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1.
A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (KA) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channel''s steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the KA channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of KA channels, and the resting potential can be an effective treatment of epilepsy. 相似文献
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3.
The γ-aminobutyric acid A (GABAA) ion channels are important drug targets for treatment of neurological and psychiatric disorders. Finding GABAA channel subtype selective allosteric modulators could lead to new improved treatments. However, the progress in this area has been obstructed by the challenging task of developing functional assays to support screening efforts and the generation of cells expressing functional GABAA ion channels with the desired subtype composition. To address these challenges, we developed a yellow fluorescent protein (YFP)-based assay to be able to study allosteric modulation of the GABAA ion channel using cryopreserved, transiently transfected, assay-ready cells. We show for the first time how the MaxCyte STX electroporation instrument can be used to generate CHO-K1 cells expressing functional GABAA α2β3γ2 along with a halide sensing YFP-H148Q/I152L (YFP-GABAA2 cells). As a basis for a cell-based assay capable of detecting allosteric modulators, experiments with antagonist, ion channel blocker and modulators were used to verify GABAA subunit composition and functionality. We found that the I− concentration used in the YFP assay affected both basal quench of YFP and potency of GABA. For the first time the assay was used to study modulation of GABA with 7 known modulators where statistical analysis showed that the assay can distinguish modulatory pEC50 differences of 0.15. In conclusion, the YFP assay proved to be a robust, reproducible and inexpensive assay. These data provide evidence that the assay is suitable for high throughput screening (HTS) and could be used to discover novel modulators acting on GABAA ion channels. 相似文献
4.
Palle Christophersen 《Channels (Austin, Tex.)》2015,9(6):336-343
This short review discusses pharmacological modulation of the opening/closing properties (gating) of small- and intermediate-conductance Ca2+-activated K+ channels (KCa2 and KCa3.1) with special focus on mechanisms-of-action, selectivity, binding sites, and therapeutic potentials. Despite KCa channel gating-modulation being a relatively novel field in drug discovery, efforts in this area have already revealed a surprising plethora of pharmacological sites-of-actions and channel subtype selectivity exerted by different chemical classes. The currently published positive modulators show that such molecules are potentially useful for the treatment of various neurodegenerative disorders such as ataxia, alcohol dependence, and epilepsy as well as hypertension. The negative KCa2 modulators are very effective agents for atrial fibrillation. The prediction is that further unraveling of the molecular details of gating pharmacology will allow for the design of even more potent and subtype selective KCa modulators entering into drug development for these indications. 相似文献
5.
Pamenter ME Buck LT 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2008,150(4):410-414
Neuronal membrane potential (Em) regulates the activity of excitatory voltage-sensitive channels. Anoxic insults lead to a severe loss of Em and excitotoxic cell death (ECD) in mammalian neurons. Conversely, anoxia-tolerant freshwater turtle neurons depress energy usage during anoxia by altering ionic conductance to reduce neuronal excitability and ECD is avoided. This wholesale alteration of ion channel and pump activity likely has a significant effect on Em. Using the whole-cell patch clamp technique we recorded changes in Em from turtle cortical neurons during a normoxic to anoxic transition in the presence of various ion channel/pump modulators. Em did not change with normoxic perfusion but underwent a reversible, mild depolarization of 8.1 ± 0.2 mV following anoxic perfusion. This mild anoxic depolarization (MAD) was not prevented by the manipulation of any single ionic conductance, but was partially reduced by pre-treatment with antagonists of GABAA receptors (5.7 ± 0.5 mV), cellular bicarbonate production (5.3 ± 0.2 mV) or K+ channels (6.0 ± 0.2 mV), or by perfusion of reactive oxygen species scavengers (5.2 ± 0.3 mV). Furthermore, all of these treatments induced depolarization in normoxic neurons. Together these data suggest that the MAD may be due to the summation of numerous altered ion conductance states during anoxia. 相似文献
6.
