Ion Channel Activity Research Articles

Mechanosensitive Piezo channels and their potential roles in peripheral auditory perception

AbstractHearing sound and responding to external and internal mechanical stimuli requires specific proteins as mechanotransducers that convert mechanical forces into biological signals. However, our understanding of the mechanotransduction process in the inner ear is still incomplete. Mechanically activated ion channels, PIEZO1 and PIEZO2, are widely distributed throughout the body and play essential roles. Recent studies have discovered that Piezo channels are expressed in inner ear hair cells, suggesting their potential involvement in auditory perception. This review summarizes the existing discoveries about the Piezo channels, including their structure, mechanogating mechanisms, and general physiological roles, explicitly focusing on Piezo channels in the auditory systems. Piezo channels play roles in ultrasound perception, generation of anomalous current, hair cell development, and potentially in the normal mechanoelectrical transduction process of hair cells. Collectively, this review aims to provide a new perspective on the Piezo channel and its potential roles in auditory perception.

Long-term changes in transmembrane voltage after electroporation are governed by the interplay between nonselective leak current and ion channel activation

Electroporation causes a temporal increase in cell membrane permeability and leads to prolonged changes in transmembrane voltage (TMV) in both excitable and non-excitable cells. However, the mechanisms of these TMV changes remain to be fully elucidated. To this end, we monitored TMV over 30 min after exposing two different cell lines to a single 100 µs electroporation pulse using the FLIPR Membrane Potential dye. In CHO-K1 cells, which express very low levels of endogenous ion channels, membrane depolarization following pulse exposure could be explained by nonselective leak current, which persists until the membrane reseals, enabling the cells to recover their resting TMV. In U-87 MG cells, which express many different ion channels, we unexpectedly observed membrane hyperpolarization following the initial depolarization phase, but only at 33 °C and not at 25 °C. We developed a theoretical model, supported by experiments with ion channel inhibitors, which indicated that hyperpolarization could largely be attributed to the activation of calcium-activated potassium channels. Ion channel activation, coupled with changes in TMV and intracellular calcium, participates in various physiological processes, including cell proliferation, differentiation, migration, and apoptosis. Therefore, our study suggests that ion channels could present a potential target for influencing the biological response after electroporation.

Molecular Insights into Single Chain Lipid Modulation of Acid-Sensing Ion Channel 3.

Polyunsaturated fatty acids (PUFAs) and their analogs play a significant role in modulating the activity of diverse ion channels, and recent studies show that these lipids potentiate acid-sensing ion channels (ASICs), leading to increased activity. The potentiation of the channel stems from multiple gating changes, but the exact mechanism of these effects remains uncertain. We posit a mechanistic explanation for one of these changes in channel function, the increase in the maximal current, by applying a combination of electrophysiology and all-atom molecular dynamics simulations on the open-state hASIC3. Microsecond-scale simulations were performed on open-state hASIC3 in the absence and presence of a PUFA, docosahexaenoic acid (DHA), and a PUFA analog, N-arachidonyl glycine (AG). Intriguingly, our simulations in the absence of PUFA or PUFA analogs reveal that a tail from the membrane phospholipid POPC inserts itself into the pore of the channel through lateral fenestrations on the sides of the transmembrane segments, obstructing ion permeation through the channel. The binding of either DHA or AG prevented POPC from accessing the pore in our simulations, relieving the block of ionic conduction by phospholipids. Finally, we use the single-channel recording to show that DHA increases the amplitude of the single-channel currents in ASIC3, which is consistent with our hypothesis that PUFAs relieve the pore block of the channel induced by POPCs. Together, these findings offer a potential mechanistic explanation of how PUFAs modulate ASIC maximal current, revealing a novel mechanism of action for PUFA-induced modulation of ion channels.

Genetic Code Expansion for Mechanistic Studies in Ion Channels: An (Un)natural Union of Chemistry and Biology.

Ion channels play central roles in biology and human health by catalyzing the transmembrane flow of electrical charge. These proteins are ideal targets for genetic code expansion (GCE) methods because it is feasible to measure ion channel activity from miniscule amounts of protein and to analyze the resulting data via rigorous, established biophysical methods. In an ideal scenario, the encoding of synthetic, noncanonical amino acids via GCE allows the experimenter to ask questions inaccessible to traditional methods. For this reason, GCE has been successfully applied to a variety of ligand- and voltage-gated channels wherein extensive structural, functional, and pharmacological data exist. Here, we provide a comprehensive summary of GCE as applied to ion channels. We begin with an overview of the methods used to encode noncanonical amino acids in channels and then describe mechanistic studies wherein GCE was used for photochemistry (cross-linking; caged amino acids) and atomic mutagenesis (isosteric manipulation of charge and aromaticity; backbone mutation). Lastly, we cover recent advances in the encoding of fluorescent amino acids for the real-time study of protein conformational dynamics.

