Structural insights into Cys-loop receptor function and ligand recognition

Nys, Mieke; Kesters, Divya; Ulens, Chris

doi:10.1016/j.bcp.2013.07.001

Cited by 125 publications

(127 citation statements)

References 101 publications

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“…Each functional channel includes five identical or homologous subunits clustered in parallel around the axis of the ion channel pore. Within each subunit, the ;200-amino acid N-terminal domain located extracellular to the plasma membrane primarily comprises an immunoglobulinlike b sandwich, and contributes to canonical agonistbinding sites at subunit interfaces (Nys et al, 2013). This extracellular domain in eukaryotic family members features a conserved disulfide bond that contributes to channel assembly (Amin et al, 1994) and to their classification as the "Cys-loop superfamily" (Collingridge et al, 2009)-although the term is less descriptive of their prokaryotic relatives, which lack this feature (Tasneem et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

Howard

Trudell

Harris³

2014

Pharmacol Rev

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Section: Introductionmentioning

confidence: 99%

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

Howard

Trudell

Harris³

2014

Pharmacol Rev

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“…One of the sides, called the principal face, is formed by three discontinuous loops of the a subunit, whereas the complementary face is formed by three discontinuous b-strands of the adjacent subunit, which in the muscle nAChR is either the « or the d subunit. Key residues of the principal face are grouped in regions called loops A, B, and C at the principal face and loops D, E, and F at the complementary face (Brejc et al, 2001;Sine and Engel, 2006;Nys et al, 2013). Residues of the principal face are highly conserved between a7 and a1 subunits, whereas less conservation is found in residues located at the complementary face (Bartos et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Neurotransmitter GABA Activates Muscle but Notα7 Nicotinic Receptors

et al. 2014

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Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABA A and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15-fold higher EC 50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face («G57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit singlechannel or macroscopic currents of a7 or the chimeric a7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of non-neuronal receptors by serum GABA.

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“…The Cys-loop receptors (CLRs), also referred as pentameric ligand-gated ion channels, all have a characteristic highly conserved 13 amino acid loop formed by a disulfide bond between two cysteine residues (66). Each CLR subunit consists of a large N-terminal extracellular ligand binding domain and four transmembrane segments (TM1-4).…”

Section: Cys-loop Receptorsmentioning

confidence: 99%

A Short Guide to Electrophysiology and Ion Channels

Rubaiy

2017

J Pharm Pharm Sci

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ABSTRACT:The birth and discovery of electrophysiological science took place in the 18 th century laying the path for our understanding of nerve membrane ionic currents. The pore-forming proteins, ion channels, are involved and play critical roles in very important physiological and pathological processes, such as neuronal signaling and cardiac excitability, therefore, they serve as therapeutic drug targets. The study of physiological, pharmacological and biophysical properties of ion channels can be done by patch clamp, a gold standard and powerful electrophysiological technique. The current review, in addition to highlight and cover the history of electrophysiology, patch clamp (conventional and automated) technique, and different types of ion channels, will also discuss the importance of ion channels in different neurological diseases and disorders. As the field of neuroscience is growing, this manuscript is intended as a guide to help in understanding the importance of ion channels, particularly in neuroscience, and also in using the patch clamp technique for the study of molecular physiology, pathophysiology, and pharmacology of neuronal ion channels. Importantly, this review will spotlight on the therapeutic aspect of neuronal ion channels.

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Structural insights into Cys-loop receptor function and ligand recognition

Cited by 125 publications

References 101 publications

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

Neurotransmitter GABA Activates Muscle but Notα7 Nicotinic Receptors

A Short Guide to Electrophysiology and Ion Channels

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