Atia, Jolene, McCloskey, Conor, Shmygol, Anatoly, Rand, D. A. (David A.), Berg, Hugo van den and Blanks, Andrew M. (2016) Reconstruction of cell surface densities of ion pumps, exchangers, and channels from mRNA expression, conductance kinetics, whole-cell calcium, and current-clamp voltage recordings, with an application to human uterine smooth muscle cells. PLoS Computational Biology, 12 (4). e1004828. doi:10.1371/journal.pcbi.1004828 ISSN 1553-7358.

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Abstract

Uterine smooth muscle cells remain quiescent throughout most of gestation, only generating spontaneous action potentials immediately prior to, and during, labor. This study presents a method that combines transcriptomics with biophysical recordings to characterise the conductance repertoire of these cells, the ‘conductance repertoire’ being the total complement of ion channels and transporters expressed by an electrically active cell. Transcriptomic analysis provides a set of potential electrogenic entities, of which the conductance repertoire is a subset. Each entity within the conductance repertoire was modeled independently and its gating parameter values were fixed using the available biophysical data. The only remaining free parameters were the surface densities for each entity. We characterise the space of combinations of surface densities (density vectors) consistent with experimentally observed membrane potential and calcium waveforms. This yields insights on the functional redundancy of the system as well as its behavioral versatility. Our approach couples high-throughput transcriptomic data with physiological behaviors in health and disease, and provides a formal method to link genotype to phenotype in excitable systems. We accurately predict current densities and chart functional redundancy. For example, we find that to evoke the observed voltage waveform, the BK channel is functionally redundant whereas hERG is essential. Furthermore, our analysis suggests that activation of calcium-activated chloride conductances by intracellular calcium release is the key factor underlying spontaneous depolarisations.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Science, Engineering and Medicine > Science > Mathematics Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Cells -- Electric properties, Myometrium
Journal or Publication Title:	PLoS Computational Biology
Publisher:	Public Library of Science
ISSN:	1553-7358
Official Date:	21 April 2016
Dates:	Date Event 21 April 2016 Published 23 February 2016 Accepted 19 May 2015 Submitted
Volume:	12
Number:	4
Article Number:	e1004828
DOI:	10.1371/journal.pcbi.1004828
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	27 April 2016
Date of first compliant Open Access:	27 April 2016
Funder:	Medical Research Council (Great Britain) (MRC)
Grant number:	G0901801 (MRC), G0800138-2 (MRC)
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