scholarly journals Disrupting inter-subunit interactions favors channel opening in P2X2 receptors

2021 ◽  
Author(s):  
Federica Gasparri ◽  
Sarune Bielickaite ◽  
Mette Homann Poulsen ◽  
Stephan Alexander Pless
Keyword(s):  
Ion Channels ◽  
Subunit Interactions ◽  
Cellular Protection ◽  
Protection Mechanism ◽  
Subunit Interface ◽  
Channel Opening ◽  
Close Proximity ◽  
Low Threshold ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

P2X receptors (P2XRs) are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding to their large extracellular domain (ECD). The seven known P2XR subtypes typically assemble as homo- or heterotrimeric complexes and they contribute to numerous physiological functions, including nociception, inflammation and hearing. Both the overall structure of P2XRs and the details of how ATP is coordinated at the subunit interface are well established. By contrast, little is known about how inter-subunit interactions in the ECD contribute to channel function. Here we investigate both single and double mutants at the subunit interface of rP2X2Rs using electrophysiological and biochemical approaches. Our data demonstrate that the vast majority of mutations that disrupt putative inter-subunit interactions result in channels with higher apparent ATP affinity and that double mutants at the subunit interface show significant energetic coupling, especially if the mutations are located in close proximity. Overall, we show that inter-subunit interactions, as well as possibly interactions in other parts of the receptor, stabilize WT rP2X2Rs in the closed state. This suggests that, unlike other ligand-gated ion channels, P2X2 receptors have not evolved for an intrinsically low threshold for activation, possibly to allow for additional modulation or as a cellular protection mechanism against overstimulation.

The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function

2004 ◽  
Vol 32 (3) ◽  
pp. 529-534 ◽  
Author(s):  
C.N. Connolly ◽  
K.A. Wafford
Keyword(s):  
Ion Channels ◽  
Conformational Changes ◽  
Channel Structure ◽  
Channel Function ◽  
Receptor Structure ◽  
Channel Opening ◽  
The Impact ◽  
Ion Pore ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

The Cys-loop receptors constitute an important superfamily of LGICs (ligand-gated ion channels) comprising receptors for acetylcholine, 5-HT3 (5-hydroxytryptamine; 5-HT3 receptors), glycine and GABA (γ-aminobutyric acid; GABAA receptors). A vast knowledge of the structure of the Cys-loop superfamily and its impact on channel function have been accrued over the last few years, leading to exciting new proposals on how ion channels open and close in response to agonist binding. Channel opening is initiated by the extracellular association of agonists to discrete binding pockets, leading to dramatic conformational changes, culminating in the opening of a central ion pore. The importance of channel structure is exemplified in the allosteric modulation of channel function by the binding of other molecules to distinct sites on the channel, which exerts an additional level of control on their function. The subsequent conformational changes (gating) lead to channel opening and ion transport. Following channel pore opening, ion selectivity is determined by receptor structure in, and around, the ion pore. As a final level of control, cytoplasmic determinants control the magnitude (conductance) of ion flow into the cell. Thus the Cys-loop receptors are complex molecular motors, with moving parts, which can transduce extracellular signals across the plasma membrane. Once the full mechanical motions involved are understood, it may be possible to design sophisticated therapeutic agents to modulate their activity, or at least be able to throw a molecular spanner into the works!

scholarly journals A Functionally Conserved Mechanism of Modulation via a Vestibule Site in Pentameric Ligand-Gated Ion Channels

2019 ◽  
Author(s):  
Marijke Brams ◽  
Cedric Govaerts ◽  
Kumiko Kambara ◽  
Kerry Price ◽  
Radovan Spurny ◽  
...  
Keyword(s):  
Ion Channels ◽  
Binding Site ◽  
Binding Sites ◽  
Allosteric Modulators ◽  
Channel Opening ◽  
Single Domain Antibodies ◽  
Allosteric Binding Sites ◽  
Target Binding ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

ABSTRACTPentameric ligand-gated ion channels (pLGICs) belong to a class of ion channels involved in fast synaptic signaling in the central and peripheral nervous systems. Molecules acting as allosteric modulators target binding sites that are remote from the neurotransmitter binding site, but functionally affect coupling of ligand binding to channel opening. Here, we investigated an allosteric binding site in the ion channel vestibule, which has converged from a series of studies on prokaryote and eukaryote channel homologs. We discovered single domain antibodies, called nanobodies, which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote channel ELIC bound either to a positive (PAM) or a negative (NAM) allosteric modulator. We extrapolate the functional importance of the vestibule binding site to eukaryote ion channels, suggesting a conserved mechanism of allosteric modulation. This work identifies key elements of allosteric binding sites and extends drug design possibilities in pLGICs using nanobodies.

Physiology and biophysics of plant ligand-gated ion channels

Plant Biology ◽  
2010 ◽  
Vol 12 ◽  
pp. 80-93 ◽  
Author(s):  
P. Dietrich ◽  
U. Anschütz ◽  
A. Kugler ◽  
D. Becker
Keyword(s):  
Ion Channels ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

scholarly journals Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

2021 ◽  
Vol 125 (4) ◽  
pp. 981-994
Author(s):  
Shanlin Rao ◽  
Gianni Klesse ◽  
Charlotte I. Lynch ◽  
Stephen J. Tucker ◽  
Mark S. P. Sansom
Keyword(s):  
Ion Channels ◽  
Molecular Simulations ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Ligand-gated ion channels as targets of neuroactive insecticides

2021 ◽  
Author(s):  
Makoto Ihara
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Functional Expression ◽  
X Ray ◽  
Acetylcholine Binding Protein ◽  
Site Selectivity ◽  
Future Drug ◽  
Cl Channels ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Abstract The Cys-loop superfamily of ligand-gated ion channels (Cys-loop receptors) is one of the most ubiquitous ion channel families in vertebrates and invertebrates. Despite their ubiquity, they are targeted by several classes of pesticides, including neonicotinoids, phenylpyrazols, and macrolides such as ivermectins. The current commercialized compounds have high target site selectivity, which contributes to the safety of insecticide use. Structural analyses have accelerated progress in this field; notably, the X-ray crystal structures of acetylcholine binding protein and glutamate-gated Cl channels revealed the details of the molecular interactions between insecticides and their targets. Recently, the functional expression of the insect nicotinic acetylcholine receptor (nAChR) has been described, and detailed evaluations using the insect nAChR have emerged. This review discusses the basic concepts and the current insights into the molecular mechanisms of neuroactive insecticides targeting the ligand-gated ion channels, particularly Cys-loop receptors, and presents insights into target-based selectivity, resistance, and future drug design.

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