The nicotinic acetylcholine receptor: from molecular model to single-channel conductance

2000 ◽  
Vol 29 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Charlotte Adcock ◽  
Graham R. Smith ◽  
Mark S.P. Sansom
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Single Channel ◽  
Molecular Model ◽  
Channel Conductance ◽  
Single Channel Conductance ◽  
Nicotinic Acetylcholine

The 5-hydroxytryptamine type 3 (5-HT3) receptor reveals a novel determinant of single-channel conductance

2004 ◽  
Vol 32 (3) ◽  
pp. 547-552 ◽  
Author(s):  
J.A. Peters ◽  
S.P. Kelley ◽  
J.I. Dunlop ◽  
E.F. Kirkness ◽  
T.G. Hales ◽  
...  
Keyword(s):  
Ion Channels ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Single Channel ◽  
Channel Conductance ◽  
Single Channel Conductance ◽  
Nicotinic Acetylcholine ◽  
Ultrastructural Studies ◽  
Arginine Residues ◽  
Type 3

5-HT3 (5-hydroxytryptamine type 3) receptors are cation-selective ion channels of the Cys-loop transmitter-gated ion channel superfamily. Two 5-HT3 receptor subunits, 5-HT3A and 5-HT3B, have been characterized in detail, although additional putative 5-HT3 subunit genes (HTR3C, HTR3D and HTR3E) have recently been reported. 5-HT3 receptors function as homopentameric assemblies of the 5-HT3 subunit, or heteropentamers of 5-HT3A and 5-HT3B subunits of unknown stoichiometry. The single-channel conductances of human recombinant homomeric and heteromeric 5-HT3 receptors are markedly different, being <1 and approx. 16 pS respectively. Paradoxically, from the results of studies performed on the closely related nicotinic acetylcholine receptor, the channel-lining M2 domain of the 5-HT3A subunit is predicted to enhance cation conduction, whereas that of the 5-HT3B subunit would not. The present study describes a novel determinant of single-channel conductance, outwith the M2 domain, which accounts for this anomaly. Utilizing a panel of chimaeric 5-HT3A and 5-HT3B subunits, a profound determinant of single-channel conductance was traced to a putative amphipathic helix (the ‘HA stretch’) within the large cytoplasmic loop of the receptor. Replacement of three arginine residues (R432, R436 and R440) unique to the HA stretch of the 5-HT3A subunit with the aligned residues (Q395, D399 and A403) of the 5-HT3B subunit increased the single-channel conductance 28-fold. Significantly, from ultrastructural studies of the Torpedo nicotinic acetylcholine receptor, the key residues may be components of narrow openings within the inner vestibule of the channel, located in the cytoplasm, which contribute to the permeation pathway. Our findings indicate an important and hitherto unappreciated function for the HA stretch in the Cys-loop family of transmitter-gated ion channels.

scholarly journals Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor

2020 ◽  
Vol 152 (9) ◽  
Author(s):  
Kathiresan Natarajan ◽  
Nuriya Mukhtasimova ◽  
Jeremías Corradi ◽  
Matías Lasala ◽  
Cecilia Bouzat ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Single Channel ◽  
Structural Motif ◽  
Site Mutation ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Low Concentrations ◽  
Channel Opening ◽  
Dynamics Simulations

The α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh. Potentiation manifests as robust increases in the frequency of channel opening and the average duration of the openings. Molecular dynamics simulations reveal that calcium binds to the periphery of the five ligand binding sites and is framed by a pair of anionic residues from the principal and complementary faces of each site. Mutation of residues identified by simulation prevents calcium from potentiating ACh-elicited channel opening. An anionic residue is conserved at each of the identified positions in all vertebrate species of α7. Thus, calcium associates with a novel structural motif on α7 and is an obligate cofactor in regions of limited ACh concentration.

scholarly journals Distinctive single-channel properties of α4β2-nicotinic acetylcholine receptor isoforms

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0213143 ◽  
Author(s):  
Maegan M. Weltzin ◽  
Andrew A. George ◽  
Ronald J. Lukas ◽  
Paul Whiteaker
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Single Channel ◽  
Nicotinic Acetylcholine ◽  
Receptor Isoforms ◽  
Channel Properties

Molecular simulation studies of hydrophobic gating in nanopores and ion channels

2015 ◽  
Vol 43 (2) ◽  
pp. 146-150 ◽  
Author(s):  
Jemma L. Trick ◽  
Prafulla Aryal ◽  
Stephen J. Tucker ◽  
Mark S. P. Sansom
Keyword(s):  
Ion Channels ◽  
Simple Model ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Single Channel ◽  
Experimental Studies ◽  
Physical Nature ◽  
Simulation Studies ◽  
Nicotinic Acetylcholine ◽  
Gating Mechanisms

Gating in channels and nanopores plays a key role in regulating flow of ions across membranes. Molecular simulations provide a ‘computational microscope’ which enables us to examine the physical nature of gating mechanisms at the level of the single channel molecule. Water enclosed within the confines of a nanoscale pore may exhibit unexpected behaviour. In particular, if the molecular surfaces lining the pore are hydrophobic this promotes de-wetting of the pore. De-wetting is observed as stochastic liquid–vapour transitions within a pore, and may lead to functional closure of a pore to the flow of ions and/or water. Such behaviour was first observed in simulations of simple model nanopores and referred to as ‘hydrophobic gating’. Simulations of both the nicotinic acetylcholine receptor and of TWIK-1 potassium channels (the latter alongside experimental studies) suggest hydrophobic gating may occur in some biological ion channels. Current studies are focused on designing hydrophobic gates into biomimetic nanopores.

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