scholarly journals Proton Sensing on the Ocular Surface: Implications in Eye Pain

2021 ◽  
Vol 12 ◽  
Author(s):  
Núria Comes ◽  
Xavier Gasull ◽  
Gerard Callejo
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ocular Surface ◽  
Tissue Injury ◽  
Critical Role ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Anterior Surface ◽  
Ocular Pain ◽  
Channel Expression

Protons reaching the eyeball from exogenous acidic substances or released from damaged cells during inflammation, immune cells, after tissue injury or during chronic ophthalmic conditions, activate or modulate ion channels present in sensory nerve fibers that innervate the ocular anterior surface. Their identification as well as their role during disease is critical for the understanding of sensory ocular pathophysiology. They are likely to mediate some of the discomfort sensations accompanying several ophthalmic formulations and may represent novel targets for the development of new therapeutics for ocular pathologies. Among the ion channels expressed in trigeminal nociceptors innervating the anterior surface of the eye (cornea and conjunctiva) and annex ocular structures (eyelids), members of the TRP and ASIC families play a critical role in ocular acidic pain. Low pH (pH 6) activates TRPV1, a polymodal ion channel also activated by heat, capsaicin and hyperosmolar conditions. ASIC1, ASIC3 and heteromeric ASIC1/ASIC3 channels present in ocular nerve terminals are activated at pH 7.2–6.5, inducing pain by moderate acidifications of the ocular surface. These channels, together with TRPA1, are involved in acute ocular pain, as well as in painful sensations during allergic keratoconjunctivitis or other ophthalmic conditions, as blocking or reducing channel expression ameliorates ocular pain. TRPV1, TRPA1 and other ion channels are also present in corneal and conjunctival cells, promoting inflammation of the ocular surface after injury. In addition to the above-mentioned ion channels, members of the K2P and P2X ion channel families are also expressed in trigeminal neurons, however, their role in ocular pain remains unclear to date. In this report, these and other ion channels and receptors involved in acid sensing during ocular pathologies and pain are reviewed.

scholarly journals Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

2016 ◽  
Vol 23 (11) ◽  
pp. R517-R525 ◽  
Author(s):  
Iman Azimi ◽  
Gregory R Monteith
Keyword(s):  
Plasma Membrane ◽  
Ion Channels ◽  
Ion Channel ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Resistance ◽  
Therapeutic Approaches ◽  
Mesenchymal Transition ◽  
Pharmacological Modulation ◽  
Channel Expression

A variety of studies have suggested that epithelial to mesenchymal transition (EMT) may be important in the progression of cancer in patients through metastasis and/or therapeutic resistance. A number of pathways have been investigated in EMT in cancer cells. Recently, changes in plasma membrane ion channel expression as a consequence of EMT have been reported. Other studies have identified specific ion channels able to regulate aspects of EMT induction. The utility of plasma membrane ion channels as targets for pharmacological modulation make them attractive for therapeutic approaches to target EMT. In this review, we provide an overview of some of the key plasma membrane ion channel types and highlight some of the studies that are beginning to define changes in plasma membrane ion channels as a consequence of EMT and also their possible roles in EMT induction.

scholarly journals Ion Channel Expression and Characterization in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Zhihan Zhao ◽  
Huan Lan ◽  
Ibrahim El-Battrawy ◽  
Xin Li ◽  
Fanis Buljubasic ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ion Channels ◽  
Ion Channel ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Biological Study ◽  
Adrenergic Stimulation ◽  
Cell Therapies ◽  
Channel Expression ◽  
Induced Pluripotent

Background. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are providing new possibilities for the biological study, cell therapies, and drug discovery. However, the ion channel expression and functions as well as regulations in hiPSC-CMs still need to be fully characterized. Methods. Cardiomyocytes were derived from hiPS cells that were generated from two healthy donors. qPCR and patch clamp techniques were used for the study. Results. In addition to the reported ion channels, INa, ICa-L, ICa-T, If, INCX, IK1, Ito, IKr, IKs IKATP, IK-pH, ISK1–3, and ISK4, we detected both the expression and currents of ACh-activated (KACh) and Na+-activated (KNa) K+, volume-regulated and calcium-activated (Cl-Ca) Cl−, and TRPV channels. All the detected ion currents except IK1, IKACh, ISK, IKNa, and TRPV1 currents contribute to AP duration. Isoprenaline increased ICa-L, If, and IKs but reduced INa and INCX, without an effect on Ito, IK1, ISK1–3, IKATP, IKr, ISK4, IKNa, ICl-Ca, and ITRPV1. Carbachol alone showed no effect on the tested ion channel currents. Conclusion. Our data demonstrate that most ion channels, which are present in healthy or diseased cardiomyocytes, exist in hiPSC-CMs. Some of them contribute to action potential performance and are regulated by adrenergic stimulation.

