scholarly journals Role of the Fourth Transmembrane Segment in TRAAK Channel Mechanosensitivity

2018 ◽  
Author(s):  
Mingfeng Zhang ◽  
Fuqiang Yao ◽  
Chengfang Pan ◽  
Zhiqiang Yan
Keyword(s):  
Ion Channels ◽  
Transmembrane Domain ◽  
Mechanical Force ◽  
Dynamic Interactions ◽  
Functional Roles ◽  
Physiological Processes ◽  
Gating Mechanism ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain

AbstractMechanosensitive ion channels such as Piezo, TRAAK, TRPs and OSCA are important transmembrane proteins that are involved in many physiological processes such as touch, hearing and blood pressure regulation. Unlike ligand-gated channels or voltage-gated ion channels, which have a canonical ligand-binding domain or voltage-sensing domain, the mechanosensitive domain and related gating mechanism remain elusive. TRAAK channels are mechanosensitive channels that convert a physical mechanical force into a flow of potassium ions. The structures of TRAAK channels have been solved, however, the functional roles of the structural domains associated with channel mechanosensitivity remains unclear. Here, we generated a series of chimeric mutations between TRAAK and a non-mechanosensitive silent TWIK-1 K2P channel. We found that the selectivity filter region functions as the major gate of outward rectification and found that lower part of fourth transmembrane domain (M4) is necessary for TRAAK channel mechanosensitivity. We further demonstrated that upper part of M4 can modulate the mechanosensitivity of TRAAK channel. Furthermore, we found that hydrophilic substitutions of W262 and F121 facing each other, and hydrophobic substitutions of Q258 and G124, which are above and below W262 and F121, respectively, greatly increase mechanosensitivity, which suggests that dynamic interactions in the upper part of M4 and PH1 domain are involved in TRAAK channel mechanosensitivity. Interestingly, these gain-of-function mutations are sensitive to cell-poking stimuli, indicating that cell-poking stimuli generate a low membrane mechanical force that opens TRAAK channels. Our results thus showed that fourth transmembrane domain of TRAAK is critical for the gating of TRAAK by mechanical force and suggested that multiple dynamic interactions in the upper part of M4 and PH1 domain are involved in this process.

scholarly journals Acid-sensing ion channels in sensory signaling

2020 ◽  
Vol 318 (3) ◽  
pp. F531-F543 ◽  
Author(s):  
Marcelo D. Carattino ◽  
Nicolas Montalbetti
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Genetically Modified ◽  
Physiological Processes ◽  
Acid Sensing Ion Channels ◽  
Genetically Modified Mice ◽  
Sensory Processes

Acid-sensing ion channels (ASICs) are cation-permeable channels that in the periphery are primarily expressed in sensory neurons that innervate tissues and organs. Soon after the cloning of the ASIC subunits, almost 20 yr ago, investigators began to use genetically modified mice to assess the role of these channels in physiological processes. These studies provide critical insights about the participation of ASICs in sensory processes, including mechanotransduction, chemoreception, and nociception. Here, we provide an extensive assessment of these findings and discuss the current gaps in knowledge with regard to the functions of ASICs in the peripheral nervous system.

Actin dynamics as critical ion channel regulator: ENaC and Piezo in focus

2021 ◽  
Author(s):  
Elena A. Morachevskaya ◽  
Anastasia V. Sudarikova
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Dynamic Balance ◽  
Cell Volume Regulation ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Actin Assembly ◽  
Excitable Cells ◽  
Physiological Processes

Ion channels in plasma membrane play a principal role in different physiological processes, including cell volume regulation, signal transduction and modulation of membrane potential in living cells. Actin-based cytoskeleton, which exists in a dynamic balance between monomeric and polymeric forms (globular and fibrillar actin), can be directly or indirectly involved in various cellular responses including modulation of ion channel activity. In this mini-review, we present an overview of the role of submembranous actin dynamics in the regulation of ion channels in excitable and non-excitable cells. Special attention is focused on the important data about the involvement of actin assembly/disassembly and some actin-binding proteins in the control of the Epithelial Na+ Channel (ENaC) and mechanosensitive Piezo channels whose integral activity has potential impact on membrane transport and multiple coupled cellular reactions. Growing evidence suggests that actin elements of the cytoskeleton can represent a "converging point" of various signaling pathways modulating the activity of ion transport proteins in cell membranes.

scholarly journals Structural basis for KCNE3 modulation of potassium recycling in epithelia

2016 ◽  
Vol 2 (9) ◽  
pp. e1501228 ◽  
Author(s):  
Brett M. Kroncke ◽  
Wade D. Van Horn ◽  
Jarrod Smith ◽  
CongBao Kang ◽  
Richard C. Welch ◽  
...  
Keyword(s):  
Gender Gap ◽  
Structural Model ◽  
Transmembrane Domain ◽  
Chloride Ion ◽  
Structural Basis ◽  
Cellular Transport ◽  
Crucial Component ◽  
Electrophysiological Studies ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain

