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Introduction
Wendy González currently works at the Center for Bioinformatics and Molecular Simulations (CBSM), Universidad de Talca. Wendy does research in Bioinformatics. Their current project is 'UNDERSTANDING THE STRUCTURAL MECHANISM OF SELECTIVE BLOCKERS OF PH-GATED K2P CHANNELS'.
Skills and Expertise
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October 2012 - present
Publications
Publications (109)
Intrinsic neuronal excitability, defined by the balance between input and output signals, is crucial to neural function, and its disruption underlies various neurological diseases. Kv3.1 channels, encoded by KCNC1 , are essential for high-frequency action potential firing. Variants in these channels are associated with several subtypes of epilepsy....
Accurately predicting the diverse bound-state conformations of small molecules is crucial for successful drug discovery, particularly when detailed protein-ligand interactions are unknown. Established tools exist, but exploring the vast conformational space efficiently remains a challenge. This work introduces Moltiverse, a novel protocol using enh...
Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematode C. elegans has one of the largest K2P...
During atrial fibrillation (AF), electrical remodeling occurs, involving ion channels like NaV1.5, KV1.5, and TASK-1. A promising AF treatment encompasses inhibiting these channels. In this study, acetamide compounds were designed based on the local anesthetic pharmacophore as potential NaV1.5, KV1.5, and TASK-1 inhibitors. Compound 6f emerged as t...
Slc4a genes encode various types of transporters, including Na+-HCO3− cotransporters, Cl−/HCO3− exchangers, or Na+-driven Cl−/HCO3− exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl−/HCO3− exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-depen...
Protein-protein interactions (PPIs) regulate crucial physiological and pathological processes. PPIs are considered a class of biological targets almost infeasible for small molecules because the binding surfaces are usually large and shallow. Peptides are molecules able to bind to these drug targets; they can be used as modulators and mimic one of...
The sensory hair cells of the inner ear use the mechano-electrical transducer (MET) channels to convert the mechanical stimuli from sound or acceleration into electrical signals, allowing us to perceive sound and maintain balance. The pore-forming subunit of the MET channel is formed by Transmembrane channel-like (TMC) 1 and 2 proteins, which are n...
The increase in and concern about neurodegenerative diseases continue to grow in an increasingly long-lived world population. Therefore, the search for new drugs continues to be a priority for medicinal chemistry. We present here the synthesis of a series of compounds with acetamide nuclei. Their structures were established using UV-Visible, NMR, H...
Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematode C. elegans has one of the largest K2P...
TRPV5 and TRPV6 are calcium-selective ion channels expressed at the apical membrane of epithelial cells. Important for systemic calcium (Ca2+) homeostasis, these channels are considered gatekeepers of this cation transcellular transport. Intracellular Ca2+ exerts a negative control over the activity of these channels by promoting inactivation. TRPV...
Chemical structures of selective blockers of TASK channels contain aromatic groups and amide bonds. Using this rationale, we designed and synthesized a series of compounds based on 3-benzamidobenzoic acid. These compounds block TASK-1 channels by binding to the central cavity. The most active compound is 3-benzoylamino-N-(2-ethyl-phenyl)-benzamide...
Two pore domain potassium channels (K2P) are strongly expressed in the nervous system (CNS), where they play a central role in excitability. These channels give rise to background K+ currents, also known as IKSO (standing-outward potassium current). We detected the expression in primary cultured cerebellar granule neurons (CGNs) of TWIK-1 (K2P1), T...
Potassium (K+) channels are highly regulated membrane proteins that control the potassium ion flux and respond to different cellular stimuli. These ion channels are grouped into three major families, Kv (voltage-gated K+ channel), Kir (inwardly rectifying K+ channel) and K2P (two-pore K+ channels), according to the structure, to mediate the K+ curr...
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blocka...
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that combined blockade...
The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited...
In this study, we reported for the first time the crystalline and molecular structure of the compound N-(naphthalen-1-yl) -2- (piperidin-1-yl) acetamide. The synthesis of the compound was carried out by amidation using a coupling reagent (N, N'-diisopropylcarbodiimide) and subsequently amination. The compound was experimentally characterized by UV-...
A large amount of human diseases have been linked to protein-protein interactions. One way of detecting such interactions is through mass-spectrometry assays; however, the post-processing of the resulting data is not a trivial task.There are currently limited options for computational tools that provide flexibility and transparency to manage and in...
TASK channels belong to the two-pore-domain potassium (K2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors...
Mass spectrometry-based proteomics methods are widely used to identify and quantify protein complexes involved in diverse biological processes. Specifically, tandem mass spectrometry methods represent an accurate and sensitive strategy for identifying protein-protein interactions. However, most of these approaches provide only lists of peptide frag...