scholarly journals Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models

2017 ◽  
Vol 114 (38) ◽  
pp. E8100-E8109 ◽  
Author(s):  
Abba E. Leffler ◽  
Alexander Kuryatov ◽  
Henry A. Zebroski ◽  
Susan R. Powell ◽  
Petr Filipenko ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Critical Role ◽  
Nicotinic Acetylcholine ◽  
Docking Algorithm ◽  
Addiction Therapy ◽  
Peptide Toxins ◽  
Homology Models

Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock α-GID and its analogs to an α4β2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive α-GID mutants (α-GID[A10V], α-GID[V13I], and α-GID[V13Y]) and one inactive variant (α-GID[A10Q]). Two mutants, α-GID[A10V] and α-GID[V13Y], had substantially reduced potency at the human α7 nAChR relative to α-GID, a desirable feature for α-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the α-GID:α4β2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available atrosie.rosettacommons.org/tox_dock.

VOCCs and TREK-1 ion channel expression in human tenocytes

2007 ◽  
Vol 292 (3) ◽  
pp. C1053-C1060 ◽  
Author(s):  
Merzesh Magra ◽  
Steven Hughes ◽  
Alicia J. El Haj ◽  
Nicola Maffulli
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ionic Currents ◽  
Cell Types ◽  
Functional Expression ◽  
Tissue Cell ◽  
Pharmacological Management ◽  
Whole Cell ◽  
Voltage Gated ◽  
Channel Expression

Mechanosensitive and voltage-gated ion channels are known to perform important roles in mechanotransduction in a number of connective tissues, including bone and muscle. It is hypothesized that voltage-gated and mechanosensitive ion channels also may play a key role in some or all initial responses of human tenocytes to mechanical stimulation. However, to date there has been no direct investigation of ion channel expression by human tenocytes. Human tenocytes were cultured from patellar tendon samples harvested from five patients undergoing routine total knee replacement surgery (mean age: 66 yr; range: 63–73 yr). RT-PCR, Western blotting, and whole cell electrophysiological studies were performed to investigate the expression of different classes of ion channels within tenocytes. Human tenocytes expressed mRNA and protein encoding voltage-operated calcium channel (VOCC) subunits (Ca α1A, Ca α1C, Ca α1D, Ca α2δ1) and the mechanosensitive tandem pore domain potassium channel (2PK+) TREK-1. They exhibit whole cell currents consistent with the functional expression of these channels. In addition, other ionic currents were detected within tenocytes consistent with the expression of a diverse array of other ion channels. VOCCs and TREK channels have been implicated in mechanotransduction signaling pathways in numerous connective tissue cell types. These mechanisms may be present in human tenocytes. In addition, human tenocytes may express other channel currents. Ion channels may represent potential targets for the pharmacological management of chronic tendinopathies.

scholarly journals Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny

2013 ◽  
Vol 2013 ◽  
pp. 1-25 ◽  
Author(s):  
Leonhard Linta ◽  
Marianne Stockmann ◽  
Qiong Lin ◽  
André Lechel ◽  
Christian Proepper ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ion Selectivity ◽  
Expression Patterns ◽  
Stem Cell Differentiation ◽  
Human Keratinocytes ◽  
Ips Cells ◽  
Cellular Processes ◽  
Gating Mechanism ◽  
Channel Expression

Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. Additionally, iPSCs express a much higher number of ion channels compared to keratinocytes. Further, to narrow down specificity of ion channel expression in iPS cells we compared their expression patterns with differentiated progeny, namely, neurons and cardiomyocytes derived from iPS cells. To conclude, hiPSCs exhibit a very considerable and diverse ion channel expression pattern. Their detailed analysis could give an insight into their contribution to many cellular processes and even disease mechanisms.

scholarly journals Ion channel expression and electrophysiology of singular human (primary and induced pluripotent stem cell derived) cardiomyocytes

2021 ◽  
Author(s):  
Christina Schmid ◽  
Najah Abi-Gerges ◽  
Dietmar Zellner ◽  
Georg Rast
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Single Cell ◽  
Action Potential Duration ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Inward Current ◽  
Beat Rate ◽  
Channel Expression

SUMMARYHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary human cardiomyocytes are used for in vitro cardiac safety testing. hiPSC-CMs have been associated with a vast heterogeneity regarding single-cell morphology, beating behavior and action potential duration, prompting a systematic analysis of single-cell characteristics. Previously published hiPSC-CM studies revealed action potentials with nodal-, atrial- or ventricular-like morphology, although ion channel expression of singular hiPSC-CMs is not fully understood. Other studies used single-cell RNA-sequencing, however, these studies did not extensively focus on expression patterns of cardiac ion channels or failed to detect ion channel transcripts. Thus, the current study used a single-cell patch-clamp-RT-qPCR approach to get insights into single-cell electrophysiology (capacitance, action potential duration at 90% of repolarization, upstroke velocity, spontaneous beat rate, and sodium-driven fast inward current) and ion channel expression (HCN4, CACNA1G, CACNA1D, KCNA5, KCNJ4, SCN5A, KCNJ2, CACNA1D, and KCNH2), the combination of both within individual cells, and their correlations in single cardiomyocytes. We used commercially available hiPSC-CMs (iCell cardiomyocytes, atrial and ventricular Pluricytes) and primary human adult atrial and ventricular cardiomyocytes. Recordings of electrophysiological parameters revealed differences between the cell groups and variation within the hiPSC-CMs groups as well as within primary ventricular cardiomyocytes. Expression analysis on mRNA level showed no-clear-cut discrimination between primary cardiac subtypes and revealed both similarities and differences between all cell groups. Higher expression of atrial-associated ion channels in primary atrial cardiomyocytes and atrial Pluricytes compared to their ventricular counterpart indicates a successful chamber-specific hiPSC differentiation. Interpretation of correlations between the single-cell parameters was challenging, as the total data set is complex, particularly for parameters depending on multiple processes, like the spontaneous beat rate. Yet, for example, expression of SCN5A correlated well with the fast inward current amplitude for all three hiPSC-CM groups. To further enhance our understanding of the physiology and composition of the investigated hiPSC-CMs, we compared beating and non-beating cells and assessed distributions of single-cell data. Investigating the single-cell phenotypes of hiPSC-CMs revealed a combination of attributes which may be interpreted as a mixture of traits of different adult cardiac cell types: (i) nodal-related pacemaking attributes are spontaneous generation of action potentials and high HCN4 expression; and (ii) non-nodal attributes: cells have a prominent INa-driven fast inward current, a fast upstroke velocity and a high expression of SCN5A. In conclusion, the combination of nodal- and non-nodal attributes in single hiPSC-CMs may hamper the interpretation of drug effects on complex electrophysiological parameters like beat rate and action potential duration. However, the proven expression of specific ion channels enables the evaluation of drug effects on ionic currents in a more realistic environment than in recombinant systems.

Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

2012 ◽  
Vol 92 (3) ◽  
pp. 1317-1358 ◽  
Author(s):  
Elise Balse ◽  
David F. Steele ◽  
Hugues Abriel ◽  
Alain Coulombe ◽  
David Fedida ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Membrane Lipids ◽  
Current Knowledge ◽  
Small Gtpases ◽  
Molecular Organization ◽  
Cardiac Sarcolemma ◽  
Channel Expression

Cardiac myocytes are characterized by distinct structural and functional entities involved in the generation and transmission of the action potential and the excitation-contraction coupling process. Key to their function is the specific organization of ion channels and transporters to and within distinct membrane domains, which supports the anisotropic propagation of the depolarization wave. This review addresses the current knowledge on the molecular actors regulating the distinct trafficking and targeting mechanisms of ion channels in the highly polarized cardiac myocyte. In addition to ubiquitous mechanisms shared by other excitable cells, cardiac myocytes show unique specialization, illustrated by the molecular organization of myocyte-myocyte contacts, e.g., the intercalated disc and the gap junction. Many factors contribute to the specialization of the cardiac sarcolemma and the functional expression of cardiac ion channels, including various anchoring proteins, motors, small GTPases, membrane lipids, and cholesterol. The discovery of genetic defects in some of these actors, leading to complex cardiac disorders, emphasizes the importance of trafficking and targeting of ion channels to cardiac function. A major challenge in the field is to understand how these and other actors work together in intact myocytes to fine-tune ion channel expression and control cardiac excitability.

scholarly journals LINKAGES OF Ca V1.2, GLUTAMATE, AND ODONTOBLAST IN THE MECHANISM OF TOOTH PAIN

2020 ◽  
Vol 5 (1) ◽  
pp. 1
Author(s):  
Juliyatin Putri Utami
Keyword(s):  
Ion Channels ◽  
Trp Channels ◽  
Sensory Cell ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Pulp Tissue ◽  
Metabotropic Receptors ◽  
Dental Injury ◽  
Delivery Mechanism