Immunogenicity and Protective Efficacy of Baculovirus-Expressed SARS-CoV-2 Envelope Protein in Mice as a Universal Vaccine Candidate.

The envelope (env) protein of SARS-CoV-2, a pivotal component of the viral architecture, plays a multifaceted role in viral assembly, replication, pathogenesis, and ion channel activity. These features make it a significant target for understanding virus-host interactions and developing vaccines to combat COVID-19. Recent structural studies provide valuable insights into the conformational dynamics and membrane topology of the SARS-CoV-2 env protein, shedding light on its functional mechanisms. The strong homology and highly conserved structure of the SARS-CoV-2 env protein shape its immunogenicity and functional characteristics. This study examines the ability of the recombinant SARS-CoV-2 env protein to stimulate an immune response. In this study, recombinant envelope proteins were produced using the baculovirus expression system, and their potential efficacy was evaluated in both in vivo and in vitro models. Our results reveal that the env protein of SARS-CoV-2 stimulates humoral and cellular responses and highlight its potential as a promising vaccine candidate for combating the ongoing pandemic.

Hyperglycemia adversely affects critical physiological events related to rat sperm capacitation

Hyperglycemia, the hallmark of diabetes mellitus (DM), is the main cause of DM-related systemic complications, including reproductive issues. Furthermore, the incidence of DM in males of reproductive ages is becoming an increasing concern, as the complexity of sperm capacitation (an essential process for fertilizing the egg) extends beyond conventional sperm parameters such as count, viability, and motility. Capacitation defects cause male infertility, and DM-related hyperglycemia may affect this process. We explore the effects of uncontrolled hyperglycemia on sperm using alloxan-induced hyperglycemic Wistar rats. In addition to assessing conventional sperm parameters, we also evaluated functional indicators, including hyperactivation (HA) with a pharmacological approach and assessed its effects with a computer-assisted sperm analysis (CASA); fluorescence indicators to monitor membrane potential (EmR, DiSC3(5)) and mitochondrial membrane potential (Ψ, JC-1); CatSper activity, using its ability to permeate Na+ ions, and ATP levels with the luciferin-luciferase reaction. We confirmed previous findings with our hyperglycemic model, which replicated the typical reduction on conventional sperm parameters. In sperm from hyperglycemic rats, we observed increased motility and HA levels after pharmacological treatment. Additionally, CatSper activity was unaffected by hyperglycemia, while EmR was hyperpolarized under non-capacitating condition. Finally, we noted a low percentage of hyperpolarized Ψ and reduced ATP content. This study highlights the significance of impact of hyperglycemia on sperm physiology and capacitation. We proposed that low ATP levels perturb energy state, signaling pathways, ion channels activity, motility, and HA. Our findings offer insight into DM-associated infertility and potential treatment strategies.

Vascular Function and Ion Channels in Alzheimer's Disease.

This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression.

Antiviral effect of the viroporin inhibitors against Taiwan isolates of infectious bronchitis virus (IBV)

Coronaviruses (CoVs) are significant animal and human pathogens, characterized by being enveloped RNA viruses with positive-sense single-stranded RNA. The Coronaviridae family encompasses four genera, among which gammacoronaviruses pose a major threat to the poultry industry, which infectious bronchitis virus (IBV) being the most prominent of these threats. Particularly, IBV adversely affects broiler growth and egg production, causing substantial losses. The IBV strains currently circulating in Taiwan include the IBV Taiwan-I (TW-I) serotype, IBV Taiwan-II (TW-II) serotype, and vaccine strains. Therefore, ongoing efforts have focused on developing novel vaccines and discovering antiviral agents. The envelope (E) proteins of CoVs accumulate in the endoplasmic reticulum-Golgi intermediate compartment prior to virus budding. These E proteins assemble into viroporins, exhibiting ion channel activity that leads to cell membrane disruption, making them attractive targets for antiviral therapy.In this study, we investigated the E proteins of IBV H-120, as well as IBV serotypes TW-I and TW-II. E protein expression resulted in inhibited bacteria growth, increased permeability of bacteria to β-galactosidase substrates, and blocked protein synthesis of bacteria by hygromycin B (HygB). Furthermore, in the presence of E proteins, HygB also impeded protein translation in DF-1 cells and damaged their membrane integrity. Collectively, these findings confirm the viroporin activity of the E proteins from IBV H-120, IBV serotype TW-I, and IBV serotype TW-II. Next, the viroporin inhibitors, 5-(N,N-hexamethylene) amiloride (HMA) and 4,4’-diisothiocyano stilbene-2,2’-disulphonic acid (DIDS) were used to inhibit the viroporin activities of the E proteins of IBV H-120, IBV serotype TW-I, and IBV serotype TW-II. In chicken embryos and chickens infected with IBV serotypes TW-I and IBV TW-II, no survivors were observed at 6 and 11 days post-infection (dpi), respectively. However, treatments with both DIDS and HMA increased the survival rates in infected chicken embryos and chickens and mitigated histopathological lesions in the trachea and kidney. Additionally, a 3D pentameric structure of the IBV E protein was constructed via homology modeling. As expected, both inhibitors were found to bind to the lipid-facing surface within the transmembrane domain of the E protein, inhibiting ion conduction. Taken together, our findings provide comprehensive evidence supporting the use of viroporin inhibitors as promising antiviral agents against IBV Taiwan isolates.

