The Editorial on the Research Topic - Roles of Ion Channels in Immune Cell

Amanda eMacKenzie

Leanne eStokes

Ronald eSluyter

English

PubMed

Leanne Stokes

Amanda B. MacKenzie

Ronald Sluyter

Crossref

Frontiers in Immunology

Editorial: Roles of Ion Channels in Immune Cells

Stokes, Leanne

MacKenzie, Amanda B.

Sluyter, Ronald

Pure

Editorial:roles of ion channels in immune cells

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Editorial: Roles of ion channels in immune cells

Mackenzie, Amanda

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February 2016 | Volume 7 | Article 481Editorialpublished: 15 February 2016doi: 10.3389/fimmu.2016.00048Frontiers in Immunology | www.frontiersin.orgEdited by: Masaaki Murakami, Hokkaido University, JapanReviewed by: Irena Levitan, University of Illinois at Chicago, USA Hideki Ogura, Yale University, USA*Correspondence:Leanne Stokes  l.stokes@uea.ac.ukSpecialty section: This article was submitted to Inflammation, a section of the journal Frontiers in ImmunologyReceived: 17 November 2015Accepted: 31 January 2016Published: 15 February 2016Citation: Stokes L, MacKenzie AB and Sluyter R (2016) Editorial: Roles of Ion Channels in Immune Cells. Front. Immunol. 7:48. doi: 10.3389/fimmu.2016.00048Editorial: roles of ion Channels in immune CellsLeanne Stokes1,2* , Amanda B. MacKenzie3 and Ronald Sluyter 4,5,61 Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia, 2 School of Pharmacy, University of East Anglia, Norwich, UK, 3 Department of Pharmacy and Pharmacology, University of Bath, Bath, UK, 4 School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia, 5 Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia, 6 Illawarra Health and Medical Research Institute, Wollongong, NSW, AustraliaKeywords: ion channels, immune cells, microglial cells, lymphocytes, calcium, signalling pathwaysThe Editorial on the Research Topic Roles of Ion Channels in Immune CellsIon channels are critical membrane proteins controlling a wide variety of cellular signaling events in many different cell types. In classical excitable cells, voltage-sensitive ion channels have well-described roles in the regulation of action potentials and contraction events. In non-excitable cells such as circulating or tissue-resident cells of the immune system, ion channels have lesser described roles in controlling cell biology. However, through enhanced pharmacological tools and gene knock-outs, we are now beginning to appreciate the plethora of cellular events in immune cells that are controlled by a variety of ion channels (1). The goal of this research topic was to highlight some of the recent advances in understanding which ion channels are important and are under investigation for novel therapeutics. This collection of six articles covers microglia, myeloid cells, and lymphocytes and provides updates and insights into the roles of various channels in these cells.Mortadza and colleagues review the latest evidence supporting a functional role for transient receptor potential melastatin (TRPM) 2 ion channels in the immune system (Syed Mortadza et al.). TRPM2 ion channels are activated by increases in reactive oxygen species (ROS) leading to Ca2+ signals in a range of immune cells. The authors discuss the use of TRPM2 knockout mice revealing an important role in the immune system and inflammatory diseases. Based on these studies in mouse models, the authors highlight a negative role for TRPM2 in colitis, ischemia-/reperfusion-mediated tissue damage, and neuropathic and inflammatory pain. They also discuss the importance of TRPM2 in inflammatory signaling including NLRP3 inflammasome activation leading to inflammatory cytokine production including bioactive interleukin (IL)-1β and chemokine-dependent dendritic cell function. Overall, the review demonstrates the importance of TRPM2 as a future therapeutic target for the treatment of inflammatory disease.Stebbing and colleagues provide a mini-review of numerous ion channels expressed in microglia (Stebbing et  al.). Ligand-gated channels belonging to P2X and N-methyl-d-aspartate (NMDA) receptor families respond to the neurotransmitters adenosine triphosphate (ATP) and glutamate, respectively. These are involved in the sensing of local microenvironments within the central nervous system and can affect microglial activation states through modulation of intracellular Ca2+ levels. In addition, K+ channels are also implicated in microglial responses including proliferation, nitric oxide generation, and cytokine secretion and, as such, are potential therapeutic targets for increasing neuroprotection in neurodegenerative disorders such as Alzheimer’s disease.Through an