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

Sofia Oliviera, Deborah K. Shoemark, Hugo Rego Campello, Susan Wonnacott, Tim Gallagher, Richard B. Sessions, Adrian J. Mulholland

Research output: Contribution to journalArticle

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.
Original languageEnglish
JournalStructure
Early online date23 May 2019
DOIs
Publication statusE-pub ahead of print - 23 May 2019

Cite this

Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations. / Oliviera, Sofia; Shoemark, Deborah K.; Rego Campello, Hugo ; Wonnacott, Susan; Gallagher, Tim; Sessions, Richard B.; Mulholland, Adrian J.

In: Structure, 23.05.2019.

Research output: Contribution to journalArticle

Oliviera, Sofia ; Shoemark, Deborah K. ; Rego Campello, Hugo ; Wonnacott, Susan ; Gallagher, Tim ; Sessions, Richard B. ; Mulholland, Adrian J. / Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations. In: Structure. 2019.
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