scholarly journals TMEM120A/TACAN inhibits mechanically activated Piezo2 channels

2021 ◽  
Author(s):  
John Smith Del Rosario ◽  
Matthew Gabrielle ◽  
Yevgen Yudin ◽  
Tibor Rohacs
Keyword(s):  
Ion Channel ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
High Threshold ◽  
Light Touch ◽  
Channel Activity ◽  
Drg Neurons ◽  
Cortical Actin ◽  
Cellular Context ◽  
Negative Modulator

Mechanically activated Piezo2 channels are key mediators of light touch and proprioception in mice and humans. Relatively little is known about what other proteins regulate Piezo2 activity in a cellular context. TACAN (TMEM120A) was proposed to act as a high threshold mechanically activated ion channel in nociceptive dorsal root ganglion (DRG) neurons. Here we find that TACAN co-expression robustly reduced mechanically activated Piezo2 currents, but did not inhibit mechanically activated Piezo1 and TREK1 currents. TACAN co-expression did not affect cell surface expression of either Piezo1 or Piezo2 and did not have major effects on the cortical actin or tubulin cytoskeleton. TACAN expression alone did not result in the appearance of mechanically activated currents above background. In addition, TACAN and Piezo2 expression in DRG neurons overlapped, and siRNA mediated knockdown of TACAN did not decrease the proportion of slowly adapting mechanically activated currents, but resulted in an increased proportion of rapidly adapting currents. Our data do not support TACAN being a mechanically activated ion channel, and identify it as a negative modulator of Piezo2 channel activity.

scholarly journals Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity

2016 ◽  
Vol 311 (5) ◽  
pp. F908-F914 ◽  
Author(s):  
Evan C. Ray ◽  
Jingxin Chen ◽  
Tanika N. Kelly ◽  
Jiang He ◽  
L. Lee Hamm ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Surface ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Channel Activity ◽  
Dietary Salt ◽  
Α Subunit ◽  
Γ Subunit ◽  
Genes Encoding ◽  
Altered Sensitivity

Mutations in genes encoding subunits of the epithelial Na+ channel (ENaC) can cause early onset familial hypertension, demonstrating the importance of this channel in modulating blood pressure. It remains unclear whether other genetic variants resulting in subtler alterations of channel function result in hypertension or altered sensitivity of blood pressure to dietary salt. This study sought to identify functional human ENaC variants to examine how these variants alter channel activity and to explore whether these variants are associated with altered sensitivity of blood pressure to dietary salt. Six-hundred participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study with salt-sensitive or salt-resistant blood pressure underwent sequencing of the genes encoding ENaC subunits. Functional effects of identified variants were examined in a Xenopus oocyte expression system. Variants that increased channel activity included three in the gene encoding the α-subunit (αS115N, αR476W, and αV481M), one in the β-subunit (βS635N), and one in the γ-subunit (γL438Q). One α-subunit variant (αA334T) and one γ-subunit variant (βD31N) decreased channel activity. Several α-subunit extracellular domain variants altered channel inhibition by extracellular Na+ (Na+ self-inhibition). One variant (αA334T) decreased and one (αV481M) increased cell surface expression. Association between these variants and salt sensitivity did not reach statistical significance. This study identifies novel functional human ENaC variants and demonstrates that some variants alter channel cell surface expression and/or Na+ self-inhibition.

Interaction of epithelial ion channels with the actin-based cytoskeleton

2006 ◽  
Vol 291 (6) ◽  
pp. F1113-F1122 ◽  
Author(s):  
C. Mazzochi ◽  
D. J. Benos ◽  
P. R. Smith
Keyword(s):  
Ion Channels ◽  
Intracellular Trafficking ◽  
Surface Expression ◽  
Actin Binding ◽  
Cell Surface Expression ◽  
Membrane Domains ◽  
Channel Activity ◽  
Filamentous Actin ◽  
Expression Activity ◽  
Excised Patches