original research article, Ferreira and colleagues describe the regulation of the intermediate conductance Ca2+-activated K+ channel, KCa3.1, by cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) via a pathway involving ROS and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in microglia (Ferreira et al.) KCa3.1 is widely expressed in February 2016 | Volume 7 | Article 482Stokes et al. Ion Channels in Immune CellsFrontiers in Immunology | www.frontiersin.orgimmune cells, but knowledge of KCa3.1 in microglia is hitherto limited. Through pharmacological approaches, and the use of the rat MLS-9 microglial cell line and alternative-activated primary rat microglia, the authors demonstrate that elevation in cGMP activates PKG to promote mitochondrial ROS formation. This in turn stimulates endoplasmic reticulum Ca2+ release, which subsequently binds to calmodulin to both open the KCa3.1 channel and activate CaMKII to increase KCa3.1 activity through a second, unknown mechanism. The authors propose that this process may serve as a positive feedback mechanism to promote KCa3.1-dependent responses in microglia under conditions such as oxidative stress.Moving to the adaptive immune system, Davenport and colleagues have reviewed the current understanding of the CaV1 subfamily of L-type voltage-gated Ca2+-channels expressed by lymphocytes (Davenport et al.). The authors discuss the evidence supporting the expression of CaV1 ion channels in immune cells including a rare genetic disease (Timothy Syndrome) that sug-gests a role for CaV1.2 in human immune responses. Evidence for CaV1 function in B lymphocytes is largely supported by phar-macological studies, and the authors present further evidence for the expression of CaV1 ion channels in B lymphocytes using a CaV1.3 deficient chicken DT40 B cell line. It is concluded that CaV1 channels play an important role in the immune system; however, there are many unanswered questions particularly sur-rounding the potential activation mechanism of immune CaV1 channels.Nohara and colleagues review the current understanding of the complex orchestration of Ca2+ responses in T lymphocytes and recent advances in understanding store-operated calcium channels (STIM/Orai), TRP channels, NMDA receptors, P2X receptors, and CaV channels in T lymphocytes (Nohara et  al.). The authors focus on CaV channels for which there is growing evidence particularly from the recent use of CaV1 channel subunit knockout mice where significant effects are observed on T lympho-cyte responses. The potential interplay between CaV and STIM proteins in T cells is discussed, and the complexity surrounding regulation of intracellular (Ca2+) in these cells is highlighted. The authors conclude by identifying that superior immunomodula-tors may be developed targeting lymphocyte-specific variants of ion channels and these may be highly beneficial in future treat-ments for autoimmune diseases or immunosuppression required for transplants.Finally, Rissiek and colleagues review the P2X7 receptor, an ATP-gated cation channel, in murine T lymphocytes (Rissiek et  al.). The authors highlight that both extracellular ATP and nicotinamide adenine dinucleotide (NAD) can activate P2X7 on murine T lymphocytes. In contrast to ATP, P2X7 activation by NAD requires covalent adenosine triphosphate (ADP)-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Notably, NAD activates only the splice isoform P2X7k and the main P2X7 subtype within murine T lymphocytes. The authors describe the roles of P2X7 in murine (and human) T cells including IL-2 production, shedding of cell surface receptors, and cell death. Lastly, the authors highlight that ATP and NAD is released during T cell isolation, which results in the preferential loss of T regulatory and natural killer T cells due to high P2X7 expression on these cells, and outline ways in which to circumvent this to improve the quality of ex vivo T cell preparations.Collectively, this Frontiers in Immunology Research Topic provides a sample of the diversity and importance of ion chan-nels in immune cells. We are grateful to each author and trust that this Research Topic will serve as a prompt to continue future investigations of ion channels in immune cells.aUtHor CoNtriBUtioNSLS, AM, and RS contributed equally to this editorial article.rEFErENCE1. Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol (2015) 33:291–353. doi:10.1146/annurev-immunol-032414-112212 Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2016 Stokes, MacKenzie and Sluyter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic prac-tice. No use, distribution or reproduction is permitted which does not comply with these terms.

