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

A. Sofia F. Oliveira, Deborah K. Shoemark, Hugo Rego Campello, Susan Wonnacott, Timothy Gallagher, Richard B. Sessions*, Adrian J. Mulholland

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

1 Citation (Scopus)
23 Downloads (Pure)

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
Pages (from-to)1171-1183.e3
Number of pages17
JournalStructure
Volume27
Issue number7
Early online date23 Apr 2019
DOIs
Publication statusPublished - 2 Jul 2019

Keywords

  • conformational changes
  • Cys-loop receptor
  • MD simulations
  • nicotine binding
  • nicotinic receptor

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