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Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations

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@article{f964cae0641542339e61653d656538bb,
title = "Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations",
abstract = "Nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission in the nervous system. These receptors have emerged as therapeutic targets in drug discovery for treating several conditions, including Alzheimer's disease, pain, and nicotine addiction. In this in silico study, we use a combination of equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in the human α4β2 nAChR. They reveal a striking pattern of communication between the extracellular binding pockets and the transmembrane domains (TMDs) and show the sequence of conformational changes associated with the initial steps in this process. We propose a general mechanism for signal transduction for Cys-loop receptors: the mechanistic steps for communication proceed firstly through loop C in the principal subunit, and are subsequently transmitted, gradually and cumulatively, to loop F of the complementary subunit, and then to the TMDs through the M2-M3 linker.",
keywords = "conformational changes, Cys-loop receptor, MD simulations, nicotine binding, nicotinic receptor",
author = "Oliveira, {A. Sofia F.} and Shoemark, {Deborah K.} and Campello, {Hugo Rego} and Susan Wonnacott and Timothy Gallagher and Sessions, {Richard B.} and Mulholland, {Adrian J.}",
year = "2019",
month = "7",
day = "2",
doi = "10.1016/j.str.2019.04.008",
language = "English",
volume = "27",
pages = "1171--1183.e3",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "7",

}

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TY - JOUR

T1 - Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor

T2 - Insights from Equilibrium and Nonequilibrium Simulations

AU - Oliveira, A. Sofia F.

AU - Shoemark, Deborah K.

AU - Campello, Hugo Rego

AU - Wonnacott, Susan

AU - Gallagher, Timothy

AU - Sessions, Richard B.

AU - Mulholland, Adrian J.

PY - 2019/7/2

Y1 - 2019/7/2

N2 - Nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission in the nervous system. These receptors have emerged as therapeutic targets in drug discovery for treating several conditions, including Alzheimer's disease, pain, and nicotine addiction. In this in silico study, we use a combination of equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in the human α4β2 nAChR. They reveal a striking pattern of communication between the extracellular binding pockets and the transmembrane domains (TMDs) and show the sequence of conformational changes associated with the initial steps in this process. We propose a general mechanism for signal transduction for Cys-loop receptors: the mechanistic steps for communication proceed firstly through loop C in the principal subunit, and are subsequently transmitted, gradually and cumulatively, to loop F of the complementary subunit, and then to the TMDs through the M2-M3 linker.

AB - Nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission in the nervous system. These receptors have emerged as therapeutic targets in drug discovery for treating several conditions, including Alzheimer's disease, pain, and nicotine addiction. In this in silico study, we use a combination of equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in the human α4β2 nAChR. They reveal a striking pattern of communication between the extracellular binding pockets and the transmembrane domains (TMDs) and show the sequence of conformational changes associated with the initial steps in this process. We propose a general mechanism for signal transduction for Cys-loop receptors: the mechanistic steps for communication proceed firstly through loop C in the principal subunit, and are subsequently transmitted, gradually and cumulatively, to loop F of the complementary subunit, and then to the TMDs through the M2-M3 linker.

KW - conformational changes

KW - Cys-loop receptor

KW - MD simulations

KW - nicotine binding

KW - nicotinic receptor

UR - http://www.scopus.com/inward/record.url?scp=85067867093&partnerID=8YFLogxK

U2 - 10.1016/j.str.2019.04.008

DO - 10.1016/j.str.2019.04.008

M3 - Article

VL - 27

SP - 1171-1183.e3

JO - Structure

JF - Structure

SN - 0969-2126

IS - 7

ER -