Roles of ion channels in immune cells

Frontiers - Publisher Connector

February 2016 | Volume 7 | Article 481
Editorial
published: 15 February 2016
doi: 10.3389/fimmu.2016.00048
Frontiers in Immunology | www.frontiersin.org
Edited by: 
Masaaki Murakami, 
Hokkaido University, Japan
Reviewed by: 
Irena Levitan, 
University of Illinois at Chicago, USA 
Hideki Ogura, 
Yale University, USA
*Correspondence:
Leanne Stokes  
l.stokes@uea.ac.uk
Specialty section: 
This article was submitted to 
Inflammation, 
a section of the journal 
Frontiers in Immunology
Received: 17 November 2015
Accepted: 31 January 2016
Published: 15 February 2016
Citation: 
Stokes L, MacKenzie AB and 
Sluyter R (2016) Editorial: Roles of Ion 
Channels in Immune Cells. 
Front. Immunol. 7:48. 
doi: 10.3389/fimmu.2016.00048
Editorial: roles of ion Channels 
in immune Cells
Leanne Stokes1,2* , Amanda B. MacKenzie3 and Ronald Sluyter 4,5,6
1 Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia, 2 School of Pharmacy, University of East 
Anglia, Norwich, UK, 3 Department of Pharmacy and Pharmacology, University of Bath, Bath, UK, 4 School of Biological 
Sciences, University of Wollongong, Wollongong, NSW, Australia, 5 Centre for Medical and Molecular Bioscience, University 
of Wollongong, Wollongong, NSW, Australia, 6 Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
Keywords: ion channels, immune cells, microglial cells, lymphocytes, calcium, signalling pathways
The Editorial on the Research Topic 
Roles of Ion Channels in Immune Cells
Ion channels are critical membrane proteins controlling a wide variety of cellular signaling events 
in many different cell types. In classical excitable cells, voltage-sensitive ion channels have well-
described roles in the regulation of action potentials and contraction events. In non-excitable cells 
such as circulating or tissue-resident cells of the immune system, ion channels have lesser described 
roles in controlling cell biology. However, through enhanced pharmacological tools and gene knock-
outs, we are now beginning to appreciate the plethora of cellular events in immune cells that are 
controlled by a variety of ion channels (1). The goal of this research topic was to highlight some of 
the recent advances in understanding which ion channels are important and are under investigation 
for novel therapeutics. This collection of six articles covers microglia, myeloid cells, and lymphocytes 
and provides updates and insights into the roles of various channels in these cells.
Mortadza and colleagues review the latest evidence supporting a functional role for transient 
receptor potential melastatin (TRPM) 2 ion channels in the immune system (Syed Mortadza et al.). 
TRPM2 ion channels are activated by increases in reactive oxygen species (ROS) leading to Ca2+ 
signals in a range of immune cells. The authors discuss the use of TRPM2 knockout mice revealing 
an important role in the immune system and inflammatory diseases. Based on these studies in mouse 
models, the authors highlight a negative role for TRPM2 in colitis, ischemia-/reperfusion-mediated 
tissue damage, and neuropathic and inflammatory pain. They also discuss the importance of TRPM2 
in inflammatory signaling including NLRP3 inflammasome activation leading to inflammatory 
cytokine production including bioactive interleukin (IL)-1β and chemokine-dependent dendritic 
cell function. Overall, the review demonstrates the importance of TRPM2 as a future therapeutic 
target for the treatment of inflammatory disease.
Stebbing and colleagues provide a mini-review of numerous ion channels expressed in microglia 
(Stebbing et  al.). Ligand-gated channels belonging to P2X and N-methyl-d-aspartate (NMDA) 
receptor families respond to the neurotransmitters adenosine triphosphate (ATP) and glutamate, 
respectively. These are involved in the sensing of local microenvironments within the central nervous 
system and can affect microglial activation states through modulation of intracellular Ca2+ levels. 
In addition, K+ channels are also implicated in microglial responses including proliferation, nitric 
oxide generation, and cytokine secretion and, as such, are potential therapeutic targets for increasing 
neuroprotection in neurodegenerative disorders such as Alzheimer’s disease.
Through an original research article, Ferreira and colleagues describe the regulation of the 
intermediate conductance Ca2+-activated K+ channel, KCa3.1, by cyclic guanosine monophosphate 
(cGMP)-dependent protein kinase (PKG) via a pathway involving ROS and Ca2+/calmodulin-
dependent protein kinase II (CaMKII) in microglia (Ferreira et al.) KCa3.1 is widely expressed in 
February 2016 | Volume 7 | Article 482
Stokes et al. Ion Channels in Immune Cells
