0
selected
-
1.
Recent advances in the pathophysiology of PIEZO1-related hereditary xerocytosis.
Jankovsky, N, Caulier, A, Demagny, J, Guitton, C, Djordjevic, S, Lebon, D, Ouled-Haddou, H, Picard, V, Garçon, L
American journal of hematology. 2021;(8):1017-1026
-
-
Free full text
-
Abstract
Hereditary xerocytosis is a rare red blood cell disease related to gain-of-function mutations in the FAM38A gene, encoding PIEZO1, in 90% of cases; PIEZO1 is a broadly expressed mechano-transducer that plays a major role in many cell systems and tissues that respond to mechanical stress. In erythrocytes, PIEZO1 adapts the intracellular ionic content and cell hydration status to the mechanical constraints induced by the environment. Until recently, the pathophysiology of hereditary xerocytosis was mainly believed to be based on the "PIEZO1-Gardos channel axis" in erythrocytes, according to which PIEZO1-activating mutations induce a calcium influx that secondarily activates the Gardos channel, leading to potassium and water efflux and subsequently to red blood cell dehydration. However, recent studies have demonstrated additional roles for PIEZO1 during early erythropoiesis and reticulocyte maturation, as well as roles in other tissues and cells such as lymphatic vessels, hepatocytes, macrophages and platelets that may affect the pathophysiology of the disease. These findings, presented and discussed in this review, broaden our understanding of hereditary xerocytosis beyond that of primarily being a red blood cell disease and identify potential therapeutic targets.
-
2.
Cardiovascular Drugs and Osteoarthritis: Effects of Targeting Ion Channels.
Vaiciuleviciute, R, Bironaite, D, Uzieliene, I, Mobasheri, A, Bernotiene, E
Cells. 2021;(10)
Abstract
Osteoarthritis (OA) and cardiovascular diseases (CVD) share many similar features, including similar risk factors and molecular mechanisms. A great number of cardiovascular drugs act via different ion channels and change ion balance, thus modulating cell metabolism, osmotic responses, turnover of cartilage extracellular matrix and inflammation. These drugs are consumed by patients with CVD for many years; however, information about their effects on the joint tissues has not been fully clarified. Nevertheless, it is becoming increasingly likely that different cardiovascular drugs may have an impact on articular tissues in OA. Here, we discuss the potential effects of direct and indirect ion channel modulating drugs, including inhibitors of voltage gated calcium and sodium channels, hyperpolarization-activated cyclic nucleotide-gated channels, β-adrenoreceptor inhibitors and angiotensin-aldosterone system affecting drugs. The aim of this review was to summarize the information about activities of cardiovascular drugs on cartilage and subchondral bone and to discuss their possible consequences on the progression of OA, focusing on the modulation of ion channels in chondrocytes and other joint cells, pain control and regulation of inflammation. The implication of cardiovascular drug consumption in aetiopathogenesis of OA should be considered when prescribing ion channel modulators, particularly in long-term therapy protocols.
-
3.
Ion Channels and Pumps in Autophagy: A Reciprocal Relationship.
Abuammar, H, Bhattacharjee, A, Simon-Vecsei, Z, Blastyák, A, Csordás, G, Páli, T, Juhász, G
Cells. 2021;(12)
Abstract
Autophagy, the process of cellular self-degradation, is intrinsically tied to the degradative function of the lysosome. Several diseases have been linked to lysosomal degradative defects, including rare lysosomal storage disorders and neurodegenerative diseases. Ion channels and pumps play a major regulatory role in autophagy. Importantly, calcium signaling produced by TRPML1 (transient receptor potential cation channel, mucolipin subfamily) has been shown to regulate autophagic progression through biogenesis of autophagic-lysosomal organelles, activation of mTORC1 (mechanistic target of rapamycin complex 1) and degradation of autophagic cargo. ER calcium channels such as IP3Rs supply calcium for the lysosome, and lysosomal function is severely disrupted in the absence of lysosomal calcium replenishment by the ER. TRPML1 function is also regulated by LC3 (microtubule-associated protein light chain 3) and mTORC1, two critical components of the autophagic network. Here we provide an overview of the current knowledge about ion channels and pumps-including lysosomal V-ATPase (vacuolar proton-ATPase), which is required for acidification and hence proper enzymatic activity of lysosomal hydrolases-in the regulation of autophagy, and discuss how functional impairment of some of these leads to diseases.
-
4.
Regulation of Ion Channel Function by Gas Molecules.
Shah, N, Zhou, L
Advances in experimental medicine and biology. 2021;:139-164
Abstract
Our understanding of the gaseous signaling molecules that play important roles in diverse physiological processes keeps expanding. These gas molecules, also called gasotransmitters, include NO, H2S, 1O2, CO, and CO2 and are generated within the cell through enzymatic pathways and photochemical reactions. These molecules are chemically unstable and directly react with amino acids such as cysteine, histidine, and so on. Compared to well-characterized reactive oxygen species (ROS), including H2O2, ONOO-, O2-, and OH·, the gasotransmitters are in general less polar and show higher solubility in hydrophobic environments like the lipid membrane. Correspondingly, accumulating evidence has begun to unveil the broad impacts of these gaseous molecules on the function of membrane proteins, including ion channels. This review summarizes the major physicochemical characteristics of representative gasotransmitters and their regulation of ion channel functions.