Background: Odontoblast is often associated with its role as sensory cell in tooth pain. Odontoblasts have ion channels that contribute to the sensitivity and release of neurotransmitters in odontoblast stimuli that are activated in pulp sensory nerve fibers. Review: Ca V1.2 has unexpected plasticity. In dental injury, the appearance of Ca V1.2 canal in odontoblast is known to change, depend on the duration of injury. The dentinal pulp tissue has the ability to release glutamate, which acts as an intercellular mediator to create neuronal signaling communication between inter-odontoblast and odontoblast- trigeminal ganglion nerve (TG). Discussion: Odontoblasts as a mechanosensitive sensory cell are indicated by the role of the TRP transduction receptor and the release of ATP. Though other canals and active compounds in odontoblast are involved, an important role in delivering the sensation of pain also needs to be known. Odontoblast will communicate with paracrine pulp nerves using ATP and glutamate. Ca2+ enters the odontoblast through activated TRP channels and other ion channels, such as L-type VGCC channels (Ca V 1.2). Followed by the release of glutamate from odontoblast through the glutamate-permeable canal, it can trigger the pulp nerve via glutamate metabotropic receptors (mGluRs). Conclusion: There is involvement of Ca V1.2 and glutamate canals in odontoblast in the delivery mechanism of pain.

scholarly journals Speed, adaptation, and stability of the response to light in cone photoreceptors: The functional role of Ca-dependent modulation of ligand sensitivity in cGMP-gated ion channels

2011 ◽  
Vol 139 (1) ◽  
pp. 31-56 ◽  
Author(s):  
Juan I. Korenbrot
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Critical Role ◽  
Enzymatic Reactions ◽  
Cone Photoreceptors ◽  
Channel Modulation ◽  
Ion Channel Modulation ◽  
Gated Ion Channels ◽  
Ligand Sensitivity

The response of cone photoreceptors to light is stable and reproducible because of the exceptional regulation of the cascade of enzymatic reactions that link visual pigment (VP) excitation to the gating of cyclic GMP (cGMP)-gated ion channels (cyclic nucleotide–gated [CNG]) in the outer segment plasma membrane. Regulation is achieved in part through negative feedback control of some of these reactions by cytoplasmic free Ca2+. As part of the control process, Ca2+ regulates the phosphorylation of excited VP, the activity of guanylate cyclase, and the ligand sensitivity of the CNG ion channels. We measured photocurrents elicited by stimuli in the form of flashes, steps, and flashes superimposed on steps in voltage-clamped single bass cones isolated from striped bass retina. We also developed a computational model that comprises all the known molecular events of cone phototransduction, including all Ca-dependent controls. Constrained by available experimental data in bass cones and cone transduction biochemistry, we achieved an excellent match between experimental photocurrents and those simulated by the model. We used the model to explore the physiological role of CNG ion channel modulation. Control of CNG channel activity by both cGMP and Ca2+ causes the time course of the light-dependent currents to be faster than if only cGMP controlled their activity. Channel modulation also plays a critical role in the regulation of the light sensitivity and light adaptation of the cone photoresponse. In the absence of ion channel modulation, cone photocurrents would be unstable, oscillating during and at the offset of light stimuli.

Ion Channels as Therapeutic Targets for Type 1 Diabetes Mellitus

2020 ◽  
Vol 21 (2) ◽  
pp. 132-147 ◽  
Author(s):  
Chandrabose Selvaraj ◽  
Gurudeeban Selvaraj ◽  
Satyavani Kaliamurthi ◽  
William C. Cho ◽  
Dong-Qing Wei ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Insulin Secretion ◽  
Ion Channels ◽  
Ion Channel ◽  
Type 1 Diabetes Mellitus ◽  
Pancreatic Beta Cells ◽  
Critical Role ◽  
Therapeutic Targets

Ion channels are integral proteins expressed in almost all living cells and are involved in muscle contraction and nutrient transport. They play a critical role in the normal functioning of the excitable tissues of the nervous system and regulate the action potential and contraction events. Dysfunction of genes encodes ion channel proteins, which disrupt the channel function and lead to a number of diseases, among which is type 1 diabetes mellitus (T1DM). Therefore, understanding the complex mechanism of ion channel receptors is necessary to facilitate the diagnosis and management of treatment. In this review, we summarize the mechanism of important ion channels and their potential role in the regulation of insulin secretion along with the limitations of ion channels as therapeutic targets. Furthermore, we discuss the recent investigations of the mechanism regulating the ion channels in pancreatic beta cells, which suggest that ion channels are active participants in the regulation of insulin secretion.

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