Frontiers in Immunology | www.frontiersin.org
immune cells, but knowledge of KCa3.1 in microglia is hitherto 
limited. Through pharmacological approaches, and the use of the 
rat MLS-9 microglial cell line and alternative-activated primary 
rat microglia, the authors demonstrate that elevation in cGMP 
activates PKG to promote mitochondrial ROS formation. This 
in turn stimulates endoplasmic reticulum Ca2+ release, which 
subsequently binds to calmodulin to both open the KCa3.1 
channel and activate CaMKII to increase KCa3.1 activity through 
a second, unknown mechanism. The authors propose that this 
process may serve as a positive feedback mechanism to promote 
KCa3.1-dependent responses in microglia under conditions such 
as oxidative stress.
Moving to the adaptive immune system, Davenport and 
colleagues have reviewed the current understanding of the CaV1 
subfamily of L-type voltage-gated Ca2+-channels expressed by 
lymphocytes (Davenport et al.). The authors discuss the evidence 
supporting the expression of CaV1 ion channels in immune cells 
including a rare genetic disease (Timothy Syndrome) that sug-
gests a role for CaV1.2 in human immune responses. Evidence 
for CaV1 function in B lymphocytes is largely supported by phar-
macological studies, and the authors present further evidence 
for the expression of CaV1 ion channels in B lymphocytes using 
a CaV1.3 deficient chicken DT40 B cell line. It is concluded that 
CaV1 channels play an important role in the immune system; 
however, there are many unanswered questions particularly sur-
rounding the potential activation mechanism of immune CaV1 
channels.
Nohara and colleagues review the current understanding of 
the complex orchestration of Ca2+ responses in T lymphocytes 
and recent advances in understanding store-operated calcium 
channels (STIM/Orai), TRP channels, NMDA receptors, P2X 
receptors, and CaV channels in T lymphocytes (Nohara et  al.). 
The authors focus on CaV channels for which there is growing 
evidence particularly from the recent use of CaV1 channel subunit 
knockout mice where significant effects are observed on T lympho-
cyte responses. The potential interplay between CaV and STIM 
proteins in T cells is discussed, and the complexity surrounding 
regulation of intracellular (Ca2+) in these cells is highlighted. The 
authors conclude by identifying that superior immunomodula-
tors may be developed targeting lymphocyte-specific variants of 
ion channels and these may be highly beneficial in future treat-
ments for autoimmune diseases or immunosuppression required 
for transplants.
Finally, Rissiek and colleagues review the P2X7 receptor, an 
ATP-gated cation channel, in murine T lymphocytes (Rissiek 
et  al.). The authors highlight that both extracellular ATP and 
nicotinamide adenine dinucleotide (NAD) can activate P2X7 
on murine T lymphocytes. In contrast to ATP, P2X7 activation 
by NAD requires covalent adenosine triphosphate (ADP)-
ribosylation catalyzed by the ecto-ADP-ribosyltransferase 
ARTC2.2. Notably, NAD activates only the splice isoform P2X7k 
and the main P2X7 subtype within murine T lymphocytes. The 
authors describe the roles of P2X7 in murine (and human) T cells 
including IL-2 production, shedding of cell surface receptors, 
and cell death. Lastly, the authors highlight that ATP and NAD is 
released during T cell isolation, which results in the preferential 
loss of T regulatory and natural killer T cells due to high P2X7 
expression on these cells, and outline ways in which to circumvent 
this to improve the quality of ex vivo T cell preparations.
Collectively, this Frontiers in Immunology Research Topic 
provides a sample of the diversity and importance of ion chan-
nels in immune cells. We are grateful to each author and trust 
that this Research Topic will serve as a prompt to continue future 
investigations of ion channels in immune cells.
aUtHor CoNtriBUtioNS
LS, AM, and RS contributed equally to this editorial article.
rEFErENCE
1. Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive 
immunity. Annu Rev Immunol (2015) 33:291–353. doi:10.1146/
annurev-immunol-032414-112212 
Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be 
construed as a potential conflict of interest.
Copyright © 2016 Stokes, MacKenzie and Sluyter. This is an open-access article 
distributed under the terms of the Creative Commons Attribution License 
(CC BY). The use, distribution or reproduction in other forums is permitted, 
provided the original author(s) or licensor are credited and that the original 
publication in this journal is cited, in accordance with accepted academic prac-
tice. No use, distribution or reproduction is permitted which does not comply 
with these terms.


