Signal Transduction Pathways in the Pentameric Ligand-Gated Ion Channels

Mowrey, D and Chen, Q and Liang, Y and Liang, J and Xu, Y and Tang, P (2013) Signal Transduction Pathways in the Pentameric Ligand-Gated Ion Channels. PLoS ONE, 8 (5).

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Abstract

The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the β1-β2 loop or through pre-TM1. The β1-β2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs. © 2013 Mowrey et al.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Mowrey, D Chen, Q qic8@pitt.edu QIC8 Liang, Y Liang, J Xu, Y xu2@pitt.edu XU2 Tang, P ptang@pitt.edu PTANG
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Nitabach, Michael N. UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	10 May 2013
Date Type:	Publication
Journal or Publication Title:	PLoS ONE
Volume:	8
Number:	5
DOI or Unique Handle:	10.1371/journal.pone.0064326
Schools and Programs:	School of Medicine > Anesthesiology School of Medicine > Computational and Systems Biology School of Medicine > Pharmacology and Chemical Biology School of Medicine > Structural Biology
Refereed:	Yes
Date Deposited:	12 Jun 2013 20:56
Last Modified:	29 Jan 2019 15:55
URI:	http://d-scholarship.pitt.edu/id/eprint/18837

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