The desensitization gate of inhibitory Cys-loop receptors

Gielen, Marc; Thomas, Philip; Smart, Trevor G.

doi:10.1038/ncomms7829

Cited by 127 publications

(170 citation statements)

References 55 publications

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“…In these structures, a local constriction was noted in the M2 intracellular end, closer to the −2′ position, which is consistent with findings that picrotoxin binding at −2′ slows desensitization (Gielen et al, 2015). Interestingly, the extent of pore closure at −2′ appears to bear some correlation with the desensitization properties of the these channels: a stronger desensitization was observed for GABA A R-β3 and nAChR-α4β2 currents (Miller and Aricescu, 2014; Morales-Perez et al, 2016) in comparison to ivermectin/glycine evoked currents for GlyR (Du et al, 2015).…”

Section: Discussionsupporting

confidence: 90%

Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

Basak

Schmandt

Gicheru

et al. 2017

eLife

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Desensitization in pentameric ligand-gated ion channels plays an important role in regulating neuronal excitability. Here, we show that docosahexaenoic acid (DHA), a key ω−3 polyunsaturated fatty acid in synaptic membranes, enhances the agonist-induced transition to the desensitized state in the prokaryotic channel GLIC. We determined a 3.25 Å crystal structure of the GLIC-DHA complex in a potentially desensitized conformation. The DHA molecule is bound at the channel-periphery near the M4 helix and exerts a long-range allosteric effect on the pore across domain-interfaces. In this previously unobserved conformation, the extracellular-half of the pore-lining M2 is splayed open, reminiscent of the open conformation, while the intracellular-half is constricted, leading to a loss of both water and permeant ions. These findings, in combination with spin-labeling/EPR spectroscopic measurements in reconstituted-membranes, provide novel mechanistic details of desensitization in pentameric channels.DOI: http://dx.doi.org/10.7554/eLife.23886.001

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Section: Discussionsupporting

confidence: 90%

Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

Basak

Schmandt

Gicheru

et al. 2017

eLife

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“…Mechanism of ASICs Desensitization-The desensitization of Cys loop receptors involves rearrangements of the M2/M3 interface, which mediates the constriction of the pore and consequent reduction of ion conductance (47)(48)(49)(50)(51). We propose that ASIC desensitization entails a series of conformational rearrangements that extend from the extracellular region to the pore of the channel.…”

Section: Discussionmentioning

confidence: 99%

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Krauson

Carattino

2016

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs) are cation-selective proton-gated channels expressed in neurons that participate in diverse physiological processes, including nociception, synaptic plasticity, learning, and memory. ASIC subunits contain intracellular N and C termini, two transmembrane domains that constitute the pore, and a large extracellular loop with defined domains termed the finger, ␤-ball, thumb, palm, and knuckle. Here we examined the contribution of the finger, ␤-ball, and thumb domains to activation and desensitization through the analysis of chimeras and the assessment of the effect of covalent modification of introduced Cys at the domain-domain interfaces. Our studies with ASIC1a-ASIC2a chimeras showed that swapping the thumb domain between subunits results in faster channel desensitization. Likewise, the covalent modification of Cys residues at selected positions in the ␤-ball-thumb interface accelerates the desensitization of the mutant channels. Studies of accessibility with thiol-reactive reagents revealed that the ␤-ball and thumb domains reside apart in the resting state but that they become closer to each other in response to extracellular acidification. We propose that the thumb domain moves upon continuous exposure to an acidic extracellular milieu, assisting with the closing of the pore during channel desensitization.Acid-sensing ion channels (ASICs) 2 are voltage-insensitive cation-permeable channels expressed in neurons of the peripheral and central nervous systems that respond to sudden changes in extracellular pH. Four genes that encode for six ASIC subunits and splice variants have been identified in mammals (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4) (1-10). In the central nervous system, disruption of ASIC1a expression causes a number of learning and memory-related phenotypes (11)(12)(13)(14). Conversely, activation of ASIC1a has been linked to neurotoxicity in a mouse model of brain ischemia (15) and in neurodegenerative diseases such as multiple sclerosis (16), Huntington disease (17), Parkinson disease (18), and spinal cord injury (19). There is a substantial body of research that indicates that ASIC subunits participate in nociception in peripheral neurons (20 -22) as well as in pain processing in the central nervous system (23-25). Therefore, ASICs represent novel therapeutic targets to treat pain as well as neurological diseases.ASIC subunits assemble to form homo-and heterotrimers that display distinct proton sensitivities for activation and desensitization kinetics (26 -29). Although the molecular determinants for channel activation have been extensively investigated, less is known about the mechanisms that promote channel desensitization in the continual presence of protons. ASIC subunits contain two membrane-spanning helices that form the pore of the channel and connect to cytoplasmic N-and C-terminal regions and to a large extracellular loop with defined domains termed the wrist, thumb, finger, ␤-ball, knuckle, and palm (see Fig. 1) (30). In the solved structure o...

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“…The simulation also suggests that a stable SR95531-bound state is a non-desensitized state. It is interesting that the non-competitive antagonist picrotoxin-bound state of the GABA A receptor is also a non-desensitized state [32] . The structural basis of the agonist-induced affinity changes in the GABA A receptor is suggested by a functional test with the rate of cysteine accessibility: narrowing the orthosteric binding pocket upon channel activation [33] .…”

Section: Discussionmentioning

confidence: 99%

Competitive antagonists facilitate the recovery from desensitization of α1β2γ2 GABAA receptors expressed in Xenopus oocytes

Roberts

Zhu

et al. 2016

Acta Pharmacol Sin

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Aim:The continuous presence of an agonist drives its receptor into a refractory state, termed desensitization. In this study, we tested the hypothesis that a competitive antagonist, SR95531, could facilitate the recovery of α1β2γ2 GABA A receptor from functional desensitization. Methods: α1β2γ2 GABA A receptors were expressed in Xenopus oocytes. GABA-evoked currents were recorded using two-electrode voltage-clamp technique. Drugs were applied through perfusion. Results: Long application of GABA (100 µmol/L) evoked a large peak current followed by a small amplitude steady-state current (desensitization). Co-application of SR95531 during the desensitization caused a larger rebound of GABA current after removal of SR95531. Furthermore, application of SR95531 after removal of GABA increased the rate of receptor recovery from desensitization, and the recovery time constant was decreased from 59±3.2 s to 33±1.6 s. SR95531-facilitated receptor recovery from desensitization was dependent on the perfusion duration of SR95531. It was also dependent on the concentration of SR95531, and the curve fitting with Hill equation revealed two potency components, which were similar to the two potency components in inhibition of the steadystate current by SR95531. Bicuculline caused similar facilitation of desensitization recovery. Conclusion: SR95531 facilitates α1β2γ2 GABA A receptor recovery from desensitization, possibly through two mechanisms: binding to the desensitized receptor and converting it to the non-desensitized state, and binding to the resting state receptor and preventing re-desensitization.

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The desensitization gate of inhibitory Cys-loop receptors

Cited by 127 publications

References 55 publications

Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Competitive antagonists facilitate the recovery from desensitization of α1β2γ2 GABAA receptors expressed in Xenopus oocytes

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