A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations

Dämgen, Marc A.; Biggin, Philip C.

doi:10.1016/j.str.2019.10.019

Cited by 38 publications

(57 citation statements)

References 74 publications

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“…2013). Interestingly, unlike pentameric ligand gated ion channels whose open state pore tends to collapse in molecular dynamics simulations (Damgen & Biggin, 2020), the open state of cASIC1 is reasonably stable, allowing more detailed examination of ion selectivity (Lynagh et al . 2017, 2020).…”

Section: The Basics Of Asicsmentioning

confidence: 99%

Coupling structure with function in acid‐sensing ion channels: challenges in pursuit of proton sensors

Rook

Musgaard

MacLean

2020

The Journal of Physiology

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Acid-sensing ion channels (ASICs) are a class of trimeric cation-selective ion channels activated by changes in pH within the physiological range. They are widely expressed in the central and peripheral nervous systems where they participate in a range of physiological and pathophysiological situations such as learning and memory, pain sensation, fear and anxiety, substance abuse and cell death. ASICs are localized to cell bodies and dendrites, including the postsynaptic density, and within the last 5 years several examples of proton-evoked ASIC excitatory postsynaptic currents have emerged. Thus, ASICs have become bona fide neurotransmitter-gated ion channels, activated by the smallest neurotransmitter possible: protons. Here we review how protons are thought to drive the conformational changes associated with ASIC activation and desensitization. In particular, we weigh the evidence for and against the so-called 'acidic pocket' being a vital proton sensor and discuss the emerging role of the β11-12 linker as a desensitization switch or 'molecular clutch'. We also examine how proton-induced conformational changes pose unique challenges to classical molecular dynamics simulations, as well as some possible solutions. Matthew Rook received his Bachelor of Science degree in pharmacology and toxicology from the University at Buffalo. He is currently a PhD candidate in the laboratory of Dr David MacLean at the University of Rochester Medical Centre within the Department of Pharmacology and Physiology. His primary research project is to define the conformational changes required for acid-sensing ion channel activation and desensitization using fast-perfusion electrophysiology and genetic code expansion.

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Section: The Basics Of Asicsmentioning

confidence: 99%

Coupling structure with function in acid‐sensing ion channels: challenges in pursuit of proton sensors

Rook

Musgaard

MacLean

2020

The Journal of Physiology

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“…The initial coordinates of the D&B-open structure of the human GlyR- α 1 were obtained from Dämgen and Biggin, 2019 (Dämgen and Biggin, 2019) (DOI: 10.5281/zenodo.3476169). Following the protocol in Cerdan et al, 2018 (Cerdan et al, 2018), the extracellular domain was removed and the transmembrane domain was embedded in a POPC membrane bilayer, surrounded by TIP3 water molecules and 150 mN NaCl using the CHARMM-GUI input generator (Lee et al, 2016, 2019).…”

Section: Methodsmentioning

confidence: 99%

“…In a recent contribution in Structure (Dämgen and Biggin, 2019), Dämgen and Biggin report on a fourth open-channel structure of GlyR, here D&B-open , which features an ion pore halfway between the wide-open and MD-open states with a radius of 3.6 Å. The enhanced structural stability of D&B-open relative to the parental wide-open structure was attributed to the occupancy of a large hydrophobic cavity in the trans-membrane domain at the interface between subunits by an alternative rotameric state of the pore-lining leucines at position 9′.…”

Section: Figurementioning

confidence: 99%

“…Moreover, in the new cryo-EM open state, the pore-lining helices M2 are tilted solely in the polar direction consistent with MD-open and in contradiction with the significant azimuthal tilting observed in the wide-open and the D&B-open structures. Last, concerning the role of the pore-lining leucines at position 9′ on the stabilization of the physiological active state of GlyR, which was raised by Dämgen and Biggin (Dämgen and Biggin, 2019), the debate seems not to be settled yet. In fact, the very recent cryo-EM structures of GlyR- α 1 in native lipid environments indicate that these leucines undergo a more pronounced rotation (away from the lumen) in the desensitized state rather than the active state.…”

Section: Figurementioning

confidence: 99%

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On the functional annotation of open-channel structures in the glycine receptor

Cerdan

Cecchini

2020

Preprint

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The glycine receptor (GlyR) is by far the best-characterized pentameric ligand-gated ion channel with several high-resolution structures from X-ray crystallography, cryo-EM and modeling. Nonetheless, the significance of the currently available openpore conformations is debated due to their diversity in the pore geometry. Here, we discuss the physiological significance of existing models of the GlyR active state based on conductance and selectivity measurements by computational electrophysiology. The results support the conclusion that the original cryo-EM reconstruction of the active state obtained in detergents as well as its subsequent refinement by Molecular Dynamics simulations are likely to be nonphysiological as they feature artificially dilated ion pores. In addition, the calculations indicate that a physiologically relevant open pore configuration should be constricted within a radius of 2.5 and 2.8Å, which is consistent with previous modeling, electrophysiology measurements, and the most recent cryo-EM structures obtained in a native lipid-membrane environment.

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“…This is actually hinted by the prime model of muscle-type nAChR activation, in which conformational changes can affect independently either of the two ACh binding sites 29 , as well as by rate-equilibrium free energy relationship analyses arguing for non-concerted rearrangements of M2 helices during nAChR activation 30 . Moreover, molecular dynamics studies also pinpoint the cytoplasmic end of the pore as a locus for asymmetric conformations at the µs timescale: the five -2' residues are often distributed in a non-symmetrical fashion during simulations of the open state of the zebrafish α1 Glycine receptor 31,32 . Of note, channels and receptors from other families are also known to rely on asymmetric gating.…”

Section: As Shown Inmentioning

confidence: 99%

The desensitization pathway of GABA_A receptors, one subunit at a time

Gielen¹,

Barilone²,

Corringer³

2020

Preprint

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GABA A receptors mediate most inhibitory synaptic transmission in the brain of vertebrates.Following GABA binding and fast activation, these receptors undergo a slower desensitization, whose conformational pathway remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABA A receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.2 Abbreviations: ECD, extracellular domain; GABA, γ-aminobutyric acid; GABA A R, type A γ-aminobutyric acid receptor; pLGIC, pentameric ligand-gated ion channel; MWC, Monod-Wyman-Changeux; nAChR, nicotinic acetylcholine receptor; TEVC, two-electrode voltage clamp; TMD, transmembrane domain.

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A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations

Cited by 38 publications

References 74 publications

Coupling structure with function in acid‐sensing ion channels: challenges in pursuit of proton sensors

Coupling structure with function in acid‐sensing ion channels: challenges in pursuit of proton sensors

On the functional annotation of open-channel structures in the glycine receptor

The desensitization pathway of GABA_A receptors, one subunit at a time

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A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations

Cited by 38 publications

References 74 publications

Coupling structure with function in acid‐sensing ion channels: challenges in pursuit of proton sensors

Coupling structure with function in acid‐sensing ion channels: challenges in pursuit of proton sensors

On the functional annotation of open-channel structures in the glycine receptor

The desensitization pathway of GABAA receptors, one subunit at a time

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The desensitization pathway of GABA_A receptors, one subunit at a time