Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Natural products and ion channel pharmacology.

ABSTRACT: An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an interdisciplinary initiative is required that combines chemical ecology and ion channel physiology. A prime source of future drug leads targeted to ion channels is the vast assortment of compounds that mediate biotic interactions in the marine environment. Many animals have evolved a chemical strategy to change the behavior of their prey, predators or competitors, which appears to require a large set of ion channel-targeted compounds acting in concert. Some of these compounds (e.g., ziconotide [Prialt(®)]) have already found important biomedical applications. The elucidation of molecular mechanisms mediating biotic interactions should yield a rich stream of potent and selective natural products for the drug pipeline.

SUBMITTER: Teichert RW

PROVIDER: S-EPMC4153603 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Natural products and ion channel pharmacology.

Teichert Russell W RW Olivera Baldomero M BM

Future medicinal chemistry 20100501 5

An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an interdisciplinary initiative is required that combines chemical ecology and ion channel physiology. A prime source of future drug leads targeted to ion channels is the vast assortment of compounds that mediate biotic interactions in the marine environment. Many animals have evolved a chemical strategy to change the behavior of thei ...[more]

PMID: 21426200

Similar Datasets

TRPV3 Ion Channel: From Gene to Pharmacology.

Project description:Transient receptor potential vanilloid subtype 3 (TRPV3) is an ion channel with a sensory function that is most abundantly expressed in keratinocytes and peripheral neurons. TRPV3 plays a role in Ca2+ homeostasis due to non-selective ionic conductivity and participates in signaling pathways associated with itch, dermatitis, hair growth, and skin regeneration. TRPV3 is a marker of pathological dysfunctions, and its expression is increased in conditions of injury and inflammation. There are also pathogenic mutant forms of the channel associated with genetic diseases. TRPV3 is considered as a potential therapeutic target of pain and itch, but there is a rather limited range of natural and synthetic ligands for this channel, most of which do not have high affinity and selectivity. In this review, we discuss the progress in the understanding of the evolution, structure, and pharmacology of TRPV3 in the context of the channel's function in normal and pathological states.

| S-EPMC10218142 | biostudies-literature

Natural products modulating the hERG channel: heartaches and hope.

Project description:Covering: 1996-December 2016The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity. Moreover, as a result of its notorious ligand promiscuity, this ion channel has emerged as an important antitarget in early drug discovery and development. Surprisingly, the hERG channel blocking profile of natural compounds present in frequently consumed botanicals (i.e. dietary supplements, spices, and herbal medicinal products) is not routinely assessed. This comprehensive review will address these issues and provide a critical compilation of hERG channel data for isolated natural products and extracts over the past two decades (1996-2016). In addition, the review will provide (i) a solid basis for the molecular understanding of the physiological functions of the hERG channel, (ii) the translational potential of in vitro/in vivo results to cardiotoxicity in humans, (iii) approaches for the identification of hERG channel blockers from natural sources, (iv) future perspectives for cardiac safety guidelines and their applications within phytopharmaceuticals and dietary supplements, and (v) novel applications of hERG channel modulation (e.g. as a drug target).

| S-EPMC5708533 | biostudies-literature

Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology.

Project description:Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology.

| S-EPMC7271128 | biostudies-literature

Use of natural products as chemical library for drug discovery and network pharmacology.

Project description:BackgroundNatural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products.MethodologyWe collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model.ConclusionsAnalysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins.

| S-EPMC3636197 | biostudies-literature

CALHM6 is an immunological synapse ion channel required for macrophage-natural killer cell communication upon bacterial infection

Project description:Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell-cell crosstalk at synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to induction of natural killer (NK) cell anti-tumour activity. Its mechanism of action and broader functions in the immune system are, however, unclear. Here we generated Calhm6-/- mice and report that CALHM6 is important for regulating the early innate control of Listeria monocytogenes infection in vivo. We find that CALHM6 is upregulated in macrophages by pathogen-derived signals, and that it relocates from intracellular compartment to the macrophage-NK cell synapse, facilitating ATP release and controlling the kinetics of NK cell activation. Anti-inflammatory cytokines terminate CALHM6 expression. CALHM6 forms an ion channel when expressed in the plasma membrane of Xenopus oocytes, where channel opening is controlled by a conserved acidic residue, E119, but CALHM6 is localized to intracellular compartments in mammalian cells. Our results contribute to understanding of neurotransmitter-like signal exchange between immune cells that fine-tunes the timing of innate immune responses.

2023-02-01 | GSE223008 | GEO

Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes.

Project description:Massive cancer genomics data have facilitated the rapid revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology. Natural products with polypharmacological profiles have been demonstrated as promising agents for the development of novel cancer therapies. In this study, we developed an integrated systems pharmacology framework that facilitated identifying potential natural products that target mutated genes across 15 cancer types or subtypes in the realm of precision medicine. High performance was achieved for our systems pharmacology framework. In case studies, we computationally identified novel anticancer indications for several US Food and Drug Administration-approved or clinically investigational natural products (e.g., resveratrol, quercetin, genistein, and fisetin) through targeting significantly mutated genes in multiple cancer types. In summary, this study provides a powerful tool for the development of molecularly targeted cancer therapies through targeting the clinically actionable alterations by exploiting the systems pharmacology of natural products.

| S-EPMC5356618 | biostudies-literature

Domain-domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel.

Project description: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 (Barhanin et al., 1996; Sanguinetti et al., 1996), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (Wrobel et al., 2012; Sun et al., 2012; Abbott, 2014). These changes are essential for the physiological role of IKs (Silva and Rudy, 2005); 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.

| S-EPMC4381907 | biostudies-literature

Subtype-selective inhibition of acid-sensing ion channel 3 by a natural flavonoid.

Project description:AIMS:Acid-sensing ion channels (ASICs) are extracellular proton-gated cation channels that have been implicated in multiple physiological and pathological processes, and peripheral ASIC3 prominently participate into the pathogenesis of chronic pain, itch, and neuroinflammation, which necessitates the need for discovery and development of novel modulators in a subtype-specific manner. METHODS:Whole-cell patch clamp recordings and behavioral assays were used to examine the effect of several natural compounds on the ASIC-mediated currents and acid-induced nocifensive behavior, respectively. RESULTS:We identified a natural flavonoid compound, (-)-epigallocatechin gallate (EGCG, compound 11), that acts as a potent inhibitor for the ASIC3 channel in an isoform-specific way. The compound 11 inhibited ASIC3 currents with an apparent half maximal inhibitory concentration of 13.2 ?mol/L when measured at pH 5.0. However, at the concentration up to 100 ?mol/L, the compound 11 had no significant impacts on the homomeric ASIC1a, 1b, and 2a channels. In contrast to most of the known ASIC inhibitors that usually bear either basic or carboxylic groups, the compound 11 belongs to the polyphenolic family. In compound 11, both the chirality and the 3-hydroxyl group of its pyrogallol part, in addition to the integrity of the gallate part, are crucial for the inhibitory efficacy. Finally, EGCG was found significantly to decrease the acid-induced nocifensive behavior in mice. CONCLUSION:Taken together, these results thus defined a novel backbone structure for small molecule drug design targeting ASIC3 channels to treat pain-related diseases.

| S-EPMC6436595 | biostudies-literature

Gene Expression In Drosophila Hearts Harboring Ion Channel Mutations

Project description:Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations Sei and KCNQ mutants were compared to their control lines, Canton S-CS and KCNQ370

2017-04-01 | GSE94589 | GEO

International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family.

Project description:Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca(2+) and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels.

| S-EPMC2964900 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data