Background and Purpose
Local anaesthetics block sodium and a variety of potassium channels. Although previous studies identified a residue in the pore signature sequence together with three residues in the S6 segment as a putative binding site, the precise molecular basis of inhibition of Kv channels by local anaesthetics remained unknown. Crystal...
Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, af...
Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1β is released by glial cells in regions associated with pain processing during ne...
Mutations in the CLCN5 gene encoding the 2Cl‐/1H⁺ exchanger ClC‐5 are associated with Dent disease 1, an inherited renal disorder characterized by low molecular weight (LMW) proteinuria and hypercalciuria. In the kidney, ClC‐5 is mostly localized in proximal tubule cells where it is thought to play a key role in the endocytosis of LMW proteins. Her...
HKT channels are a plant protein family involved in sodium (Na+) and potassium (K+) uptake and Na+-K+ homeostasis. Some HKTs underlie salt tolerance responses in plants, while others provide a mechanism to cope with short-term K+ shortage by allowing increased Na+ uptake under K+ starvation conditions. HKT channels present a functionally versatile...
Advances in different technological and scientific fields have led to the development of tools that allow the design of drugs in a rational way, using defined therapeutic targets, and through simulations that offer a molecular view of the ligand–receptor interactions, giving precise information for the design and synthesis of new compounds. Ion cha...
Geomfinder is a ligand-independent and alignment-free algorithm for estimating similarities between all pairs of 3D patterns detected in two given protein structures. It is based on the measurement of four energetic and structural features of 3D amino acid patterns. It is useful for protein clustering, drug repurposing, protein classification, and...
Withaferin A (WFA), a C5,C6-epoxy steroidal lactone isolated from the medicinal plant Withania somnifera (L.) Dunal, inhibits growth of tumor cells in different cancer types. However, the mechanisms underlying the effect of WFA on tumor cells are not fully understood. In the present study, we evaluated the blockade of TASK-3 channels by WFA in TASK...
Essential for calcium homeostasis, TRPV5 and TRPV6 are calcium-selective channels belonging to the transient receptor potential (TRP) gene family. In this study, we investigated the evolutionary history of these channels to add an evolutionary context to the already available physiological information. Phylogenetic analyses revealed that paralogs f...
Transient receptor potential melastatin 4 (TRPM4) is a Ca²⁺‐activated nonselective cationic channel that regulates cell migration and contractility. Increased TRPM4 expression has been related to pathologies, in which cytoskeletal rearrangement and cell migration are altered, such as metastatic cancer. Here, we identify the K⁺ channel tetramerizati...
Two-pore domain potassium (K2P) channels maintain the cell's background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P channels were crystallized in "up" and "down" states. The movements of the pore-lining transmembrane TM4 helix produce the aperture or c...
In recent years, green chemistry has been strengthening, showing how basic and applied sciences advance globally, protecting the environment and human health. A clear example of this evolution is the synergy that now exists between theoretical and computational methods to design new drugs in the most efficient possible way, using the minimum of rea...
Incidence and mortality of gastric cancer is increasing worldwide, in part, because of the lack of new therapeutic targets to treat this disease. Different types of ion channels participate in the hallmarks of cancer. In this context, ion channels are known to exert control over the cell cycle, mechanisms that support survival, angiogenesis, migrat...
This article comments on:
Villette J, Cuéllar T, Zimmermann SD, Verdeil JL, Gaillard I. 2019. Unique features of the grapevine VvK5.1 channel support novel functions for outward K+ channels in plants. Journal of Experimental Botany 70, 6181–6193.
TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several n...
Background
HKT channels mediate sodium uniport or sodium and potassium symport in plants. Monocotyledons express a higher number of HKT proteins than dicotyledons, and it is only within this clade of HKT channels that cation symport mechanisms are found. The prevailing ion composition in the extracellular medium affects the transport abilities of v...
Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are mod...
Finding new potential antagonists of potassium channels is a continuing task. TASK potassium channels operate over a large physiological range of membrane voltages, why they are thought to contribute to the excitability and resting potential of mammalian membrane potentials. Additionally, they are regulated by extracellular stimuli like changes in...
Transient receptor potential melastatin 4 (TRPM4) is a Ca²⁺‐activated nonselective cationic channel involved in a wide variety of physiologic and pathophysiological processes. Bioinformatics analyses of the primary sequence of TRPM4 allowed us to identify a putative motif for interaction with end‐binding (EB) proteins, which are microtubule plus‐en...
