Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848283 (rundown)
 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma-Aminobirtyric acid (GABA) is one of the major neurotransmitters in the mammalian central nervous system (CNS). The activation of post-synaptic GABAA receptor-chloride channel complex is thought to underlie inhibitory postsynaptic potentials ubiquitously in various CNS regions. GABAA receptors are modulated by convulsant, hypnotic-anticonvulsant, anxiolytic and anxiogenic agents and endogenous agents such as nurosteroids and intracellular calcium, ATP, and cyclic AMP. The function of GABAA receptor in CNS neuron is also affected by some pathophysiological processes, e.g., anoxia. For example, it is currently believed that delayed neuronal death after brain ischemia results from excessive cell excitability and/or loss of inhibition. In the present study, we investigated how the GABA-gated chloride current is affected by anoxic conditions. All experiments were carried out on neurons freshly dissociated from rat CNS by the use of both conventional and nystatin perforated patch recording configurations. The GABA response showed a considerable rundown with time in anoxic condition. The rundown was prevented by adding either ouabain or SPAI-I (Na+-K+ ATPase inhibitor-I), suggesting that the experimental anoxia reduced GABA response by decreasing intracellular ATP synthesis. This result was also confirmed by finding that the direct decrease of intracellular ATP concentration using a conventional whole-cell patch recording mode inhibited the GABA-gated chloride response in mammalian CNS neurons.
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PMID:Time-dependent rundown of GABA response in mammalian cns neuron during experimental anoxia. 865 61

1. Ca2+ imaging and simultaneous intracellular recording were performed on CA3 pyramidal neurons in hippocampal slice cultures and standard acute slices. Both fura-2 and a dextran conjugate of fura-2 (MW = 10,000) were used in the Ca2+ measurements to control for compartmentalization artifacts. Experiments were performed under conditions giving minimal ligand- and voltagegated Ca2+ influx, with the use of competitive and noncompetitive antagonists of ionotropic glutamate receptors and steady-state depolarization, respectively. 2. Tetanic stimulation of stratum lucidum evoked dendritic Ca2+ transients with rapid onset that were blocked by the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (2-5 microM), but not by the competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10-50 microM). Zn(2+)-containing mossy fiber terminals (assessed by Timm's staining) and postsynaptic structures (thorny excrescences) are preserved in s. lucidum of hippocampal slice cultures. 3. A Ca2+ store loading protocol, consisting of brief repolarizations followed by steady depolarization, primed most of the neurons so that a subsequent tetanus gave a Ca2+ increase in the presence of MK-801 that was reported by both fura-2 and the dextran conjugate. The onset of the Ca2+ increase was significantly delayed (by 2-3 s) with respect to the MK-801-sensitive increase, and often had a different spatial pattern within the neuron. Response characteristics were similar in slice cultures and acute slices. 4. The delayed Ca2+ increase showed a steep rundown with subsequent stimuli, but was restored by further priming by the Ca2+ store loading paradigm. Postsynaptic currents evoked by the tetani under these conditions were not correlated with the magnitude of the delayed Ca2+ transients. 5. Delayed Ca2+ increases were observed in 44% of the neurons dialyzed with normal intracellular solution at room temperature. The success rate of observing delayed Ca2+ transients was increased to 86% in neurons maintained at 30 degrees C, and dialyzed with an inhibitor of the inositol-triphosphate-3-kinase. 6. The delayed Ca2+ transients could not be initiated after inhibition of endosomal Ca(2+)-ATPase-mediated uptake by thapsigargin. 7. Both fura-2 and the dextran conjugate reported increases in resting Ca2+ levels after the loading protocols, that were absent after priming in thapsigargin, and decreases in resting Ca2+ levels after successive tetani in MK-801, suggesting that the Ca2+ changes were largely cytosolic. 8. The present results support the hypothesis that these synaptically mediated, delayed Ca2+ transients represent release from intracellular Ca2+ stores that can be loaded and depleted repeatedly, and are evoked by presynaptic release of endogenous neurotransmitter.
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PMID:Ca2+ release from intracellular stores induced by afferent stimulation of CA3 pyramidal neurons in hippocampal slices. 883 43