Potential roles of voltage-gated ion channel disruption in Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is a lynchpin disorder, as it results in overactive mammalian target of rapamycin (mTOR) signaling, which has been implicated in a multitude of disease states. TSC is an autosomal dominant disease where 90% of affected individuals develop epilepsy. Epilepsy results from aberrant neuronal excitability that leads to recurring seizures. Under neurotypical conditions, the coordinated activity of voltage-gated ion channels keep neurons operating in an optimal range, thus providing network stability. Interestingly, loss or gain of function mutations in voltage-gated potassium, sodium, or calcium channels leads to altered excitability and seizures. To date, little is known about voltage-gated ion channel expression and function in TSC. However, data is beginning to emerge on how mTOR signaling regulates voltage-gated ion channel expression in neurons. Herein, we provide a comprehensive review of the literature describing common seizure types in patients with TSC, and suggest possible parallels between acquired epilepsies with known voltage-gated ion channel dysfunction. Furthermore, we discuss possible links toward mTOR regulation of voltage-gated ion channels expression and channel kinetics and the underlying epileptic manifestations in patients with TSC.

The effect of triple CFTR modulator therapy and azithromycin on ion channels and inflammation in cystic fibrosis

Inflammation in cystic fibrosis (CF) airways is difficult to treat with well-established regimens often including azithromycin (AZ) as an immunomodulatory drug. As AZ has been reported to require CFTR to be able to reduce IL-8 and given the emergence of highly effective CFTR “triple” modulator therapy (elexacaftor/tezacaftor/ivacaftor; ETI), the aim of this study was to investigate the effect of AZ and ETI, singly and in combination, on ion channel activity and to assess potential anti-inflammatory effects. Electrophysiological assessment of ETI and AZ was performed on 3D cultures of primary CF human bronchial epithelial (HBE) cells using Multi Trans-Epithelial Current Clamp (MTECC). IL-8 from NuLi-1 (non-CF) and CuFi-1 (CF) cells treated with AZ was measured by ELISA. Inflammatory mediators from primary CF HBE cells exposed to tumour necrosis factor-alpha (TNF-α) in the presence of AZ, ETI and their combination, were screened using the Proteome Profiler™ Human Cytokine Array Kit, with selected targets validated by ELISA. AZ did not alter CFTR chloride efflux, nor did it have any synergistic/antagonistic effect in combination with ETI. AZ reduced IL-8 in NuLi-1 but not CuFi-1 cells. The Proteome Profiler™ screen identified several disease-relevant cytokines that were modulated by treatment. Subsequent analysis by ELISA showed IL-8, IL-6, CXCL1 and GM-CSF to be significantly reduced by treatment with ETI, but not by AZ. Incorporating ETI into the standard of CF care provides an opportunity to re-evaluate therapeutic regimens to reduce treatment burden and safely discontinue chronic treatments such as AZ, without loss of clinical benefit. Identification of redundant treatments in the era of CFTR modulation may improve medication adherence and overcome potential adverse effects associated with the chronic use AZ and other drugs.

Activation of the TRPML1 Ion Channel Induces Proton Secretion in the Human Gastric Parietal Cell Line HGT-1.