        Citation for published version:Stokes, L, MacKenzie, AB & Sluyter, R 2016, 'Editorial: roles of ion channels in immune cells', Frontiers inImmunology, vol. 7, 48. https://doi.org/10.3389/fimmu.2016.00048DOI:10.3389/fimmu.2016.00048Publication date:2016Document VersionPublisher's PDF, also known as Version of recordLink to publicationPublisher RightsCC BYUniversity of BathAlternative formatsIf you require this document in an alternative format, please contact:openaccess@bath.ac.ukGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 09. Jan. 2026February 2016 | Volume 7 | Article 481Editorialpublished: 15 February 2016doi: 10.3389/fimmu.2016.00048Frontiers in Immunology | www.frontiersin.orgEdited by: Masaaki Murakami, Hokkaido University, JapanReviewed by: Irena Levitan, University of Illinois at Chicago, USA Hideki Ogura, Yale University, USA*Correspondence:Leanne Stokes  l.stokes@uea.ac.ukSpecialty section: This article was submitted to Inflammation, a section of the journal Frontiers in ImmunologyReceived: 17 November 2015Accepted: 31 January 2016Published: 15 February 2016Citation: Stokes L, MacKenzie AB and Sluyter R (2016) Editorial: Roles of Ion Channels in Immune Cells. Front. Immunol. 7:48. doi: 10.3389/fimmu.2016.00048Editorial: roles of ion Channels in immune CellsLeanne Stokes1,2* , Amanda B. MacKenzie3 and Ronald Sluyter 4,5,61 Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia, 2 School of Pharmacy, University of East Anglia, Norwich, UK, 3 Department of Pharmacy and Pharmacology, University of Bath, Bath, UK, 4 School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia, 5 Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia, 6 Illawarra Health and Medical Research Institute, Wollongong, NSW, AustraliaKeywords: ion channels, immune cells, microglial cells, lymphocytes, calcium, signalling pathwaysThe Editorial on the Research Topic Roles of Ion Channels in Immune CellsIon channels are critical membrane proteins controlling a wide variety of cellular signaling events in many different cell types. In classical excitable cells, voltage-sensitive ion channels have well-described roles in the regulation of action potentials and contraction events. In non-excitable cells such as circulating or tissue-resident cells of the immune system, ion channels have lesser described roles in controlling cell biology. However, through enhanced pharmacological tools and gene knock-outs, we are now beginning to appreciate the plethora of cellular events in immune cells that are controlled by a variety of ion channels (1). The goal of this research topic was to highlight some of the recent advances in understanding which ion channels are important and are under investigation for novel therapeutics. This collection of six articles covers microglia, myeloid cells, and lymphocytes and provides updates and insights into the roles of various channels in these cells.Mortadza and colleagues review the latest evidence supporting a functional role for transient receptor potential melastatin (TRPM) 2 ion channels in the immune system (Syed Mortadza et al.). TRPM2 ion channels are activated by increases in reactive oxygen species (ROS) leading to Ca2+ signals in a range of immune cells. The authors discuss the use of TRPM2 knockout mice revealing an important role in the immune system and inflammatory diseases. Based on these studies in mouse models, the authors highlight a negative role for TRPM2 in colitis, ischemia-/reperfusion-mediated tissue damage, and neuropathic and inflammatory pain. They also discuss the importance of TRPM2 in inflammatory signaling including NLRP3 inflammasome activation leading to inflammatory cytokine production including bioactive interleukin (IL)-1β and chemokine-dependent dendritic cell function. Overall, the review demonstrates the importance of TRPM2 as a future therapeutic target for the treatment of inflammatory disease.Stebbing and colleagues provide a mini-review of numerous ion channels expressed in microglia (Stebbing et  al.). Ligand-gated channels belonging to P2X and N-methyl-d-aspartate (NMDA) receptor families respond to the neurotransmitters adenosine triphosphate (ATP) and glutamate, respectively. These are involved in the sensing of local microenvironments within the central nervous system and can affect microglial activation states through modulation of intracellular Ca2+ levels. In addition, K+ channels are also implicated in microglial responses including proliferation, nitric oxide generation, and cytokine secretion and, as such, are potential therapeutic targets for increasing neuroprotection in neurodegenerative disorders such as Alzheimer’s disease.Through an original