The potassium conductance of the basolateral membrane (BLM) of proximal tubule cells is a critical regulator of transport since it is the major determinant of the negative cell membrane potential and is necessary for pump-leak coupling to the Na+,K+-ATPase pump. Despite this pivotal physiological role, the properties of this conductance have been incompletely characterized, in part due to difficulty gaining access to the BLM. We have investigated the properties of this BLM K+ conductance in dissociated, polarized Ambystoma proximal tubule cells. Nearly all seals made on Ambystoma cells contained inward rectifier K+ channels (gammaslope, in = 24.5 +/- 0.6 pS, gammachord, out = 3.7 +/- 0.4 pS). The rectification is mediated in part by internal Mg2+. The open probability of the channel increases modestly with hyperpolarization. The inward conducting properties are described by a saturating binding-unbinding model. The channel conducts Tl+ and K+, but there is no significant conductance for Na+, Rb+, Cs+, Li+, NH4+, or Cl-. The channel is inhibited by barium and the sulfonylurea agent glibenclamide, but not by tetraethylammonium. Channel rundown typically occurs in the absence of ATP, but cytosolic addition of 0. 2 mM ATP (or any hydrolyzable nucleoside triphosphate) sustains channel activity indefinitely. Phosphorylation processes alone fail to sustain channel activity. Higher doses of ATP (or other nucleoside triphosphates) reversibly inhibit the channel. The K+ channel opener diazoxide opens the channel in the presence of 0.2 mM ATP, but does not alleviate the inhibition of millimolar doses of ATP. We conclude that this K+ channel is the major ATP-sensitive basolateral K+ conductance in the proximal tubule.
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PMID:Properties of an inwardly rectifying ATP-sensitive K+ channel in the basolateral membrane of renal proximal tubule. 941 41

Functional coupling of Na+,K+-ATPase pump activity to a basolateral membrane (BLM) K+ conductance is crucial for sustaining transport in the proximal tubule. Apical sodium entry stimulates pump activity, lowering cytosolic [ATP], which in turn disinhibits ATP-sensitive K+ (KATP) channels. Opening of these KATP channels mediates hyperpolarization of the BLM that facilitates Na+ reabsorption and K+ recycling required for continued Na+,K+-ATPase pump turnover. Despite its physiological importance, little is known about the regulation of this channel. The present study focuses on the regulation of the BLM KATP channel by second messengers and protein kinases using membrane patches from dissociated, polarized Ambystoma proximal tubule cells. The channel is regulated by protein kinases A and C, but in opposing directions. The channel is activated by forskolin in cell-attached (c/a) patches, and by PKA in inside-out (i/o) membrane patches. However, phosphorylation by PKA is not sufficient to prevent channel rundown. In contrast, the channel is inhibited by phorbol ester in c/a patches, and PKC decreases channel activity (nPo) in i/o patches. The channel is pH sensitive, and lowering cytosolic pH reduces nPo. Increasing intracellular [Ca2+] ([Ca2+]i) in c/a patches decreases nPo, and this effect is direct since [Ca2+]i inhibits nPo with a Ki of approximately 170 nM in i/o patches. Membrane stretch and hypotonic swelling do not significantly affect channel behavior, but the channel appears to be regulated by the actin cytoskeleton. Finally, the activity of this BLM KATP channel is coupled to transcellular transport. In c/a patches, maneuvers that inhibit turnover of the Na+,K+-ATPase pump reduce nPo, presumably due to a rise in intracellular [ATP], although the associated cell depolarization cannot be ruled out as the possible cause. Conversely, stimulation of transport (and thus pump turnover) leads to increases in nPo, presumably due to a fall in intracellular [ATP]. These results show that the inwardly rectifying KATP channel in the BLM of the proximal tubule is a key element in the feedback system that links cellular metabolism with transport activity. We conclude that coupling of this KATP channel to the activity of the Na+,K+-ATPase pump is a mechanism by which steady state NaCl reabsorption in the proximal tubule may be maintained.
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PMID:Regulation of an inwardly rectifying ATP-sensitive K+ channel in the basolateral membrane of renal proximal tubule. 941 42

