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Role of Ion-Channels in Signal Transduction and Gene Regulation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 19659

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Special Issue Editors

Dr. Rainer Schindl

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Guest Editor

Gottfried Schatz Research Center, Medical University of Graz, A-8010 Graz, Austria
Interests: calcium signaling; STIM; orai proteins
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Dr. Romana Schober

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Institute for Biophysics, Johannes Kepler University Linz, A-4040 Linz, Austria
Interests: calcium signaling; CRAC; STIM; Orai; autophagy; transcription factor activation; MITF; TFEB

Special Issue Information

Dear Colleagues,

Signal transduction subsequent to ion flux across channels that are located in the plasma membrane and organelle membranes can regulate the expression of several genes. Extensive research is still required in order to understand how these signaling pathways are controlled in time and space, and which specific signaling proteins are involved. Therefore, we are organizing this Special Issue in order to resolve ion-dependent signaling pathways. The activity of several ion channels regulates various intracellular ion concentrations and activates either locally (microdomains) or globally specific signaling cascades. The most prominent second messenger ion is represented by calcium in excitable and non-excitable cells. This ion can lead to transcription factor activation followed by associated gene expression. However, other ions like Mg²⁺ and K⁺ also contribute to the regulation of transcription factor activation.

The aim of this Special Issue of the International Journal of Molecular Sciences is to further expand our current knowledge on the relationship between ion flux, signal transduction, and gene expression. We welcome reviews and original research articles that explore, but are not limited to, the structure and function of calcium signaling complexes and ion-dependent stimulation of gene regulation.

Dr. Rainer Schindl
Dr. Romana Schober
Guest Editors

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Keywords

ion channels
ion channel signaling complexes
transcription factor
calcium
potassium
autophagy
transcriptional regulation
gene expression

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Published Papers (7 papers)

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Research

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14 pages, 2766 KiB

Open AccessArticle

Calmodulin Regulates Transient Receptor Potential TRPM3 and TRPM8-Induced Gene Transcription

by Gerald Thiel and Oliver G. Rössler

Int. J. Mol. Sci. 2023, 24(9), 7902; https://doi.org/10.3390/ijms24097902 - 26 Apr 2023

Cited by 3 | Viewed by 2179

Abstract

Calmodulin is a small protein that binds Ca²⁺ ions via four EF-hand motifs. The Ca²⁺/calmodulin complex as well as Ca²⁺-free calmodulin regulate the activities of numerous enzymes and ion channels. Here, we used genetic and pharmacological tools to study the functional role of calmodulin in regulating signal transduction of TRPM3 and TRPM8 channels. Both TRPM3 and TRPM8 are important regulators of thermosensation. Gene transcription triggered by stimulation of TRPM3 or TRPM8 channels was significantly impaired in cells expressing a calmodulin mutant with mutations in all four EF-hand Ca²⁺ binding motifs. Similarly, incubation of cells with the calmodulin inhibitor ophiobolin A reduced TRPM3 and TRPM8-induced signaling. The Ca²⁺/calmodulin-dependent protein phosphatase calcineurin was shown to negatively regulate TRPM3-induced gene transcription. Here, we show that TRPM8-induced transcription is also regulated by calcineurin. We propose that calmodulin plays a dual role in regulating TRPM3 and TRPM8 functions. Calmodulin is required for the activation of TRPM3 and TRPM8-induced intracellular signaling, most likely through a direct interaction with the channels. Ca²⁺ influx through TRPM3 and TRPM8 feeds back to TRPM3 and TRPM8-induced signaling by activation of the calmodulin-regulated enzyme calcineurin, which acts as a negative feedback loop for both TRPM3 and TRPM8 channel signaling. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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16 pages, 2425 KiB

Open AccessArticle

Expression of the C-Terminal Domain of Phospholipase Cβ3 Inhibits Signaling via Gαq-Coupled Receptors and Transient Receptor Potential Channels

by Gerald Thiel and Oliver G. Rössler

Int. J. Mol. Sci. 2022, 23(17), 9590; https://doi.org/10.3390/ijms23179590 - 24 Aug 2022