research article, Ferreira and colleagues describe the regulation of the intermediate conductance Ca2+-activated K+ channel, KCa3.1, by cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) via a pathway involving ROS and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in microglia (Ferreira et al.) KCa3.1 is widely expressed in February 2016 | Volume 7 | Article 482Stokes et al. Ion Channels in Immune CellsFrontiers in Immunology | www.frontiersin.orgimmune cells, but knowledge of KCa3.1 in microglia is hitherto limited. Through pharmacological approaches, and the use of the rat MLS-9 microglial cell line and alternative-activated primary rat microglia, the authors demonstrate that elevation in cGMP activates PKG to promote mitochondrial ROS formation. This in turn stimulates endoplasmic reticulum Ca2+ release, which subsequently binds to calmodulin to both open the KCa3.1 channel and activate CaMKII to increase KCa3.1 activity through a second, unknown mechanism. The authors propose that this process may serve as a positive feedback mechanism to promote KCa3.1-dependent responses in microglia under conditions such as oxidative stress.Moving to the adaptive immune system, Davenport and colleagues have reviewed the current understanding of the CaV1 subfamily of L-type voltage-gated Ca2+-channels expressed by lymphocytes (Davenport et al.). The authors discuss the evidence supporting the expression of CaV1 ion channels in immune cells including a rare genetic disease (Timothy Syndrome) that sug-gests a role for CaV1.2 in human immune responses. Evidence for CaV1 function in B lymphocytes is largely supported by phar-macological studies, and the authors present further evidence for the expression of CaV1 ion channels in B lymphocytes using a CaV1.3 deficient chicken DT40 B cell line. It is concluded that CaV1 channels play an important role in the immune system; however, there are many unanswered questions particularly sur-rounding the potential activation mechanism of immune CaV1 channels.Nohara and colleagues review the current understanding of the complex orchestration of Ca2+ responses in T lymphocytes and recent advances in understanding store-operated calcium channels (STIM/Orai), TRP channels, NMDA receptors, P2X receptors, and CaV channels in T lymphocytes (Nohara et  al.). The authors focus on CaV channels for which there is growing evidence particularly from the recent use of CaV1 channel subunit knockout mice where significant effects are observed on T lympho-cyte responses. The potential interplay between CaV and STIM proteins in T cells is discussed, and the complexity surrounding regulation of intracellular (Ca2+) in these cells is highlighted. The authors conclude by identifying that superior immunomodula-tors may be developed targeting lymphocyte-specific variants of ion channels and these may be highly beneficial in future treat-ments for autoimmune diseases or immunosuppression required for transplants.Finally, Rissiek and colleagues review the P2X7 receptor, an ATP-gated cation channel, in murine T lymphocytes (Rissiek et  al.). The authors highlight that both extracellular ATP and nicotinamide adenine dinucleotide (NAD) can activate P2X7 on murine T lymphocytes. In contrast to ATP, P2X7 activation by NAD requires covalent adenosine triphosphate (ADP)-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Notably, NAD activates only the splice isoform P2X7k and the main P2X7 subtype within murine T lymphocytes. The authors describe the roles of P2X7 in murine (and human) T cells including IL-2 production, shedding of cell surface receptors, and cell death. Lastly, the authors highlight that ATP and NAD is released during T cell isolation, which results in the preferential loss of T regulatory and natural killer T cells due to high P2X7 expression on these cells, and outline ways in which to circumvent this to improve the quality of ex vivo T cell preparations.Collectively, this Frontiers in Immunology Research Topic provides a sample of the diversity and importance of ion chan-nels in immune cells. We are grateful to each author and trust that this Research Topic will serve as a prompt to continue future investigations of ion channels in immune cells.aUtHor CoNtriBUtioNSLS, AM, and RS contributed equally to this editorial article.rEFErENCE1. Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol (2015) 33:291–353. doi:10.1146/annurev-immunol-032414-112212 Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2016 Stokes, MacKenzie and Sluyter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic prac-tice. No use, distribution or reproduction is permitted which does not comply with these terms.