Pei-Chun Chen Yelena N. Kryukova Show-Ling Shyng 《The Journal of biological chemistry》2013,288(47):34098-34109
Pancreatic β-cells secrete insulin in response to metabolic and hormonal signals to maintain glucose homeostasis. Insulin secretion is under the control of ATP-sensitive potassium (KATP) channels that play key roles in setting β-cell membrane potential. Leptin, a hormone secreted by adipocytes, inhibits insulin secretion by increasing KATP channel conductance in β-cells. We investigated the mechanism by which leptin increases KATP channel conductance. We show that leptin causes a transient increase in surface expression of KATP channels without affecting channel gating properties. This increase results primarily from increased channel trafficking to the plasma membrane rather than reduced endocytosis of surface channels. The effect of leptin on KATP channels is dependent on the protein kinases AMP-activated protein kinase (AMPK) and PKA. Activation of AMPK or PKA mimics and inhibition of AMPK or PKA abrogates the effect of leptin. Leptin activates AMPK directly by increasing AMPK phosphorylation at threonine 172. Activation of PKA leads to increased channel surface expression even in the presence of AMPK inhibitors, suggesting AMPK lies upstream of PKA in the leptin signaling pathway. Leptin signaling also leads to F-actin depolymerization. Stabilization of F-actin pharmacologically occludes, whereas destabilization of F-actin simulates, the effect of leptin on KATP channel trafficking, indicating that leptin-induced actin reorganization underlies enhanced channel trafficking to the plasma membrane. Our study uncovers the signaling and cellular mechanism by which leptin regulates KATP channel trafficking to modulate β-cell function and insulin secretion. 相似文献
7.
Spontaneous, single channel, chloride currents were recorded in 48% of cell-attached patches on neurones in the CA1 region
of rat hippocampal slices. In some patches, there was more than 1 channel active. They showed outward rectification: both
channel conductance and open probability were greater at depolarized than at hyperpolarized potentials. Channels activated
by γ-aminobutyric acid (GABA) in silent patches on the same neurones had similar conductance and outward rectification. The
spontaneous currents were inhibited by bicuculline and potentiated by diazepam. It was concluded that the spontaneously opening
channels were constitutively active, nonsynaptic GABAA channels. Such spontaneously opening GABAA channels may provide a tonic inhibitory mechanism in these cells and perhaps in other cells that have GABAA receptors although not having a GABAA synaptic input. They may also be a target for clinically useful drugs such as the benzodiazepines.
Received: 31 August 1999/Revised: 2 November 1999 相似文献
8.
Maria Grazia Zizzo Alessandra Bonomo Natale Belluardo Flavia Mulè Rosa Serio 《Life sciences》2009,84(21-22):772-778
AimsWe investigated the effects induced by exogenous adenosine on the spontaneous contractile activity of the longitudinal muscle of a mouse ileum, the receptor subtypes activated, the involvement of enteric nerves and whether opening of K+ channels was a downstream event leading to the observed effects.Main methodsMechanical responses of the mouse ileal longitudinal muscle to adenosine were examined in vitro as changes in isometric tension.Key findingsAdenosine caused a concentration-dependent reduction of the spontaneous contraction amplitude of the ileal longitudinal muscle up to its complete disappearance. This effect induced was markedly reduced by an A1 receptor antagonist, but not by A2 and A3 receptor antagonists and mimicked only by the A1 receptor agonist. Adenosine uptake inhibitors did not change adenosine potency. A1 receptor expression was detected at the smooth muscle level. Adenosine responses were insensitive to tetrodotoxin, atropine or nitric oxide synthase inhibitor. Tetraethylammonium and iberiotoxin, BKCa channel blockers, significantly reduced adenosine effects, whilst 4-aminopyridine, a Kv blocker, apamin, a small conductance Ca2+-activated K+ (SKCa) channel blocker, charybdotoxin, an intermediate conductance Ca2+-activated K+ (IKCa) and BKCa channel blocker, or glibenclamide, an ATP-sensitive K+ channel blocker, had no effects. The combination of apamin plus iberiotoxin caused a reduction of the purinergic effects greater than iberiotoxin alone.SignificanceAdenosine acts as an inhibitory modulator of the contractility of mouse ileal longitudinal muscle through postjunctional A1 receptors, which in turn would induce opening of BKCa and SKCa potassium channels. This study would provide new insight in the pharmacology of purinergic receptors involved in the modulation of the gastrointestinal contractility. 相似文献
9.
Electrokinetic measurements, of streaming potential, were carried out on an excised inside-out patch of the vacuolar membrane of Chara corallina. A water activity gradient was imposed across the patch membrane containing a single K+ channel by addition of sorbitol to one side. Two different K+ channels were found in the tonoplast. Their open channel conductance was investigated as a function of KCl concentration. They had a maximal open channel conductance of 247 and 173 pS, and an apparent affinity (KM) of 116 and 92 mM, respectively. Single-channel zero-current potentials were determined in the presence of an osmotic gradient, and dilution artifacts were corrected for by addition of valinomycin to the bath. Our results suggest that 29 water molecules were coupled to the transport of one K+ ion in the large conductance K+ channel which has a pore radius of ~1.5 nm. 相似文献
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11.