We examined the role of SNAPs, soluble proteins that attach N-ethylmaleimide-sensitive factor (NSF), in regulating exocytosis in single rat adrenal chromaffin cells. Whole-cell dialysis of Ca2+-buffered solution or photolysis of caged-Ca2+ was used to manipulate cytosolic Ca2+ concentration ([Ca2+]i), whereas exocytosis was measured via carbon fiber amperometry or membrane capacitance. Buffering [Ca2+]i to approximately 170 nm produced a mean rate of exocytosis of approximately one amperometric event per minute. Including alpha-SNAP (60 or 500 nm) in the intracellular solution dramatically increased the mean rate of exocytosis. The stimulatory action of alpha-SNAP requires ATP hydrolysis mediated via NSF, because this action was blocked by intracellular dialysis of ATP-gamma-S (2 mm) and could not be mimicked by a mutant alpha-SNAP that does not stimulate the ATPase activity of NSF. This action of alpha-SNAP was significant only at [Ca2+]i between 100 and 300 nm and was not shared by beta-SNAP (500 nm), suggesting that alpha-SNAP enhanced a component of exocytosis that is regulated by a high-affinity Ca2+ sensor. In cells dialyzed with both alpha- and beta-SNAP, the rate of exocytosis was smaller than that produced by alpha-SNAP alone, suggesting that alpha- and beta-SNAP interact competitively. Although only alpha-SNAP stimulated exocytosis at [Ca2+]i between 100 and 300 nm, both alpha- and beta-SNAP isoforms equally slowed the time-dependent rundown of the exocytic response. Our results indicate that alpha- and beta-SNAP have different actions in exocytosis. Thus, the ratio of different isoforms of SNAPs can determine release probability at the levels of [Ca2+]i that are involved in regulation of exocytosis.
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PMID:Differential regulation of exocytosis by alpha- and beta-SNAPs. 1175 88

Short (<1 sec) duration depolarization of Xenopus laevis oocytes to voltages greater than +40 mV activates a sodium-selective channel (Na(x)) with sodium permeability five to six times greater than the permeability of other monovalent cations examined, including K+, Rb+, Cs+, TMA+, and Choline+. The permeability to Li+ is about equal to that of Na+. This channel was present in all oocytes examined. The kinetics, voltage dependence and pharmacology of Na(x)distinguish it from TTX-sensitive or epithelial sodium channels. It is also different from the sodium channel of Xenopus oocytes activated by prolonged depolarization, which is more highly selective for Na+, requires prolonged depolarization to be activated, and is blocked by Li+. Intracellular Mg2+ reversibly inhibits Na(x), whereas extracellular Mg2+ does not have an inhibitory effect. Intracellular Mg2+ inhibition of Na(x), is voltage dependent, suggesting that Mg2+ binding occurs within the membrane field. Eosin is also a reversible voltage-dependent intracellular inhibitor of Na(x), suggesting that a P-type ATPase may mediate the current. An additional cytoplasmic factor is involved in maintaining Na(x) since the current runs down in internally perfused oocytes and excised membrane patches. The rundown is reversible by reintroduction of the membrane patch into oocyte cytoplasm. The cytoplasmic factor is not ATP, because ATP has no effect on Na(x) current magnitude in either cut-open or inside-out patch preparations. Extracellular Gd3+ is also an inhibitor of Na(x). Na(x) activation follows a sigmoid time course. Its half-maximal activation potential is +100 mV and the effective valence estimated from the steepness of conductance activation is 1.0. Na(x) deactivates monoexponentially upon return to the holding potential (-40 mV). The deactivation rate is voltage dependent, increasing at more negative membrane potentials.
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PMID:Properties of a sodium channel (Na(x)) activated by strong depolarization of Xenopus oocytes. 1189 81