The single-span membrane protein KCNE3 modulates a variety of voltage-gated ion channels in diverse biological contexts. In epithelial cells, KCNE3 regulates the function of the KCNQ1 potassium ion (K+) channel to enable K+ recycling coupled to transepithelial chloride ion (Cl−) secretion, a physiologically critical cellular transport process in various organs and whose malfunction causes diseases, such as cystic fibrosis (CF), cholera, and pulmonary edema. Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K+ recycling. Central to this mechanism are direct interactions of KCNE3 residues at both ends of its transmembrane domain with residues on the intra- and extracellular ends of the KCNQ1 voltage-sensing domain S4 helix. These interactions appear to stabilize the activated “up” state configuration of S4, a prerequisite for full opening of the KCNQ1 channel gate. In addition, the integrative structural model was used to guide electrophysiological studies that illuminate the molecular basis for how estrogen exacerbates CF lung disease in female patients, a phenomenon known as the “CF gender gap.”

scholarly journals Disrupting information coding via block of 4-AP-sensitive potassium channels

2014 ◽  
Vol 112 (5) ◽  
pp. 1054-1066 ◽  
Author(s):  
Krishnan Padmanabhan ◽  
Nathaniel N. Urban
Keyword(s):  
Ion Channels ◽  
Potassium Channels ◽  
Single Type ◽  
Mitral Cells ◽  
Variable Expression ◽  
Neuronal Coding ◽  
Output Spike ◽  
Voltage Gated Ion Channels ◽  
Spike Patterns

Recent interest has emerged on the role of intrinsic biophysical diversity in neuronal coding. An important question in neurophysiology is understanding which voltage-gated ion channels are responsible for this diversity and how variable expression or activity of one class of ion channels across neurons of a single type affects they way populations carry information. In mitral cells in the olfactory bulb of mice, we found that biophysical diversity was conferred in part by 4-aminopyridine (4-AP)-sensitive potassium channels and reduced following block of those channels. When populations of mitral cells were stimulated with identical inputs, the diversity exhibited in their output spike patterns reduced with the addition of 4-AP, decreasing the stimulus information carried by ensembles of 15 neurons from 437 ± 15 to 397 ± 19 bits/s. Decreases in information were due to reduction in the diversity of population spike patterns generated in response to different features of the stimulus, suggesting that the coding capacity of a population can be altered by changes in the function of single ion channel types.

scholarly journals Role of Ring6 in the function of the E. coli MCE protein LetB

2021 ◽  
Author(s):  
Casey Vieni ◽  
Nicolas Coudray ◽  
Georgia L Isom ◽  
Gira Bhabha ◽  
Damian Charles Ekiert
Keyword(s):  
Cell Envelope ◽  
Primary Sequence ◽  
Functional Roles ◽  
E Coli ◽  
Outer Membranes ◽  
Gating Mechanism ◽  
Pore Lining ◽  
Insight Into ◽  
Modular Nature

LetB is a tunnel-forming protein found in the cell envelope of some double-membraned bacteria, and is thought to be important for the transport of lipids between the inner and outer membranes. In Escherichia coli the LetB tunnel is formed from a stack of seven rings (Ring1 - Ring7), in which each ring is composed of a homo-hexameric assembly of MCE domains. The primary sequence of each MCE domain of the LetB protein is substantially divergent from the others, making each MCE ring unique in nature. The role of each MCE domain and how it contributes to the function of LetB is not well understood. Here we probed the importance of each MCE ring for the function of LetB, using a combination of bacterial growth assays and cryo-EM. Surprisingly, we find that ΔRing3 and ΔRing6 mutants, in which Ring3 and Ring6 have been deleted, confer increased resistance to membrane perturbing agents. Specific mutations in the pore-lining loops of Ring6 similarly confer increased resistance. A cryo-EM structure of the ΔRing6 mutant shows that despite the absence of Ring6, which leads to a shorter assembly, the overall architecture is maintained, highlighting the modular nature of MCE proteins. Previous work has shown that Ring6 is dynamic and in its closed state, may restrict the passage of substrate through the tunnel. Our work suggests that removal of Ring6 may relieve this restriction. The deletion of Ring6 combined with mutations in the pore-lining loops leads to a model for the tunnel gating mechanism of LetB. Together, these results provide insight into the functional roles of individual MCE domains and pore-lining loops in the LetB protein.

Role of Ion Channels and Transporters in Cell Migration

2012 ◽  
Vol 92 (4) ◽  
pp. 1865-1913 ◽  
Author(s):  
Albrecht Schwab ◽  
Anke Fabian ◽  
Peter J. Hanley ◽  
Christian Stock
Keyword(s):  
Cell Migration ◽  
Ion Channels ◽  
Immune Defense ◽  
The Body ◽  
Cellular Migration ◽  
Physiological Processes ◽  
Life Threatening ◽  
Health And Disease ◽  
Tumor Metastases