The lysosomal Ca2+ channel TRPML1 was found to be responsible for gastric acid secretion in murine gastric parietal cells by inducing the trafficking of H+/K+-ATPase containing tubulovesicles to the apical membrane. Therefore, we hypothesized a similar role of TRPML1 in regulating proton secretion in the immortalized human parietal cell line HGT-1. The primary focus was to investigate the involvement of TRPML1 in proton secretion using the known synthetic agonists ML-SA1 and ML-SA5 and the antagonist ML-SI3 and, furthermore, to identify food-derived compounds that target the channel. Proton secretion stimulated by ML-SA1 was reduced by 122.2 ± 22.7% by the antagonist ML-SI3. The steroid hormone 17β-estradiol, present in animal-derived foods, diminished the proton secretory effect of ML-SA1 by 63.4 ± 14.5%. We also demonstrated a reduction in the proton secretory effects of ML-SA1 and ML-SA5 on TRPML1 knock-down cells. The food-derived compounds sulforaphane and trehalose promoted proton secretion in HGT-1 cells but may act independently of TRPML1. Also, histamine- and caffeine-induced proton secretion were affected by neither the TRPML1 antagonist ML-SI3 nor the TRPML1 knock-down. In summary, the results obtained suggest that the activation of TRPML1 promotes proton secretion in HGT-1 cells, but the channel may not participate in canonical signaling pathways.

Exploring phytoremediation potential of willow NJU513 for cadmium-contaminated soil with and without epibrassinolide treatment

There has been a growing concern over soil cadmium (Cd) pollution, underscoring the importance of finding effective remediation strategies. Willow trees have emerged as promising candidates for phytoremediation of Cd-contaminated soils. Nevertheless, the specific potential of a novel willow genotype, NJU513, in remediating Cd-polluted soil remains unexplored. Hence, the primary objectives of this study were twofold: firstly, to ascertain the suitability of the willow genotype NJU513 for remediating Cd-contaminated soil; and secondly, to elevate its remediation efficciency with the application of epibrassinolide (Brs). In the pot-culture experiment without Brs, its leaf and stem Cd concentrations were 203 mg kg−1 and 65.1 mg kg−1, with a bioaccumulation factor (BCF) of 20.8 and 6.68, respectively. In the pot-culture experiment with Brs, the corresponding Cd concentrations were 226 mg kg−1 and 59.2 mg kg−1, with a BCF of 23.1 and 6.06, respectively. In addition, the extracted Cd contents were higher in the Brs treatments (1.11–1.37 mg plant−1) than in the no-Brs treatments (0.78–0.96 mg plant−1) because Brs increased the plant biomass and leaf BCF. The mechanism underlying the Cd accumulation of NJU513 leaves with and without Brs was revealed by a transcriptome analysis. The expression levels of genes related to metal ion binding, channel activity, and transporters in leaves were up-regulated, which contributed to the high Cd accumulation and stress tolerance. Analyses of soil metabolites and bacteria in the presence and absence of Brs spraying on willow leaves indicated that soil organic compounds with carboxyl and amino groups may induce Cd activation and passivation, respectively. This study provides valuable insights for developing woody plant varieties that can be used for remediating Cd-contaminated soil.

UNVEILING THERAPEUTIC TARGETS THROUGH PATHWAY ANALYSIS AND IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES IN ULCERATIVE COLITIS

Objective: This study utilizes integrated bioinformatics to investigate Differentially Expressed Genes (DEGs) and pathways related to ulcerative colitis (UC). Material and Method: Differentially Expressed Genes were identified from UC patients' colonic mucosal samples and controls using GSE13367 and GSE134025 datasets. Differentially Expressed Genes selection utilized GEO2R and Venn diagrams, followed by functional annotation, pathway analysis, PPI determination via the STRING database, and GO/KEGG enrichment analysis using Metascape. Result and Discussion: Analysis unveiled 197 DEGs, with 76 up-regulated and 121 down-regulated genes. Up-regulated genes were enriched in humoral immune response, peptidoglycan binding, and NADPH oxidase complex, while down-regulated genes were linked to inorganic anion transport, transmitter-gated ion channel activity, and integral plasma membrane components. In the PPI network, up-regulated DEGs formed a dense network (75 nodes, 190 edges), indicating significant interactions, whereas down-regulated DEGs formed a less dense network (114 nodes, 63 edges). Five hub genes (CXCR4, CXCL13, CXCL1, MMP3) were identified among the 197 DEGs. These findings provide new insights into UC's causes and offer promise for more effective therapeutic approaches.