        Citation for published version:Stokes, L, MacKenzie, AB & Sluyter, R 2016, 'Editorial: roles of ion channels in immune cells', Frontiers inImmunology, vol. 7, 48. https://doi.org/10.3389/fimmu.2016.00048DOI:10.3389/fimmu.2016.00048Publication date:2016Document VersionPublisher's PDF, also known as Version of recordLink to publicationPublisher RightsCC BYUniversity of BathGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 13. May. 2019February 2016 | Volume 7 | Article 481Editorialpublished: 15 February 2016doi: 10.3389/fimmu.2016.00048Frontiers in Immunology | www.frontiersin.orgEdited by: Masaaki Murakami, Hokkaido University, JapanReviewed by: Irena Levitan, University of Illinois at Chicago, USA Hideki Ogura, Yale University, USA*Correspondence:Leanne Stokes  l.stokes@uea.ac.ukSpecialty section: This article was submitted to Inflammation, a section of the journal Frontiers in ImmunologyReceived: 17 November 2015Accepted: 31 January 2016Published: 15 February 2016Citation: Stokes L, MacKenzie AB and Sluyter R (2016) Editorial: Roles of Ion Channels in Immune Cells. Front. Immunol. 7:48. doi: 10.3389/fimmu.2016.00048Editorial: roles of ion Channels in immune CellsLeanne Stokes1,2* , Amanda B. MacKenzie3 and Ronald Sluyter 4,5,61 Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia, 2 School of Pharmacy, University of East Anglia, Norwich, UK, 3 Department of Pharmacy and Pharmacology, University of Bath, Bath, UK, 4 School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia, 5 Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia, 6 Illawarra Health and Medical Research Institute, Wollongong, NSW, AustraliaKeywords: ion channels, immune cells, microglial cells, lymphocytes, calcium, signalling pathwaysThe Editorial on the Research Topic Roles of Ion Channels in Immune CellsIon channels are critical membrane proteins controlling a wide variety of cellular signaling events in many different cell types. In classical excitable cells, voltage-sensitive ion channels have well-described roles in the regulation of action potentials and contraction events. In non-excitable cells such as circulating or tissue-resident cells of the immune system, ion channels have lesser described roles in controlling cell biology. However, through enhanced pharmacological tools and gene knock-outs, we are now beginning to appreciate the plethora of cellular events in immune cells that are controlled by a variety of ion channels (1). The goal of this research topic was to highlight some of the recent advances in understanding which ion channels are important and are under investigation for novel therapeutics. This collection of six articles covers microglia, myeloid cells, and lymphocytes and provides updates and insights into the roles of various channels in these cells.Mortadza and colleagues review the latest evidence supporting a functional role for transient receptor potential melastatin (TRPM) 2 ion channels in the immune system (Syed Mortadza et al.). TRPM2 ion channels are activated by increases in reactive oxygen species (ROS) leading to Ca2+ signals in a range of immune cells. The authors discuss the use of TRPM2 knockout mice revealing an important role in the immune system and inflammatory diseases. Based on these studies in mouse models, the authors highlight a negative role for TRPM2 in colitis, ischemia-/reperfusion-mediated tissue damage, and neuropathic and inflammatory pain. They also discuss the importance of TRPM2 in inflammatory signaling including NLRP3 inflammasome activation leading to inflammatory cytokine production including bioactive interleukin (IL)-1β and chemokine-dependent dendritic cell function. Overall, the review demonstrates the importance of TRPM2 as a future therapeutic target for the treatment of inflammatory disease.Stebbing and colleagues provide a mini-review of numerous ion channels expressed in microglia (Stebbing et  al.). Ligand-gated channels belonging to P2X and N-methyl-d-aspartate (NMDA) receptor families respond to the neurotransmitters adenosine triphosphate (ATP) and glutamate, respectively. These are involved in the sensing of local microenvironments within the central nervous system and can affect microglial activation states through modulation of intracellular Ca2+ levels. In addition, K+ channels are also implicated in microglial responses including proliferation, nitric oxide generation, and cytokine secretion and, as such, are potential therapeutic targets for increasing neuroprotection in neurodegenerative disorders such as Alzheimer’s disease.Through an original research article, Ferreira and colleagues describe the regulation of the