The interaction of ion channels with the actin-based cytoskeleton in epithelial cells not only maintains the polarized expression of ion channels within specific membrane domains, it also functions in the intracellular trafficking and regulation of channel activity. Initial evidence supporting an interaction between epithelial ion channels and the actin-based cytoskeleton came from patch-clamp studies examining the effects of cytochalasins on channel activity. Cytochalasins were shown to either activate or inactivate epithelial ion channels. An interaction between the actin-based cytoskeleton and epithelial ion channels was further supported by the fact that the addition of monomeric or filamentous actin to excised patches had an effect on channel activity comparable to that of cytochalasins. Through the recent application of molecular and proteomic approaches, we now know that the interactions between epithelial ion channels and actin can either be direct or indirect, the latter being mediated through scaffolding or actin-binding proteins that serve as links between the channels and the actin-based cytoskeleton. This review discusses recent advances in our understanding of the interactions between epithelial ion channels and the actin-based cytoskeleton, and the roles these interactions play in regulating the cell surface expression, activity, and intracellular trafficking of epithelial ion channels.

scholarly journals Acid-sensing ion channel 3 (ASIC3) cell surface expression is modulated by PSD-95 within lipid rafts

2008 ◽  
Vol 295 (3) ◽  
pp. C732-C739 ◽  
Author(s):  
Jayasheel O. Eshcol ◽  
Anne Marie S. Harding ◽  
Tomonori Hattori ◽  
Vivian Costa ◽  
Michael J. Welsh ◽  
...  
Keyword(s):  
Cell Surface ◽  
Ion Channel ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Ph Sensor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Membrane Microdomains ◽  
Metabolic Disturbances ◽  
Raft Fraction

Acid-sensing ion channel 3 (ASIC3) is a H+-gated cation channel primarily found in sensory neurons, where it may function as a pH sensor in response to metabolic disturbances or painful conditions. We previously found that ASIC3 interacts with the postsynaptic density protein PSD-95 through its COOH terminus, which leads to a decrease in ASIC3 cell surface expression and H+-gated current. PSD-95 has been implicated in recruiting proteins to lipid rafts, which are membrane microdomains rich in cholesterol and sphingolipids that organize receptor/signaling complexes. We found ASIC3 and PSD-95 coimmunoprecipitated within detergent-resistant membrane fractions. When cells were exposed to methyl-β-cyclodextrin to deplete membrane cholesterol and disrupt lipid rafts, PSD-95 localization to lipid raft fractions was abolished and no longer inhibited ASIC3 current. Likewise, mutation of two cysteine residues in PSD-95 that undergo palmitoylation (a lipid modification that targets PSD-95 to lipid rafts) prevented its inhibition of ASIC3 current and cell surface expression. In addition, we found that cell surface ASIC3 is enriched in the lipid raft fraction. These data suggest that PSD-95 and ASIC3 interact within lipid rafts and that this raft interaction is required for PSD-95 to modulate ASIC3.

scholarly journals PSD-95 and SAP97 Exhibit Distinct Mechanisms for Regulating K+ Channel Surface Expression and Clustering

2000 ◽  
Vol 148 (1) ◽  
pp. 147-157 ◽  
Author(s):  
Amanda M. Tiffany ◽  
Louis N. Manganas ◽  
Eunjoon Kim ◽  
Yi-Ping Hsueh ◽  
Morgan Sheng ◽  
...  
Keyword(s):  
Cell Surface ◽  
Ion Channel ◽  
Membrane Vesicles ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
K Channel ◽  
Neuronal Membrane ◽  
K Channels ◽  
Kv Channels ◽  
Abundance And Distribution

Mechanisms of ion channel clustering by cytoplasmic membrane-associated guanylate kinases such as postsynaptic density 95 (PSD-95) and synapse-associated protein 97 (SAP97) are poorly understood. Here, we investigated the interaction of PSD-95 and SAP97 with voltage-gated or Kv K+ channels. Using Kv channels with different surface expression properties, we found that clustering by PSD-95 depended on channel cell surface expression. Moreover, PSD-95–induced clusters of Kv1 K+ channels were present on the cell surface. This was most dramatically demonstrated for Kv1.2 K+ channels, where surface expression and clustering by PSD-95 were coincidentally promoted by coexpression with cytoplasmic Kvβ subunits. Consistent with a mechanism of plasma membrane channel–PSD-95 binding, coexpression with PSD-95 did not affect the intrinsic surface expression characteristics of the different Kv channels. In contrast, the interaction of Kv1 channels with SAP97 was independent of Kv1 surface expression, occurred intracellularly, and prevented further biosynthetic trafficking of Kv1 channels. As such, SAP97 binding caused an intracellular accumulation of each Kv1 channel tested, through the accretion of SAP97 channel clusters in large (3–5 μm) ER-derived intracellular membrane vesicles. Together, these data show that ion channel clustering by PSD-95 and SAP97 occurs by distinct mechanisms, and suggests that these channel-clustering proteins may play diverse roles in regulating the abundance and distribution of channels at synapses and other neuronal membrane specializations.