Cited by 3 | Viewed by 1695

Abstract

Transient receptor potential (TRP) channels are cation channels that play a regulatory role in pain and thermosensation, insulin secretion, and neurotransmission. It has been proposed that activation of TRP channels requires phosphatidylinositol 4,5-bisphosphate, the major substrate for phospholipase C (PLC). We investigated whether inhibition of PLCβ has an impact on TRP channel signaling. A genetic approach was used to avoid off-target effects observed when using a pharmacological PLCβ inhibitor. In this study, we show that expression of PLCβ1ct and PLCβ3ct, truncated forms of PLCβ1 or PLCβ3 that contain the C-terminal membrane binding domains, almost completely blocked the signal transduction of a Gαq-coupled designer receptor, including the phosphorylation of ERK1/2. In contrast, expression of the helix-turn-helix motif (Hα1—Hα2) of the proximal C-terminal domain of PLCβ3 did not affect Gαq-coupled receptor signaling. PLCβ3ct expression impaired signaling of the TRP channels TRPM3 and TRPM8, stimulated with either prognenolone sulfate or icilin. Thus, the C-terminal domain of PLCβ3 interacts with plasma membrane targets, most likely phosphatidylinositol 4,5-bisphosphate, and in this way blocks the biological activation of TRPM3 and TRPM8, which require interaction with this phospholipid. PLCβ thus regulates TRPM3 and TRPM8 channels by masking phosphatidylinositol 4,5-bisphosphate with its C-terminal domain. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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14 pages, 1507 KiB

Open AccessArticle

cADPR Does Not Activate TRPM2

by Winnie Maria Riekehr, Simon Sander, Jelena Pick, Henning Tidow, Andreas Bauche, Andreas H. Guse and Ralf Fliegert

Int. J. Mol. Sci. 2022, 23(6), 3163; https://doi.org/10.3390/ijms23063163 - 15 Mar 2022

Cited by 6 | Viewed by 2590

Abstract

cADPR is a second messenger that releases Ca²⁺ from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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19 pages, 3426 KiB

Open AccessArticle

Immune Synapse Residency of Orai1 Alters Ca²⁺ Response of T Cells

by Orsolya Voros, György Panyi and Péter Hajdu

Int. J. Mol. Sci. 2021, 22(21), 11514; https://doi.org/10.3390/ijms222111514 - 26 Oct 2021

Cited by 5 | Viewed by 2613

Abstract

CRAC, which plays important role in Ca²⁺-dependent T-lymphocyte activation, is composed of the ER-resident STIM1 and the plasma membrane Orai1 pore-forming subunit. Both accumulate at the immunological synapse (IS) between a T cell and an antigen-presenting cell (APC). We hypothesized that adapter/interacting proteins regulate Orai1 residence in the IS. We could show that mGFP-tagged Orai1-Full channels expressed in Jurkat cells had a biphasic IS-accumulation kinetics peaked at 15 min. To understand the background of Orai1 IS-redistribution we knocked down STIM1 and SAP97 (adaptor protein with a short IS-residency (15 min) and ability to bind Orai1 N-terminus): the mGFP-Orai1-Full channels kept on accumulating in the IS up to the 60th minute in the STIM1- and SAP97-lacking Jurkat cells. Deletion of Orai1 N terminus (mGFP-Orai1-Δ72) resulted in the same time course as described for STIM1/SAP97 knock-down cells. Ca²⁺-imaging of IS-engaged T-cells revealed that of Orai1 residency modifies the Ca²⁺-response: cells expressing mGFP-Orai1-Δ72 construct or mGFP-Orai1-Full in SAP-97 knock-down cells showed higher number of Ca²⁺-oscillation up to the 90th minute after IS formation. Overall, these data suggest that SAP97 may contribute to the short-lived IS-residency of Orai1 and binding of STIM1 to Orai1 N-terminus is necessary for SAP97-Orai1 interaction. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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16 pages, 1430 KiB

Open AccessArticle

Near-UV Light Induced ROS Production Initiates Spatial Ca²⁺ Spiking to Fire NFATc3 Translocation

by Furkan E. Oflaz, Zhanat Koshenov, Martin Hirtl, Rene Rost, Olaf A. Bachkoenig, Benjamin Gottschalk, Corina T. Madreiter-Sokolowski, Roland Malli and Wolfgang F. Graier

Int. J. Mol. Sci. 2021, 22(15), 8189; https://doi.org/10.3390/ijms22158189 - 30 Jul 2021

