and the gating machinery Review requires an interconnected allosteric network, through which the binding energy can be transduced to the gating energy to open the channel [5] .…”

Section: Introductionmentioning

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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“…Fig. 2A schematically illustrates the state transitions of an RyR energetically coupled to two neighbors, following a strategy used in studies of bacterial chemotaxis (Duke and Bray, 1999;Duke et al, 2001) and similar in spirit to numerous previous studies of allostery in various biological systems (see Changeux and Edelstein (1998), Bray and Duke (2004) for review). The diagram in Fig.…”

Section: Effect Of Ryr Coupling On [Ca 2+ ] I Sensitivitymentioning

confidence: 99%

The Ca2+ leak paradox and “rogue ryanodine receptors”: SR Ca2+ efflux theory and practice

Sobie

Guatimosim

Gómez-Víquez

et al. 2006

Progress in Biophysics and Molecular Biology

115

126

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Ca 2+ efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca 2+ release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca 2+ influx through L-type Ca 2+ channels (dihydropyridine receptors, DHPR), Ca 2+ sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca 2+ together ensure the stability of this positive-feedback system of Ca 2+ amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca 2+ ] i there is little clear evidence to date showing an increase in Ca 2+ spark rate. Indeed, there is some evidence that the SR Ca 2+ content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca 2+ "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca 2+ ] i in diastole and during the [Ca 2+ ] i transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyperphosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca 2+ signaling.

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Allosteric receptors after 30 years

Cited by 69 publications

References 255 publications

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn ²⁺ and NR1 antagonist

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn ²⁺ and NR1 antagonist

Allosteric activation mechanism of the cys-loop receptors

The Ca2+ leak paradox and “rogue ryanodine receptors”: SR Ca2+ efflux theory and practice

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Allosteric receptors after 30 years

Cited by 69 publications

References 255 publications

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn 2+ and NR1 antagonist

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn 2+ and NR1 antagonist

Allosteric activation mechanism of the cys-loop receptors

The Ca2+ leak paradox and “rogue ryanodine receptors”: SR Ca2+ efflux theory and practice

Contact Info

Product

Resources

About

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn ²⁺ and NR1 antagonist

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn ²⁺ and NR1 antagonist