-
5.
Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease.
Dietl, P, Frick, M
Cells. 2021;(1)
Abstract
The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.
-
6.
Structural biology of coronavirus ion channels.
Barrantes, FJ
Acta crystallographica. Section D, Structural biology. 2021;(Pt 4):391-402
Abstract
Viral infection compromises specific organelles of the cell and readdresses its functional resources to satisfy the needs of the invading body. Around 70% of the coronavirus positive-sense single-stranded RNA encodes proteins involved in replication, and these viruses essentially take over the biosynthetic and transport mechanisms to ensure the efficient replication of their genome and trafficking of their virions. Some coronaviruses encode genes for ion-channel proteins - the envelope protein E (orf4a), orf3a and orf8 - which they successfully employ to take control of the endoplasmic reticulum-Golgi complex intermediate compartment or ERGIC. The E protein, which is one of the four structural proteins of SARS-CoV-2 and other coronaviruses, assembles its transmembrane protomers into homopentameric channels with mild cationic selectivity. Orf3a forms homodimers and homotetramers. Both carry a PDZ-binding domain, lending them the versatility to interact with more than 400 target proteins in infected host cells. Orf8 is a very short 29-amino-acid single-passage transmembrane peptide that forms cation-selective channels when assembled in lipid bilayers. This review addresses the contribution of biophysical and structural biology approaches that unravel different facets of coronavirus ion channels, their effects on the cellular machinery of infected cells and some structure-functional correlations with ion channels of higher organisms.
-
7.
Analysis of an electrostatic mechanism for ΔpH dependent gating of the voltage-gated proton channel, HV1, supports a contribution of protons to gating charge.
Sokolov, VS, Cherny, VV, Ayuyan, AG, DeCoursey, TE
Biochimica et biophysica acta. Bioenergetics. 2021;(11):148480
Abstract
Voltage-gated proton channels (HV1) resemble the voltage-sensing domain of other voltage-gated ion channels, but differ in containing the conduction pathway. Essential to the functions of HV1 channels in many cells and species is a unique feature called ΔpH dependent gating. The pH on both sides of the membrane strictly regulates the voltage range of channel opening, generally resulting in exclusively outward proton current. Two types of mechanisms could produce ΔpH dependent gating. The "countercharge" mechanism proposes that protons destabilize salt bridges between amino acids in the protein that stabilize specific gating configurations (closed or open). An "electrostatic" mechanism proposes that protons bound to the channel alter the electrical field sensed by the protein. Obligatory proton binding within the membrane electrical field would contribute to measured gating charge. Estimations on the basis of the electrostatic model explain ΔpH dependent gating, but quantitative modeling requires calculations of the electric field inside the protein which, in turn, requires knowledge of its structure. We conclude that both mechanisms operate and contribute to ΔpH dependent gating of HV1.
-
8.
Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.
Mitini-Nkhoma, SC, Chimbayo, ET, Mzinza, DT, Mhango, DV, Chirambo, AP, Mandalasi, C, Lakudzala, AE, Tembo, DL, Jambo, KC, Mwandumba, HC
Frontiers in immunology. 2021;:665785
Abstract
Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb's differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host's antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.
-
9.
Calmodulin Mutations Associated with Heart Arrhythmia: A Status Report.
Chazin, WJ, Johnson, CN
International journal of molecular sciences. 2020;(4)
Abstract
Calmodulin (CaM) is a ubiquitous intracellular Ca2+ sensing protein that modifies gating of numerous ion channels. CaM has an extraordinarily high level of evolutionary conservation, which led to the fundamental assumption that mutation would be lethal. However, in 2012, complete exome sequencing of infants suffering from recurrent cardiac arrest revealed de novo mutations in the three human CALM genes. The correlation between mutations and pathophysiology suggests defects in CaM-dependent ion channel functions. Here, we review the current state of the field for all reported CaM mutations associated with cardiac arrhythmias, including knowledge of their biochemical and structural characteristics, and progress towards understanding how these mutations affect cardiac ion channel function.
-
10.
Modulation of Ion Channels and Receptors by p11 (S100A10).
Seo, JS, Svenningsson, P
Trends in pharmacological sciences. 2020;(7):487-497
Abstract
p11 (S100A10, annexin II light chain, calpactin I light chain) is a multifunctional protein that forms a heterotetrameric complex with Annexin A2, particularly at cell membranes. p11, alone or together with Annexin A2, interacts with several ion channels and receptors and regulates their cellular localization and function. Altered levels of p11 are implicated in the pathophysiology of several forms of cancer, psychiatric disorders, and neurodegeneration. Via interactions with ion channels and receptors, p11 modulates therapeutic actions of drugs targeting brain disorders. By serving as a plasminogen receptor, p11 plays an important role in plasmin generation, fibrinolysis, angiogenesis, tumor progression, and metastasis. Here, we review mechanisms whereby p11 regulates functions of ion channels and receptors in health and disease states.