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Ligand-gated Ion Channels (ligand-gated + ion_channel)
Selected AbstractsIon-dependent gating of kainate receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 1 2010Derek Bowie Ligand-gated ion channels are an important class of signalling protein that depend on small chemical neurotransmitters such as acetylcholine, l -glutamate, glycine and ,-aminobutyrate for activation. Although numerous in number, neurotransmitter substances have always been thought to drive the receptor complex into the open state in much the same way and not rely substantially on other factors. However, recent work on kainate-type (KAR) ionotropic glutamate receptors (iGluRs) has identified an exception to this rule. Here, the activation process fails to occur unless external monovalent anions and cations are present. This absolute requirement of ions singles out KARs from all other ligand-gated ion channels, including closely related AMPA- and NMDA-type iGluR family members. The uniqueness of ion-dependent gating has earmarked this feature of KARs as a putative target for the development of selective ligands; a prospect all the more compelling with the recent elucidation of distinct anion and cation binding pockets. Despite these advances, much remains to be resolved. For example, it is still not clear how ion effects on KARs impacts glutamatergic transmission. I conclude by speculating that further analysis of ion-dependent gating may provide clues into how functionally diverse iGluRs families emerged by evolution. Consequently, ion-dependent gating of KARs looks set to continue to be a subject of topical inquiry well into the future. [source] Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1AGING CELL, Issue 3 2009Sang-Kyu Park Summary Oxidative stress has been hypothesized to play a role in normal aging. The response to oxidative stress is regulated by the SKN-1 transcription factor, which also is necessary for intestinal development in Caenorhabditis elegans. Almost a thousand genes including the antioxidant and heat-shock responses, as well as genes responsible for xenobiotic detoxification were induced by the oxidative stress which was found using transcriptome analysis. There were also 392 down-regulated genes including many involved in metabolic homeostasis, organismal development, and reproduction. Many of these oxidative stress-induced transcriptional changes are dependent on SKN-1 action; the induction of the heat-shock response is not. When RNAi to inhibit genes was used, most had no effect on either resistance to oxidative stress or longevity; however two SKN-1-dependent genes, nlp-7 and cup-4, that were up-regulated by oxidative stress were found to be required for resistance to oxidative stress and for normal lifespan. nlp-7 encodes a neuropeptide-like protein, expressed in neurons, while cup-4 encodes a coelomocyte-specific, ligand-gated ion channel. RNAi of nlp-7 or cup-4 increased sensitivity to oxidative stress and reduced lifespan. Among down-regulated genes, only inhibition of ent-1, a nucleoside transporter, led to increased resistance to oxidative stress; inhibition had no effect on lifespan. In contrast, RNAi of nhx-2, a Na+/H+ exchanger, extended lifespan significantly without affecting sensitivity to oxidative stress. These findings showed that a transcriptional shift from growth and maintenance towards the activation of cellular defense mechanisms was caused by the oxidative stress; many of these transcriptional alterations are SKN-1 dependent. [source] Existence and distinction of acid-evoked currents in rat astrocytesGLIA, Issue 12 2010Chao Huang Abstract Astrocytes are vital structures that support and/or protect neighboring neurons from pathology. Although it is generally accepted that glutamate receptors mediate most astrocyte effects, acid-evoked currents have recently attracted attention for their role in this regard. Here, we identified the existence and characteristics of acid-sensing ion channels (ASICs) and the transient receptor potential vanilloid type 1 (TRPV1) in astrocytes. There were two types of currents recorded under the application of acidic solution (pH 6.0) in cultured rat astrocytes. Transient currents were exhibited by 10% of the astrocytes, and sustained currents were exhibited by the other 90%, consistent with the features of ASIC and TRPV1 currents, respectively. Western blotting and immunofluorescence confirmed the expression of ASIC1, ASIC2a, ASIC3, and TRPV1 in cultured and in situ astrocytes. Unlike the ASICs expressed in neurons, which were mainly distributed in the cell membrane/cytoplasm, most of the ASICs in astrocytes were expressed in the nucleus. TRPV1 was more permeable to Na+ in cultured astrocytes, which differed from the typical neuronal TRPV1 that was mainly permeable to Ca2+. This study demonstrates that there are two kinds of acid-evoked currents in rat astrocytes, which may provide a new understanding about the functions of ligand-gated ion channels in astrocytes. © 2010 Wiley-Liss, Inc. [source] Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: focus on ligand-gated channelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2008Liping Huang Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)A receptor channel (apparent IC50 = 0.040 ± 0.001 mg mL,1), but had no effect on N -methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01,1 mg mL,1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABAA antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported. [source] Pharmacological profile of an essential oil derived from Melissa officinalis with anti-agitation properties: focus on ligand-gated channelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2008Sawsan Abuhamdah A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t -butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)A receptor channel (apparent IC50 0.040±0.001 mg mL,1), but had no effect on N -methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01,1 mg mL,1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABAA antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. [source] Ethanol Potentiation of Glycine Receptors Expressed in Xenopus Oocytes Antagonized by Increased Atmospheric PressureALCOHOLISM, Issue 5 2003Daryl L. Davies Background: Behavioral and biochemical studies indicate that exposure to 12 times normal atmospheric pressure (12 ATA) of helium-oxygen gas (heliox) is a direct, selective ethanol antagonist. The current study begins to test the hypothesis that ethanol acts by a common mechanism on ligand-gated ion channels by expanding previous hyperbaric investigations on ,-aminobutyric acid type A (GABAA) receptors (GABAARs) at the biochemical level to ,1glycine (GlyRs) expressed in Xenopus oocytes. Methods: Oocytes expressing wild-type ,1 homomeric GlyRs were voltage-clamped (,70 mV) and tested in the presence of glycine (EC2) ± ethanol (50,200 mM) under 1 ATA control and 3 to 12 ATA heliox conditions. Glycine concentration response curves, strychnine/glycine interactions, and zinc (Zn2+) modulation of GlyR function was also tested. Results: Pressure reversibly antagonized the action of ethanol. The degree of antagonism increased as pressure increased. Pressure did not significantly alter the effects of glycine, strychnine, or Zn2+, indicating that ethanol antagonism by pressure cannot be attributed to alterations by pressure of normal GlyR function. The antagonism did not reflect tolerance to ethanol, receptor desensitization, or receptor rundown. Conclusion: This is the first use of hyperbarics to investigate the mechanism of action of ethanol in recombinant receptors. The findings indicate that pressure directly and selectively antagonizes ethanol potentiation of ,1GlyR function in a reversible and concentration- and pressure-dependent manner. The sensitivity of ethanol potentiation of GlyR function to pressure antagonism indicates that ethanol acts by a common, pressure-antagonism,sensitive mechanism in GlyRs and GABAARs. The findings also support the hypothesis that ethanol potentiation of GlyR function plays a role in mediating the sedative-hypnotic effects of ethanol. [source] Ion-dependent gating of kainate receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 1 2010Derek Bowie Ligand-gated ion channels are an important class of signalling protein that depend on small chemical neurotransmitters such as acetylcholine, l -glutamate, glycine and ,-aminobutyrate for activation. Although numerous in number, neurotransmitter substances have always been thought to drive the receptor complex into the open state in much the same way and not rely substantially on other factors. However, recent work on kainate-type (KAR) ionotropic glutamate receptors (iGluRs) has identified an exception to this rule. Here, the activation process fails to occur unless external monovalent anions and cations are present. This absolute requirement of ions singles out KARs from all other ligand-gated ion channels, including closely related AMPA- and NMDA-type iGluR family members. The uniqueness of ion-dependent gating has earmarked this feature of KARs as a putative target for the development of selective ligands; a prospect all the more compelling with the recent elucidation of distinct anion and cation binding pockets. Despite these advances, much remains to be resolved. For example, it is still not clear how ion effects on KARs impacts glutamatergic transmission. I conclude by speculating that further analysis of ion-dependent gating may provide clues into how functionally diverse iGluRs families emerged by evolution. Consequently, ion-dependent gating of KARs looks set to continue to be a subject of topical inquiry well into the future. [source] Guide to Receptors and Channels (GRAC)BRITISH JOURNAL OF PHARMACOLOGY, Issue 2009British Journal of Clinical Pharmacology The fourth edition of the Guide to Receptors and Channels is a compilation of the major pharmacological targets divided into seven sections: 7-transmembrane receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside suggestions for further reading. [source] ILLUMINATING THE STRUCTURE AND FUNCTION OF CYS-LOOP RECEPTORSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2008Stephan A Pless SUMMARY 1Cys-loop receptors are an important class of ligand-gated ion channels. They mediate fast synaptic neurotransmission, are implicated in various ,channelopathies' and are important pharmacological targets. Recent progress in X-ray crystallography and electron microscopy has provided a considerable insight into the structure of Cys-loop receptors. However, data from these experiments only provide ,snapshots' of the proteins under investigation. They cannot provide information about the various conformations the protein adopts during transition from the closed to the open and desensitized states. 2Voltage-clamp fluorometry helps overcome this problem by simultaneously monitoring movements at the channel gate (through changes in current) and conformational rearrangements in a domain of interest (through changes in fluorescence) in real time. Thus, the technique can provide information on both transitional and steady state conformations and serves as a real time correlate of the channel structure and its function. 3Voltage-clamp fluorometry experiments on Cys-loop receptors have yielded a large body of data concerning the mechanisms by which agonists, antagonists and modulators act on these receptors. They have shed new light on the conformational mobility of both the ligand-binding and the transmembrane domain of Cys-loop receptors. [source] | |||||||||||||