Cell motility is central to tissue homeostasis in health and disease, and there is hardly any cell in the body that is not motile at a given point in its life cycle. Important physiological processes intimately related to the ability of the respective cells to migrate include embryogenesis, immune defense, angiogenesis, and wound healing. On the other side, migration is associated with life-threatening pathologies such as tumor metastases and atherosclerosis. Research from the last ∼15 years revealed that ion channels and transporters are indispensable components of the cellular migration apparatus. After presenting general principles by which transport proteins affect cell migration, we will discuss systematically the role of channels and transporters involved in cell migration.

scholarly journals Domain–domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Mark A Zaydman ◽  
Marina A Kasimova ◽  
Kelli McFarland ◽  
Zachary Beller ◽  
Panpan Hou ◽  
...  
Keyword(s):  
Ion Channels ◽  
Physiological Role ◽  
Specific Expression ◽  
Electrical Currents ◽  
Voltage Gated ◽  
State Dependent ◽  
Domain Interactions ◽  
Voltage Gated Ion Channels ◽  
Hormonal Release

Voltage-gated ion channels generate electrical currents that control muscle contraction, encode neuronal information, and trigger hormonal release. Tissue-specific expression of accessory (β) subunits causes these channels to generate currents with distinct properties. In the heart, KCNQ1 voltage-gated potassium channels coassemble with KCNE1 β-subunits to generate the IKs current (<xref ref-type="bibr" rid="bib3">Barhanin et al., 1996</xref>; <xref ref-type="bibr" rid="bib57">Sanguinetti et al., 1996</xref>), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (<xref ref-type="bibr" rid="bib77">Wrobel et al., 2012</xref>; <xref ref-type="bibr" rid="bib66">Sun et al., 2012</xref>; <xref ref-type="bibr" rid="bib1">Abbott, 2014</xref>). These changes are essential for the physiological role of IKs (<xref ref-type="bibr" rid="bib62">Silva and Rudy, 2005</xref>); however, after 18 years of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent interactions that functionally couple the voltage-sensing domains (VSDs) to the pore.

scholarly journals Analysis of Single Nucleotide Polymorphisms in human Voltage-Gated Ion Channels

2018 ◽  
Author(s):  
Katerina C. Nastou ◽  
Michail A. Batskinis ◽  
Zoi I. Litou ◽  
Stavros J. Hamodrakas ◽  
Vassiliki A. Iconomidou
Keyword(s):  
Ion Channels ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Topological Information ◽  
Single Nucleotide ◽  
Voltage Gated ◽  
Arginine Residues ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

AbstractVoltage-Gated Ion Channels (VGICs) are one of the largest groups of transmembrane proteins. Due to their major role in the generation and propagation of electrical signals, VGICs are considered important from a medical viewpoint and their dysfunction is often associated with a group of diseases known as “Channelopathies”. We identified disease associated mutations and polymorphisms in these proteins through mapping missense Single Nucleotide Polymorphisms (SNPs) from the UniProt and ClinVar databases on their amino acid sequence, taking into consideration their special topological and functional characteristics. Statistical analysis revealed that disease associated SNPs are mostly found in the Voltage Sensor Domain – and especially at its fourth transmembrane segment (S4) – and in the Pore Loop. Both these regions are extremely important for the activation and ion conductivity of VGICs. Moreover, amongst the most frequently observed mutations are those of arginine to glutamine, to histidine or to cysteine, which can probably be attributed to the extremely important role of arginine residues in the regulation of membrane potential in these proteins. We suggest that topological information in combination with genetic variation data can contribute towards a better evaluation of the effect of currently unclassified mutations in VGICs. It is hoped that potential associations with certain disease phenotypes will be revealed in the future, with the use of similar approaches.

scholarly journals Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1447
Author(s):  
Veronica Zelli ◽  
Chiara Compagnoni ◽  
Roberta Capelli ◽  
Alessandra Corrente ◽  
Jessica Cornice ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Mirna Biogenesis ◽  
Comprehensive Overview ◽  
Functional Roles ◽  
Sequencing Errors ◽  
Sequencing Technologies ◽  
Physiological Processes ◽  
Cancer Types ◽  
State Of Research

The advent of Next Generation Sequencing technologies brought with it the discovery of several microRNA (miRNA) variants of heterogeneous lengths and/or sequences. Initially ascribed to sequencing errors/artifacts, these isoforms, named isomiRs, are now considered non-canonical variants that originate from physiological processes affecting the canonical miRNA biogenesis. To date, accurate IsomiRs abundance, biological activity, and functions are not completely understood; however, the study of isomiR biology is an area of great interest due to their high frequency in the human miRNome, their putative functions in cooperating with the canonical miRNAs, and potential for exhibiting novel functional roles. The discovery of isomiRs highlighted the complexity of the small RNA transcriptional landscape in several diseases, including cancer. In this field, the study of isomiRs could provide further insights into the miRNA biology and its implication in oncogenesis, possibly providing putative new cancer diagnostic, prognostic, and predictive biomarkers as well. In this review, a comprehensive overview of the state of research on isomiRs in different cancer types, including the most common tumors such as breast cancer, colorectal cancer, melanoma, and prostate cancer, as well as in the less frequent tumors, as for example brain tumors and hematological malignancies, will be summarized and discussed.

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