(Invited) Drug Delivery System of Photoresponsive Donor-Acceptor-Linked Molecules to Mouse Retina

Neurotransmission is mediated by electrical pulses that are generated by coordinated activation and deactivation of ion channels in the plasma membrane of neuronal cells. The ion channels control the plasma membrane potential (V m) by influx/efflux of ions. In our retina, the V m is controlled by light and photo-excitable ion channels in photoreceptor cells and voltage-dependent ion channels in neuronal ganglion cells, which transmit visual signal to the brain. In contrast, patients with visual impairment and blindness, e.g., with age-related macular degeneration, lose response to light due to irreversible elimination of photoreceptor cells. Therefore, restoring vision is potentially possible by direct photoexcitation of neuronal ganglion cells with photoresponsive V m-controlling molecules. As one of such molecules, we have focused on donor-acceptor-linked molecules (D–A molecules) capable of photoinduced intramolecular long-lived charge separation [1–4]. In this symposium, I will introduce my recent research mainly on drug delivery system of D–A molecules to the retina in mice [5].REFERENCES[1] Imahori, H. et al., J. Am. Chem. Soc. 2001, 123, 2607–2617.[2] Numata, T. et al., J. Am. Chem. Soc. 2012, 134, 6092–6095.[3] Takano, Y. et al., Chem. Sci. 2016, 7, 3331–3337.[4] Numata, T. et al., Cell. Physiol. Biochem. 2020, 54, 899–916.[5] Fukuda, R. et al., Adv. Therap. 2023, 6, 2300186.

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells.

Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally specialized subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GCs) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and suprathreshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations would not yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for while assessing GCs and their robustness under physiological and pathological conditions.NEW & NOTEWORTHY A recent study from our laboratory had demonstrated pronounced heterogeneities in a set of 17 electrophysiological measurements obtained from a large population of rat hippocampal granule cells. Here, we demonstrate the manifestation of ion-channel degeneracy in a heterogeneous population of morphologically realistic conductance-based granule cell models that were validated against these measurements and their cross-dependencies. Our analyses show that single neurons are complex entities whose functions emerge through intricate interactions among several functionally specialized subsystems.

Semisupervised Learning to Boost hERG, Nav1.5, and Cav1.2 Cardiac Ion Channel Toxicity Prediction by Mining a Large Unlabeled Small Molecule Data Set.

Predicting drug toxicity is a critical aspect of ensuring patient safety during the drug design process. Although conventional machine learning techniques have shown some success in this field, the scarcity of annotated toxicity data poses a significant challenge in enhancing models' performance. In this study, we explore the potential of leveraging large unlabeled small molecule data sets using semisupervised learning to improve drug cardiotoxicity predictive performance across three cardiac ion channel targets: the voltage-gated potassium channel (hERG), the voltage-gated sodium channel (Nav1.5), and the voltage-gated calcium channel (Cav1.2). We extensively mined the ChEMBL database, comprising approximately 2 million small molecules, and then employed semisupervised learning to construct robust classification models for this purpose. We achieved a performance boost on highly diverse (i.e., structurally dissimilar) test data sets across all three targets. Using our built models, we screened the whole ChEMBL database and a large set of FDA-approved drugs, identifying several compounds with potential cardiac ion channel activity. To ensure broad accessibility and usability for both technical and nontechnical users, we developed a cross-platform graphical user interface that allows users to make predictions and gain insights into the cardiotoxicity of drugs and other small molecules. The software is made available as open source under the permissive MIT license at https://github.com/issararab/CToxPred2.

Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Materials-driven strategies in bacterial engineering.

This perspective article focuses on the innovative field of materials-based bacterial engineering, highlighting interdisciplinary research that employs material science to study, augment, and exploit the attributes of living bacteria. By utilizing exogenous abiotic material interfaces, researchers can engineer bacteria to perform new functions, such as enhanced bioelectric capabilities and improved photosynthetic efficiency. Additionally, materials can modulate bacterial communities and transform bacteria into biohybrid microrobots, offering promising solutions for sustainable energy production, environmental remediation, and medical applications. Finally, the perspective discusses a general paradigm for engineering bacteria through the materials-driven modulation of their transmembrane potential. This parameter regulates their ion channel activity and ultimately their bioenergetics, suggesting that controlling it could allow scientists to hack the bioelectric language bacteria use for communication, task execution, and environmental response.

Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation

Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC–dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics.

From viruses to humans – Exploring the structure–function relationship of the Kesv protein for the future of biomedicine

Viruses often use ion channel proteins to initialise host infections. Defects in ion channel proteins are also linked to several metabolic disorders in humans. In that instance, modulation of ion channel activities becomes central to development of antiviral therapies and drug design. Kesv, a potassium-selective ion channel protein expressed by Ectocarpus siliculosus virus (EsV), possesses remarkable properties which can help to characterise the molecular basis of the functional processes relevant to virus biology and human physiology. The small structural features of this ion channel could serve as a fundamental primer to study more complex ion channels from humans. Therefore, in spite of their evolutionary distance, the potential link between viral and human ion channel proteins could provide opportunities for therapeutic and biotechnological applications.