intermediate conductance Ca2+-activated K+ channel, KCa3.1, by cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) via a pathway involving ROS and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in microglia (Ferreira et al.) KCa3.1 is widely expressed in February 2016 | Volume 7 | Article 482Stokes et al. Ion Channels in Immune CellsFrontiers in Immunology | www.frontiersin.orgimmune cells, but knowledge of KCa3.1 in microglia is hitherto limited. Through pharmacological approaches, and the use of the rat MLS-9 microglial cell line and alternative-activated primary rat microglia, the authors demonstrate that elevation in cGMP activates PKG to promote mitochondrial ROS formation. This in turn stimulates endoplasmic reticulum Ca2+ release, which subsequently binds to calmodulin to both open the KCa3.1 channel and activate CaMKII to increase KCa3.1 activity through a second, unknown mechanism. The authors propose that this process may serve as a positive feedback mechanism to promote KCa3.1-dependent responses in microglia under conditions such as oxidative stress.Moving to the adaptive immune system, Davenport and colleagues have reviewed the current understanding of the CaV1 subfamily of L-type voltage-gated Ca2+-channels expressed by lymphocytes (Davenport et al.). The authors discuss the evidence supporting the expression of CaV1 ion channels in immune cells including a rare genetic disease (Timothy Syndrome) that sug-gests a role for CaV1.2 in human immune responses. Evidence for CaV1 function in B lymphocytes is largely supported by phar-macological studies, and the authors present further evidence for the expression of CaV1 ion channels in B lymphocytes using a CaV1.3 deficient chicken DT40 B cell line. It is concluded that CaV1 channels play an important role in the immune system; however, there are many unanswered questions particularly sur-rounding the potential activation mechanism of immune CaV1 channels.Nohara and colleagues review the current understanding of the complex orchestration of Ca2+ responses in T lymphocytes and recent advances in understanding store-operated calcium channels (STIM/Orai), TRP channels, NMDA receptors, P2X receptors, and CaV channels in T lymphocytes (Nohara et  al.). The authors focus on CaV channels for which there is growing evidence particularly from the recent use of CaV1 channel subunit knockout mice where significant effects are observed on T lympho-cyte responses. The potential interplay between CaV and STIM proteins in T cells is discussed, and the complexity surrounding regulation of intracellular (Ca2+) in these cells is highlighted. The authors conclude by identifying that superior immunomodula-tors may be developed targeting lymphocyte-specific variants of ion channels and these may be highly beneficial in future treat-ments for autoimmune diseases or immunosuppression required for transplants.Finally, Rissiek and colleagues review the P2X7 receptor, an ATP-gated cation channel, in murine T lymphocytes (Rissiek et  al.). The authors highlight that both extracellular ATP and nicotinamide adenine dinucleotide (NAD) can activate P2X7 on murine T lymphocytes. In contrast to ATP, P2X7 activation by NAD requires covalent adenosine triphosphate (ADP)-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Notably, NAD activates only the splice isoform P2X7k and the main P2X7 subtype within murine T lymphocytes. The authors describe the roles of P2X7 in murine (and human) T cells including IL-2 production, shedding of cell surface receptors, and cell death. Lastly, the authors highlight that ATP and NAD is released during T cell isolation, which results in the preferential loss of T regulatory and natural killer T cells due to high P2X7 expression on these cells, and outline ways in which to circumvent this to improve the quality of ex vivo T cell preparations.Collectively, this Frontiers in Immunology Research Topic provides a sample of the diversity and importance of ion chan-nels in immune cells. We are grateful to each author and trust that this Research Topic will serve as a prompt to continue future investigations of ion channels in immune cells.aUtHor CoNtriBUtioNSLS, AM, and RS contributed equally to this editorial article.rEFErENCE1. Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol (2015) 33:291–353. doi:10.1146/annurev-immunol-032414-112212 Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2016 Stokes, MacKenzie and Sluyter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic prac-tice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Roles of ion channels in immune cells

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