Jeremy D. Bushman Joel W. Gay Paul Tewson Charles A. Stanley Show-Ling Shyng 《The Journal of biological chemistry》2010,285(9):6012-6023
The inwardly rectifying potassium channel Kir6.2 assembles with sulfonylurea receptor 1 to form the ATP-sensitive potassium (KATP) channels that regulate insulin secretion in pancreatic β-cells. Mutations in KATP channels underlie insulin secretion disease. Here, we report the characterization of a heterozygous missense Kir6.2 mutation, G156R, identified in congenital hyperinsulinism. Homomeric mutant channels reconstituted in COS cells show similar surface expression as wild-type channels but fail to conduct potassium currents. The mutated glycine is in the pore-lining transmembrane helix of Kir6.2; an equivalent glycine in other potassium channels has been proposed to serve as a hinge to allow helix bending during gating. We found that mutation of an adjacent asparagine, Asn-160, to aspartate, which converts the channel from a weak to a strong inward rectifier, on the G156R background restored ion conduction in the mutant channel. Unlike N160D channels, however, G156R/N160D channels are not blocked by intracellular polyamines at positive membrane potential and exhibit wild-type-like nucleotide sensitivities, suggesting the aspartate introduced at position 160 interacts with arginine at 156 to restore ion conduction and gating. Using tandem Kir6.2 tetramers containing G156R and/or N160D in designated positions, we show that one mutant subunit in the tetramer is insufficient to abolish conductance and that G156R and N160D can interact in the same or adjacent subunits to restore conduction. We conclude that the glycine at 156 is not essential for KATP channel gating and that the Kir6.2 gating defect caused by the G156R mutation could be rescued by manipulating chemical interactions between pore residues. 相似文献
12.
Summary Intact adrenal chromaffin granules and purified granule membrane ghosts were allowed to fuse with acidic phospholipid planar bilayer membranes in the presence of Ca2+ (1 mm). From both preparations, we were able to detect a large conductance potassium channel (ca. 160 pS in symmetrical 400 mm K+), which was highly selective for K+ over Na+ (P
k/P
Na = 11) as estimated from the reversal potential of the channel current. Channel activity was unaffected by charybdotoxin, a blocker of the [Ca2+] activated K+ channel of large conductance. Furthermore, this channel proved quite different from the previously described channels from other types of secretory vesicle preparations, not only in its selectivity and conductance, but also in its insensitivity to both calcium and potential across the bilayer. We conclude that the chromaffin granule membrane contains a K+-selective channel with large conductance. We suggest that the role of this channel may include ion movement during granule assembly or recycling, and do not rule out events leading to exocytosis. 相似文献
13.
GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABAA-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABAA receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABAA-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABAA-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABAA reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K+ transients can augment GABAA-mediated excitation, but not cause it. Our model also suggests the potential for GABAA-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition. 相似文献
14.
Internal perfusion of tetraethylammonium ions (TEA) in squid axons produces a significant high frequency noise component. Although internal TEA suppresses the potassium conductance (G
K) noise at relatively low frequencies, it induces high frequency noise which exceeds the intensity of the normal potassium and sodium noise. In addition, the induced noise is dependent on the presence of internal potassium ions (K+) suggesting that this source of noise arises from a modulation of the K+ conductance due to the blocking and unblocking of the K+ channel. The simplest model describing the TEA data is a two-step sequential pseudo-unimolecular reaction where TEA binds during an open conductance state. A unit channel conductance of 2 pS is estimated from the TEA data as well as noise induced by triethyldecylammonium (TEDA) ions. Thus, these data are consistent with the hypothesis that the channel is blocked whenever the quaternary ammonium ion binding site, located near or within the K+ channel, is occupied. 相似文献
15.
