Project description:Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.
Project description:Four end-functionalized star polymers that could attenuate the flow of ionic currents across biological ion channels were first de novo designed computationally, then synthesized and tested experimentally on mammalian K+ channels. The 4-arm ethylene glycol conjugate star polymers with lysine or a tripeptide attached to the end of each arm were specifically designed to mimic the action of scorpion toxins on K+ channels. Molecular dynamics simulations showed that the lysine side chain of the polymers physically occludes the pore of Kv1.3, a target for immuno-suppression therapy. Two of the compounds tested were potent inhibitors of Kv1.3. The dissociation constants of these two compounds were computed to be 0.1 ?M and 0.7 ?M, respectively, within 3-fold to the values derived from subsequent experiments. These results demonstrate the power of computational methods in molecular design and the potential of star polymers as a new infinitely modifiable platform for ion channel drug discovery.
Project description:Genomic profile of transporters and ion channels in differentiated or undifferentiated Caco-2 cells grown for 5 days, 1 week, 2 weeks or 3 weeks in flasks or filters Keywords: ordered
Project description:Pharmacological targeting of ion channels has long been recognized as an attractive strategy for the treatment of various diseases. Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system with a prominent neurodegenerative component. A multitude of different cell types are involved in the complex pathophysiology of this disorder, including cells of the immune system (e.g. T and B lymphocytes and microglia), the neurovascular unit (e.g. endothelial cells and astrocytes) and the central nervous system (e.g. astrocytes and neurons). The pleiotropic expression and function of ion channels gives rise to the attractive opportunity of targeting different players and pathophysiological aspects of MS by the modulation of ion channel function in a cell-type and context-specific manner. We discuss the emerging knowledge about ion channels in the context of autoimmune neuroinflammation. While some pharmacological targets are at the edge of clinical translation, others have only recently been discovered and are still under investigation. Special focus is given to those candidates that could be attractive novel targets for future therapeutic approaches in neuroimmune autoinflammation.
Project description:Pain is more than an unpleasant sensory experience associated with actual or potential tissue damage: it is the most common reason for physician consultation and often dramatically affects quality of life. The management of pain is often difficult and new targets are required for more effective and specific treatment. SuperPain (http://bioinformatics.charite.de/superpain/) is freely available database for pain-stimulating and pain-relieving compounds, which bind or potentially bind to ion channels that are involved in the transmission of pain signals to the central nervous system, such as TRPV1, TRPM8, TRPA1, TREK1, TRESK, hERG, ASIC, P2X and voltage-gated sodium channels. The database consists of ∼8700 ligands, which are characterized by experimentally measured binding affinities. Additionally, 100 000 putative ligands are included. Moreover, the database provides 3D structures of receptors and predicted ligand-binding poses. These binding poses and a structural classification scheme provide hints for the design of new analgesic compounds. A user-friendly graphical interface allows similarity searching, visualization of ligands docked into the receptor, etc.
Project description:Specific macromolecular transport systems, ion channels and pumps, provide the pathways to facilitate and control the passage of ions across the lipid membrane. Ion channels provide energetically favourable passage for ions to diffuse rapidly and passively according to their electrochemical potential. Selective ion channels are essential for the excitability of biological membranes: the action potential is a transient phenomenon that reflects the rapid opening and closing of voltage-dependent Na+-selective and K+-selective channels. One of the most critical functional aspects of K+ channels is their ability to remain highly selective for K+ over Na+ while allowing high-throughput ion conduction at a rate close to the diffusion limit. Permeation through the K+ channel selectivity filter is believed to proceed as a 'knockon' mechanism, in which 2-3 K+ ions interspersed by water molecules move in a single file. Permeation through the comparatively wider and less selective Na+ channels also proceeds via a loosely coupled knockon mechanism, although the ions do not need to be fully dehydrated. While simple structural concepts are often invoked to rationalize the mechanism of ion selectivity, a deeper analysis shows that subtle effects play an important role in these flexible dynamical structures.
Project description:The study of ion channels dates back to the 1950s and the groundbreaking electrophysiology work of Hodgin and Huxley, who used giant squid axons to probe how action potentials in neurons were initiated and propagated. More recently, several experiments using different structural biology techniques and approaches have been conducted to try to understand how potassium ions permeate through the selectivity filter of potassium ion channels. Two mechanisms of permeation have been proposed, and each of the two mechanisms is supported by different experiments. The key structural biology experiments conducted so far to try to understand how ion permeation takes place in potassium ion channels are reviewed and discussed. Protein crystallography has made, and continues to make, key contributions in this field, often through the use of anomalous scattering. Other structural biology techniques used to study the contents of the selectivity filter include solid-state nuclear magnetic resonance and two-dimensional infrared spectroscopy, both of which make clever use of isotopic labeling techniques, while molecular-dynamics simulations of ion flow through the selectivity filter have been enabled by the growing number of potassium ion channel structures deposited in the Protein Data Bank.
Project description:Migraine is one of the most common neurological disorders. Despite its prevalence, the basic physiology of the molecules and mechanisms that contribute to migraine headache is still poorly understood, making the discovery of more effective treatments extremely difficult. The consistent presence of head-specific pain during migraine suggests an important role for activation of the peripheral nociceptors localized to the head. Accordingly, this review will cover the current understanding of the biological mechanisms leading to episodic activation and sensitization of the trigeminovascular pain pathway, focusing on recent advances regarding activation and modulation of ion channels.
Project description:Phosphoinositides serve as signature motifs for different cellular membranes and often are required for the function of membrane proteins. Here, we summarize clear evidence supporting the concept that many ion channels are regulated by membrane phosphoinositides. We describe tools used to test their dependence on phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate, and consider mechanisms and biological meanings of phosphoinositide regulation of ion channels. This lipid regulation can underlie changes of channel activity and electrical excitability in response to receptors. Since different intracellular membranes have different lipid compositions, the activity of ion channels still in transit towards their final destination membrane may be suppressed until they reach an optimal lipid environment. This article is part of a Special Issue entitled Phosphoinositides.
Project description:We describe the incorporation of gated ion channels into probes for scanning ion conductance microscopy (SICM) as a robust platform for collecting spatial information at interfaces. Specifically, a dual-barrel pipet is used, where one barrel controls the pipet position and the second barrel houses voltage-gated transient receptor potential vanilloid 1 (TRPV1) channels excised in a sniffer-patch configuration. Spatially resolved sensing with TRPV1 channels is demonstrated by imaging a porous membrane where a transmembrane potential across the membrane generates local electric field gradients at pores that activate TRPV1 channels when the probe is in the vicinity of the pore. The scanning routine and automated signal analysis demonstrated provide a generalizable approach to employing gated ion channels as sensors for imaging applications.