Cited by 6 | Viewed by 2606

Abstract

Ca²⁺-dependent gene regulation controls several functions to determine the fate of the cells. Proteins of the nuclear factor of activated T-cells (NFAT) family are Ca²⁺ sensitive transcription factors that control the cell growth, proliferation and insulin secretion in β-cells. Translocation of NFAT proteins to the nucleus occurs in a sequence of events that starts with activating calmodulin-dependent phosphatase calcineurin in a Ca²⁺-dependent manner, which dephosphorylates the NFAT proteins and leads to their translocation to the nucleus. Here, we examined the role of IP₃-generating agonists and near-UV light in the induction of NFATc3 migration to the nucleus in the pancreatic β-cell line INS-1. Our results show that IP₃ generation yields cytosolic Ca²⁺ rise and NFATc3 translocation. Moreover, near-UV light exposure generates reactive oxygen species (ROS), resulting in cytosolic Ca²⁺ spiking via the L-type Ca²⁺ channel and triggers NFATc3 translocation to the nucleus. Using the mitochondria as a Ca²⁺ buffering tool, we showed that ROS-induced cytosolic Ca²⁺ spiking, not the ROS themselves, was the triggering mechanism of nuclear import of NFATc3. Collectively, this study reveals the mechanism of near-UV light induced NFATc3 migration. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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14 pages, 1714 KiB

Open AccessArticle

Electrophysiological Properties of Endogenous Single Ca²⁺ Activated Cl⁻ Channels Induced by Local Ca²⁺ Entry in HEK293

by Dmitrii Kolesnikov, Anastasiia Perevoznikova, Konstantin Gusev, Lyubov Glushankova, Elena Kaznacheyeva and Alexey Shalygin

Int. J. Mol. Sci. 2021, 22(9), 4767; https://doi.org/10.3390/ijms22094767 - 30 Apr 2021

Cited by 7 | Viewed by 2899

Abstract

Microdomains formed by proteins of endoplasmic reticulum and plasma membrane play a key role in store-operated Ca²⁺ entry (SOCE). Ca²⁺ release through inositol 1,4,5-trisphosphate receptor (IP₃R) and subsequent Ca²⁺ store depletion activate STIM (stromal interaction molecules) proteins, sensors of intraluminal Ca²⁺, which, in turn, open the Orai channels in plasma membrane. Downstream to this process could be activated TRPC (transient receptor potential-canonical) calcium permeable channels. Using single channel patch-clamp technique we found that a local Ca²⁺ entry through TRPC1 channels activated endogenous Ca²⁺-activated chloride channels (CaCCs) with properties similar to Anoctamin6 (TMEM16F). Our data suggest that their outward rectification is based on the dependence from membrane potential of both the channel conductance and the channel activity: (1) The conductance of active CaCCs highly depends on the transmembrane potential (from 3 pS at negative potentials till 60 pS at positive potentials); (2) their activity (NPo) is enhanced with increasing Ca²⁺ concentration and/or transmembrane potential, conversely lowering of intracellular Ca²⁺ concentration reduced the open state dwell time; (3) CaCC amplitude is only slightly increased by intracellular Ca²⁺ concentration. Experiments with Ca²⁺ buffering by EGTA or BAPTA suggest close local arrangement of functional CaCCs and TRPC1 channels. It is supposed that Ca²⁺-activated chloride channels are involved in Ca²⁺ entry microdomains. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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Review

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28 pages, 8212 KiB

Open AccessReview

Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

by Adéla Tiffner and Isabella Derler

Int. J. Mol. Sci. 2021, 22(15), 8020; https://doi.org/10.3390/ijms22158020 - 27 Jul 2021

Cited by 15 | Viewed by 3185

Abstract

Ca²⁺ ion channels are critical in a variety of physiological events, including cell growth, differentiation, gene transcription and apoptosis. One such essential entry pathway for calcium into the cell is the Ca²⁺ release-activated Ca²⁺ (CRAC) channel. It consists of the Ca²⁺ sensing protein, stromal interaction molecule 1 (STIM1) located in the endoplasmic reticulum (ER) and a Ca²⁺ ion channel Orai in the plasma membrane. The Orai channel family includes three homologues Orai1, Orai2 and Orai3. While Orai1 is the “classical” Ca²⁺ ion channel within the CRAC channel complex and plays a universal role in the human body, there is increasing evidence that Orai2 and Orai3 are important in specific physiological and pathophysiological processes. This makes them an attractive target in drug discovery, but requires a detailed understanding of the three Orai channels and, in particular, their differences. Orai channel activation is initiated via Ca²⁺ store depletion, which is sensed by STIM1 proteins, and induces their conformational change and oligomerization. Upon STIM1 coupling, Orai channels activate to allow Ca²⁺ permeation into the cell. While this activation mechanism is comparable among the isoforms, they differ by a number of functional and structural properties due to non-conserved regions in their sequences. In this review, we summarize the knowledge as well as open questions in our current understanding of the three isoforms in terms of their structure/function relationship, downstream signaling and physiology as well as pathophysiology. Full article

(This article belongs to the Special Issue Role of Ion-Channels in Signal Transduction and Gene Regulation)

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