Ann Swijsen Bert Brône Jean‐Michel Rigo Govert Hoogland 《Developmental neurobiology》2012,72(12):1516-1527
Febrile seizures (FS) are the most common type of seizures in childhood and are suggested to play a role in the development of temporal lobe epilepsy (TLE). Animal studies demonstrated that experimental FS induce a long‐lasting change in hippocampal excitability, resulting in enhanced seizure susceptibility. Hippocampal neurogenesis and altered ion channel expression have both been proposed as mechanisms underlying this decreased seizure threshold. The present study aimed to analyze whether dentate gyrus (DG) cells that were born after FS and matured for 8 weeks display an altered repertoire of ligand‐gated ion channels. To this end, we applied an established model, in which FS are elicited in 10‐day‐old rat pups by hyperthermia (HT). Normothermia littermates served as controls. From postnatal day 11 (P11) to P16, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells immediately following FS. At P66, we evaluated BrdU‐labeled DG cells for coexpression with γ‐aminobutyric acid‐type A receptors (GABAARs) and N‐methyl‐D ‐aspartate receptors (NMDARs). In control animals, 40% of BrdU‐labeled cells coexpressed GABAAR β2/3, whereas in rats that had experienced FS, 60% of BrdU‐labeled cells also expressed GABAAR β2/3. The number of BrdU‐NMDAR NR2A/B coexpressing cells was in both groups about 80% of BrdU‐labeled cells. The results demonstrate that developmental seizures cause a long‐term increase in GABAAR β2/3 expression in newborn DG cells. This may affect hippocampal physiology. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012 相似文献
16.
《Molecular membrane biology》2013,30(3):239-253
Notexin belongs to a class of snake venom neurotoxins and myotoxins that have phospholipase A2 activity. Previous studies have shown that these toxins affect target cells differently from phospholipases that are not neurotoxic or myotoxic. Notexin inhibited the Ca2+ uptake into fragmented sarcoplasmic reticulum from rabbit skeletal muscle, but it did not cause an efflux of previously accumulated Ca2+ or inhibit the Ca2+–ATPase activity. It is suggested that notexin specifically binds to and decreases the conductance for Ca2+ of the Ca2+ pump and/or the conductance of a channel for an ion that facilitates Ca2+ transport. The K+ ionophore valinomycin reversed the notexin-induced inhibition of Ca2+ uptake into sarcoplasmic reticulum, suggesting that the molecular target of notexin could be a K+ channel. Two types of reconstitution experiments make it unlikely that notexin acts by degrading a minor lipid that is resistant to hydrolysis by nontoxic phospholipases A2. Notexininactivated sarcoplasmic reticulum vesicles were reactivated (with respect to Ca2+ uptake) by simple solubilization with detergent and subsequent reconstitution by detergent removal. Second, notexin was still active on sarcoplasmic reticulum vesicles after >94% of the lipids were replaced by soybean phosphoglycerides during the reconstitution procedure. 相似文献
17.
Summary Delayed potassium channels were studied in internally perfused neurone somata from land snails. Relaxation and fluctuation analysis of this class of ion channels revealed Hodgkin-Huxley type K channels with an average single channel conductance (
K) of 2.40±0.15 pS. The conductance of open channels is independent of voltage and virtually all K channels seem to be open at maximum K conductance (g
K) of the membrane. Voltage dependent time constants of activation ofg
K, calculated from K current relaxation and from cut-off frequencies of power spectra, are very similar indicating dominant first-order kinetics. Ion selectivity of K channels was studied by ion substitution in the external medium and exhibited the following sequence: T1+>K+>Rb+>Cs+>NH
4
+
>Li+>Na+. The sequence of the alkali cations does not conform to any of the sequences predicted by Eisenman's theory. However, the data are well accommodated by a new theory assuming a single rate-limiting barrier that governs ion movement through the channel.This paper is dedicated to the memory of Walther Wilbrandt. 相似文献
18.
Sérgio José Macedo-Junior Francisney Pinto Nascimento Murilo Luiz-Cerutti Adair Roberto Soares Santos 《Purinergic signalling》2013,9(1):51-58
Inosine is the first metabolite of adenosine. It exerts an antinociceptive effect by activating the adenosine A1 and A2A receptors. We have previously demonstrated that inosine exhibits antinociceptive properties in acute and chronic mice models of nociception. The aim of this study was to investigate the involvement of pertussis toxin-sensitive G-protein-coupled receptors, as well as K+ and Ca2+ channels, in the antinociception promoted by inosine in the formalin test. Mice were pretreated with pertussis toxin (2.5 μg/site, i.t., an inactivator of Gi/0 protein); after 7 days, they received inosine (10 mg/kg, i.p.) or morphine (2.5 mg/kg, s.c., used as positive control) immediately before the formalin test. Another group of animals received tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (1 μg/site, i.t., a non-specific voltage-gated K+ channel blockers), apamin (50 ng/site, i.t., a small conductance Ca2+-activated K+ channel blocker), charybdotoxin (250 pg/site, i.t., a large-conductance Ca2+-activated K+ channel blocker), glibenclamide (100 μg/site, i.t., an ATP-sensitive K+ channel blocker) or CaCl2 (200 nmol/site, i.t.). Afterwards, the mice received inosine (10 mg/kg, i.p.), diclofenac (10 mg/kg, i.p., a positive control), or morphine (2.5 mg/kg, s.c., a positive control) immediately before the formalin test. The antinociceptive effect of inosine was reversed by the pre-administration of pertussis toxin (2.5 μg/site, i.t.), TEA, 4-aminopyridine, charybdotoxin, glibenclamide, and CaCl2, but not apamin. Further, all K+ channel blockers and CaCl2 reversed the antinociception induced by diclofenac and morphine, respectively. Taken together, these data suggest that the antinociceptive effect of inosine is mediated, in part, by pertussis toxin-sensitive G-protein coupled receptors and the subsequent activation of voltage gated K+ channel, large conductance Ca2+-activated and ATP-sensitive K+ channels or inactivation of voltage-gated Ca2+ channels. Finally, small conductance Ca2+-activated K+ channels are not involved in the antinociceptive effect of inosine. 相似文献
19.