TASK-3 potassium (K+) channels are highly expressed in the central nervous system, regulating the membrane potential of excitable cells. TASK-3 is involved in neurotransmitter action and has been identified as an oncogenic K+ channel. For this reason, the understanding of the action mechanism of pharmacological modulators of these channels is essen...
Transient receptor potential vanilloid 1 (TRPV1) is a polymodal cation channel activated by heat, voltage, and ligands. Also known as the capsaicin receptor, TRPV1 is expressed in numerous tissues by different cell types, including peripheral sensory fibers where acts as a thermal and chemical detector in nociceptive pathways. TRPV1 channels are ab...
Fundamental for calcium homeostasis in vertebrates, TRPV5 and TRPV6 are calcium-selective ion channels belonging to the Transient Receptor Potential (TRP) gene family. Detailed phylogenetic analysis suggests that duplications from which TRPV5 and TRPV6 originated occurred independently in the ancestors of mammals, sauropsids, amphibians, and chondr...
Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medica...
A key to potassium channel activation
Using drugs to activate potassium channels has the potential to treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with a defined pharmacore that use a similar mechanism to activate many types of potassium channels. X-ray crystallogr...
Under normal conditions, connexin (Cx) hemichannels have a low open probability, which can increase under pathological conditions. Since hemichannels are permeable to relatively large molecules, their exacerbated activity has been linked to cell damage. Cx46 is highly expressed in the lens and its mutations have been associated to cataract formatio...
Most snake venom toxins are proteins, and participate to envenomation through a diverse array of bioactivities, such as bleeding, inflammation, and pain, cytotoxic, cardiotoxic or neurotoxic effects. The venom of a single snake species contains hundreds of toxins, and the venoms of the 725 species of venomous snakes represent a large pool of potent...
HKT channels mediate sodium uniport or sodium and potassium symport in plants. Monocotyledons express a higher number of HKT proteins than dicotyledons, and it is only within this clade of HKT channels that cation symport mechanisms are found. The prevailing ion composition in the extracellular medium affects the transport abilities of various HKT...
Plants from temperate climates, such as the model plant Arabidopsis thaliana, are challenged with seasonal low temperatures that lead to increased freezing tolerance in fall in a process termed cold acclimation. Among other adaptations, this involves the accumulation of cold-regulated (COR) proteins, such as the intrinsically disordered chloroplast...
During dental caries, the dental biofilm modifies the composition of the hundreds of involved bacterial species. Changing environmental conditions predisposes competition. A pertinent model to exemplify the complex interplay of the microorganisms in the human dental biofilm is the competition between Streptococcus sanguinis (S. sanguinis) and Strep...
Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human tissues and organs. CaV channels are divided into two group...
A1899 is a potent and selective inhibitor of the two-pore domain potassium (K2P) channel TASK-1. It was previously reported that A1899 acts as an open-channel blocker and binds to residues of the P1, P2 regions, the M2, M4 segments and the halothane response element. The recently described crystal structures of K2P channels together with the newly...
TRPV5 and TRPV6 are Ca2+ selective channels belonging to the family of Transient Receptor Potential (TRP) channels. TRPV5 and TRPV6 are viewed as the gatekeepers of epithelial calcium transport, being key elements in the regulation of the intracellular and systemic calcium homeostasis. It has been described that intracellular Ca2+ exerts a negative...
Review Process File
Commercial strawberry, Fragaria x ananassa Duch., is a species sensitive to salinity. Under saline conditions, Na(+) uptake by the plant is increased, while K(+) uptake is significantly reduced. Maintaining an adequate K(+)/Na(+) cytosolic ratio determines the ability of the plant to survive in saline environments. The goal of the present work was...
In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2P potassium channel TREK-1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1. In addition, mutant channels exhibit a hypersensitivity to stretch-activ...
Phospholipases A2 (PLA2s) constitute a class of extensively studied toxins, isolated from snake venoms. Basic PLA2 isoforms mediate various toxicological effects, while the acidic isoforms generally have higher enzymatic activities, but do not promote evident toxic effects. The functions of these acidic isoforms in snake venoms are still not comple...
Nitrogen is an essential macronutrient for plants and other living organisms. The main source of nitrogen for plants in agricultural soils is nitrate (NO3⁻). This ion is transported through specific nitrate transporters located in the plant cell plasma membrane. In addition to its role in metabolism, NO3⁻ can also act as a signal to regulate many b...
Control of cell volume and osmolarity is central to cellular homeostasis in all eukaryotes. It lies at the heart of the century-old problem of how plants regulate turgor, mineral and water transport. Plants use strongly electrogenic H+-ATPases, and the substantial membrane voltages they foster, to drive solute accumulation and generate turgor press...