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      Ion channel noise shapes the electrical activity of endocrine cells

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          Abstract

          Endocrine cells in the pituitary gland typically display either spiking or bursting electrical activity, which is related to the level of hormone secretion. Recent work, which combines mathematical modelling with dynamic clamp experiments, suggests the difference is due to the presence or absence of a few large-conductance potassium channels. Since endocrine cells only contain a handful of these channels, it is likely that stochastic effects play an important role in the pattern of electrical activity. Here, for the first time, we explicitly determine the effect of such noise by studying a mathematical model that includes the realistic noisy opening and closing of ion channels. This allows us to investigate how noise affects the electrical activity, examine the origin of spiking and bursting, and determine which channel types are responsible for the greatest noise. Further, for the first time, we address the role of cell size in endocrine cell electrical activity, finding that larger cells typically display more bursting, while the smallest cells almost always only exhibit spiking behaviour.

          Author summary

          The pituitary gland, situated just below the brain, is the body’s master hormone gland. Hormones produced by the pituitary control many essential functions, including growth, reproduction, and our response to emotional and physical stress. The cells that produce these hormones generate electrical activity, exactly like neurons, and this electrical activity controls the amount of hormone that is released. Here, we use mathematics and computing to help understand the electrical activity of these cells. This allows us to perform manipulations that we cannot do experimentally. In particular, we analyse a type of mathematical model that, for the first time, takes into account the role that is played by random processes within pituitary cells. These random processes are particularly important for these types of cell. Using this approach, we determine what causes the different types of electrical activity seen in pituitary cells. A particularly exciting aspect of this work is that it allows us, for the first time, to find out how the electrical activity of big cells is different to that for small cells. Long term, the aim of this work is to understand better how drugs affect hormone production and so suggest ways to reduce their side effects.

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          Most cited references42

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          Channel noise in neurons.

          The probabilistic gating of voltage-dependent ion channels is a source of electrical 'channel noise' in neurons. This noise has long been implicated in limiting the reliability (repeatability) of neuronal responses to repeated presentations of identical stimuli. More recently, it has been shown to increase the range of spiking behaviors exhibited in some neural populations. Channel numbers are tied to metabolic efficiency and the stability of resting potential, and channel noise might be exploited by future cochlear implants in order to improve the temporal representation of sound.
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            Noise in biology.

            Noise permeates biology on all levels, from the most basic molecular, sub-cellular processes to the dynamics of tissues, organs, organisms and populations. The functional roles of noise in biological processes can vary greatly. Along with standard, entropy-increasing effects of producing random mutations, diversifying phenotypes in isogenic populations, limiting information capacity of signaling relays, it occasionally plays more surprising constructive roles by accelerating the pace of evolution, providing selective advantage in dynamic environments, enhancing intracellular transport of biomolecules and increasing information capacity of signaling pathways. This short review covers the recent progress in understanding mechanisms and effects of fluctuations in biological systems of different scales and the basic approaches to their mathematical modeling.
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              Control of K(Ca) channels by calcium nano/microdomains.

              Transient elevations in cytoplasmic Ca(2+) trigger a multitude of Ca(2+)-dependent processes in CNS neurons and many other cell types. The specificity, speed, and reliability of these processes is achieved and ensured by tightly restricting Ca(2+) signals to very local spatiotemporal domains, "Ca(2+) nano- and microdomains," that are centered around Ca(2+)-permeable channels. This arrangement requires that the Ca(2+)-dependent effectors reside within these spatial boundaries where the properties of the Ca(2+) domain and the Ca(2+) sensor of the effector determine the channel-effector activity. We use Ca(2+)-activated K(+) channels (K(Ca)) with either micromolar (BK(Ca) channels) or submicromolar (SK(Ca) channels) affinity for Ca(2+) ions to provide distance constraints for Ca(2+)-effector coupling in local Ca(2+) domains and review their significance for the cell physiology of K(Ca) channels in the CNS. The results may serve as a model for other processes operated by local Ca(2+) domains.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, CA USA )
                1553-734X
                1553-7358
                April 2020
                6 April 2020
                : 16
                : 4
                : e1007769
                Affiliations
                [1 ] Living Systems Institute, University of Exeter, Exeter, United Kingdom
                [2 ] College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom
                [3 ] Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
                [4 ] University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
                University of Pittsburgh, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-6255-8761
                Article
                PCOMPBIOL-D-19-01667
                10.1371/journal.pcbi.1007769
                7162531
                32251433
                43eeef2e-a253-4247-9b2f-ef0d361f7974
                © 2020 Richards et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 September 2019
                : 3 March 2020
                Page count
                Figures: 7, Tables: 0, Pages: 24
                Funding
                Funded by: Medical Research Council (UK)
                Award ID: MR/P022405/1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: WT105618MA
                Award Recipient :
                Funded by: Medical Research Council (UK)
                Award ID: MR/N008936/1
                Award Recipient :
                Funded by: Engineering and Physical Sciences Research Council (UK)
                Award ID: EP/N014391/1
                Award Recipient :
                DMR gratefully acknowledges financial support from the Medical Research Council (MR/P022405/1). JJW was funded from MRC Grant MR/N008936/1 and EPSRC grant EP/N014391/1. DMR, JT and JJW were also supported by a Wellcome Trust Institutional Strategic Support Award (WT105618MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Action Potentials
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Action Potentials
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Action Potentials
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                Neurophysiology
                Action Potentials
                Biology and Life Sciences
                Neuroscience
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                Biophysics
                Ion Channels
                Potassium Channels
                Calcium-Activated Potassium Channels
                Physical Sciences
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                Ion Channels
                Potassium Channels
                Calcium-Activated Potassium Channels
                Biology and Life Sciences
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                Ion Channels
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                Ion Channels
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                Biology and Life Sciences
                Neuroscience
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                Ion Channels
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                Biology and Life Sciences
                Biochemistry
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                Biophysics
                Ion Channels
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                Physical Sciences
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                Ion Channels
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                Ion Channels
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                Anatomy
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                Pituitary Gland
                Medicine and Health Sciences
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                Endocrine System
                Pituitary Gland
                Biology and Life Sciences
                Anatomy
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                Biology and Life Sciences
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                Neuroanatomy
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                Physiology
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                Ion Channels
                Physical Sciences
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                Ion Channels
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                Medicine and Health Sciences
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                Biology and Life Sciences
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                Medicine and Health Sciences
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                Ion Channels
                Biology and Life Sciences
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                Ion Channels
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Endocrine Cells
                Biology and Life Sciences
                Anatomy
                Endocrine System
                Endocrine Cells
                Medicine and Health Sciences
                Anatomy
                Endocrine System
                Endocrine Cells
                Custom metadata
                vor-update-to-uncorrected-proof
                2020-04-16
                All relevant data are within the manuscript and its Supporting Information files.

                Quantitative & Systems biology
                Quantitative & Systems biology

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