In order to study the mechanism and regulation of K+ resorption from the xylem by the cells that border the xylem vessels (the xylem parenchyma cells), K+ inward-rectifying channels (KIRCs) in the plasma membrane of xylem parenchyma cells from Hordeum vulgare L. cv. Apex were studied using the patch-clamp technique. In the inside-out configuration, three different types of K+ channel and a further K+ conductance could be identified. Two of these channels, named KIRC1 and KIRC2, were activated by guanosine 5′-[β,γ-imido]triphosphate
(Gpp(NH)p; 150 μM), a non-hydrolyzable derivative of GTP, indicating that channel activity was up-regulated by G-proteins;
modulation of channel activity occurred via a membrane-delimited pathway, since the effect could be demonstrated in cell-free
patches. At 100 mM external K+, KIRC1 had a conductance of 8 pS. There was no effect of ATP on channel activity. Likewise, addition of 150 μM guanosine
5′-[β-thio]diphosphate (GDPβS) or adenosine 5′-[γ-thio]triphosphate (ATPγS) failed to activate KIRC1, indicating nucleotide
specificity of the effect. A second K+ channel, activated by Gpp(NH)p (KIRC2) with gating properties clearly different from the first one was less frequently observed.
Four different substates could be identified; the main level had a conductance of about 2 pS. Gating below the Nernst potential
of K+ (EK) was voltage-independent. The channel closed at potentials more positive than EK. A third, hyperpolarization-activated K+ channel, KIRC3, with a low open probability was encountered in inside-out patches. It had a conductance of 45 pS in 100 mM
K+. Channel activity was not affected by the addition of G-protein modulators. Moreover, slowly activating inward currents carried
by K+ were recorded in several patches that are ascribed to a `subpicosiemens conductance'. Neither GDPβS nor Gpp(NH)p appeared
to have an effect on the currents. Whole-cell measurements with these G-protein modulators included in the pipette solution
were in general agreement with the results obtained on cell-free patches. A statistical evaluation revealed that time-dependent
inward currents were larger when the G-protein activator Gpp(NH)p was included in the pipette medium compared to measurements
with the inhibitor GDPβS. With the GTP analogue, an additional instantaneous component was elicited that was ascribed to KIRC2
activity. Data are discussed with respect to the putative role of G-proteins in conveying hormonal signals. Regulation by
G-protein may either serve to fine-tune K+ uptake by xylem parenchyma cells or to initiate depolarization, followed by salt-efflux through depolarization-activated
cation and anion channels.
Received 11 October 1996 / Accepted: 21 April 1997 相似文献
20.
Yuk-Man Leung 《Life sciences》2010,86(21-22):775-780
A manifestation in neurodegeneration is apoptosis of neurons. Neurons undergoing apoptosis may lose a substantial amount of cytosolic K+ through a number of pathways including K+ efflux via voltage-gated K+ (Kv) channels. The consequent drop in cytosolic [K+] relieves inhibition of an array of pro-apoptotic enzymes such as caspases and nucleases. Blocking Kv channels has been known to prevent neuronal apoptosis by preventing K+ efflux. Some neural diseases such as epilepsy are caused by neuronal hyperexcitability, which eventually may lead to neuronal apoptosis. Reduction in activities of A-type Kv channels and Kv7 subfamily members is amongst the etiological causes of neuronal hyperexcitation; enhancing the opening of these channels may offer opportunities of remedy. This review discusses the potential uses of Kv channel modulators as neuroprotective drugs. 相似文献