Myrsinane and related diterpenes from Euphorbia falcata with selective potassium ion channel activity

Planta Medica ◽  
2015 ◽  
Vol 81 (16) ◽  
Author(s):  
A Vasas ◽  
P Orvos ◽  
L Tálosi ◽  
P Forgo ◽  
G Pinke ◽  
...  
Keyword(s):  
Ion Channel ◽  
Potassium Ion ◽  
Channel Activity ◽  
Potassium Ion Channel

Increased Expression of u-PA and u-PAR on Monocytes by LDL and Lp(a) Lipoproteins – Consequences for Plasmin Generation and Monocyte Adhesion

1999 ◽  
Vol 81 (04) ◽  
pp. 594-560 ◽  
Author(s):  
Florence Ganné ◽  
Marc Vasse ◽  
Jean-Louis Beaudeu ◽  
Jacqueline Peynet ◽  
Arnaud François ◽  
...  
Keyword(s):  
Fold Increase ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Atheromatous Plaque ◽  
Monocyte Adhesion ◽  
Blood Monocytes ◽  
Proteolytic Cascade ◽  
Ecm Degradation ◽  
Dose Dependent Increase ◽  
Dose Dependent

SummaryMonocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaque. As urokinase/urokinase-receptor (u-PA/u-PAR) is the trigger of a proteolytic cascade responsible for ECM degradation, we have examined the effect of atherogenic lipoproteins on monocyte surface expression of u-PAR and u-PA. Peripheral blood monocytes, isolated from 10 healthy volunteers, were incubated with 10 to 200 µg/ml of native or oxidised (ox-) atherogenous lipoproteins for 18 h and cell surface expression of u-PA and u-PAR was analysed by flow cytometry. Both LDL and Lp(a) induced a dose-dependent increase in u-PA (1.6-fold increase with 200 μg/ml of ox-LDL) and u-PAR [1.7-fold increase with 200 μg/ml of ox-Lp(a)]. There is a great variability of the response among the donors, some of them remaining non-responders (absence of increase of u-PA or u-PAR) even at 200 μg/ml of lipoproteins. In positive responders, enhanced u-PA/u-PAR is associated with a significant increase of plasmin generation (1.9-fold increase with 200 μg/ml of ox-LDL), as determined by an amidolytic assay. Furthermore, monocyte adhesion to vitronectin and fibrinogen was significantly enhanced by the lipoproteins [respectively 2-fold and 1.7-fold increase with 200 μg/ml of ox-Lp(a)], due to the increase of u-PAR and ICAM-1, which are receptors for vitronectin and fibrinogen. These data suggest that atherogenous lipoproteins could contribute to the development of atheromatous plaque by increasing monocyte adhesion and trigger plaque weakening by inducing ECM degradation.

Persistent HIV Transcription Induces Sialyl-Lewis-X Glyco-Antigen Cell-Surface Expression

2020 ◽  
Author(s):  
Florent Colomb ◽  
Leila B. Giron ◽  
Leticia Kuri Cervantes ◽  
Tongcui Ma ◽  
Samson Adeniji ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Expression ◽  
Sialyl Lewis X ◽  
Cell Surface Expression ◽  
Lewis X ◽  
Hiv Transcription ◽  
Sialyl Lewis

Influence of β-D-mannuronic acid, as a new member of non-steroidal anti-inflammatory drugs family, on expression pattern of chemokines and their receptors in rheumatoid arthritis

2019 ◽  
Vol 16 ◽  
Author(s):  
Mona Aslani ◽  
Arman Ahmadzadeh ◽  
Zahra Aghazadeh ◽  
Majid Zaki-Dizaji ◽  
Laleh Sharifi ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mrna Expression ◽  
Surface Expression ◽  
Phase Iii ◽  
Cell Surface Expression ◽  
Optimum Dose ◽  
High Dose ◽  
Mannuronic Acid ◽  
Anti Inflammatory ◽  
High Doses

Background: : Based on the encouraging results of phase III clinical trial of β-D-mannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. Methods:: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 μg/mL) of M2000 and optimum dose (1 μg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. Results:: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression down-regulated significantly followed by treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by treatment of these cells with high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by treatment of these cells with high dose of M2000 and optimum dose of diclofenac. Conclusion:: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

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