A failure in membrane excitability, defined as an inability of the sarcolemma and T-tubule to translate the neural discharge command into repetitive action potentials, represents an inviting cause of mechanical disfunction in both health and disease. A failure at this level would precipitate a disturbance in signal transmission between the T-tubule and the calcium release channels of the sarcoplasmic reticulum, resulting in reduced release of Ca2+, lower cytosolic free Ca2+ levels, and depressed myofibrillar activation and force generation. The ability of the sarcolemma and T-tubules to conduct repetitive action potentials is intimately dependent on active transport of Na+ and K+ following an action potential. The active transport of these cations is mediated by the Na+-K+-ATPase, an integral membrane protein that uses the energy from the hydrolysis of 1 ATP to transport 3 Na+ out of the cell and 2 K+ into the cell. A failure to recruit sufficient Na+-K+-ATPase activity during contractile activity could result in a rundown of the transmembrane gradients for Na+ and K+, leading to a loss of membrane excitability. The Na+-K+-ATPase activity depends on the amount and isoform composition of the protein, substrate availability, and acute regulatory factors. Each of these factors is examined as a potential cause of altered activation of the Na+-K+-ATPase activity and loss of membrane excitability in fatigue. Regular exercise represents a potent stimulus for upregulating Na+-K+-ATPase levels and for increasing the ability for cation transport across the sarcolemma and T-tubule membrane. As such, training may be a valuable tool in the management of fatigue in health and disease.
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PMID:Membrane excitability, weakness, and fatigue. 1519 28

Na(+)-K(+)-ATPase pump failure during either anoxia or ouabain perfusion induces rapid axonal depolarization by dissipating ionic gradients. In this study, we examined the interplay between cation and anion transporting pathways mediating axonal depolarization during anoxia or selective Na(+)-K(+)-ATPase inhibition. Compound resting membrane (V(m)) potential of rat optic nerve was measured in a grease gap at 37 degrees C. Chemical anoxia (2 mM NaCN or NaN(3)) or ouabain (1 mM) caused a loss of resting potential to 42 +/- 11% and 47 +/- 2% of control after 30 min, respectively. Voltage-gated Na(+)-channel blockade was partially effective in abolishing this depolarization. TTX (1 microM) reduced depolarization to 73 +/- 10% (chemical anoxia) and 68 +/- 4% (ouabain) of control. Quaternary amine Na(+) channel blockers QX-314 (1 mM) or prajmaline (100 microM) produced similar results. Residual ionic rundown largely representing co-efflux of K(+) and Cl(-) during chemical anoxia in the presence of Na(+)-channel blockade was further spared with DIDS (500 microM), a broad-spectrum anion transport inhibitor (95 +/- 8% of control after 30 min in anoxia + TTX vs. 73 +/- 10% in TTX alone). Addition of DIDS was slightly more effective than TTX alone in ouabain (74 +/- 5% DIDS + TTX vs. 68 +/- 4% in TTX alone, P < 0.05). Additional Na(+)-entry pathways such as the Na-K-Cl cotransporter were examined using bumetanide, which produced a modest albeit significant sparing of V(m) during ouabain-induced depolarization. Although cation-transporting pathways play the more important role in mediating pathological depolarization of central axons, anion-coupled transporters also contribute to a significant, albeit more minor, degree.
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PMID:Differential effects of Na-K-ATPase pump inhibition, chemical anoxia, and glycolytic blockade on membrane potential of rat optic nerve. 1577 66