Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biochemical abnormalities in peripheral nerve are thought to precede and condition the development of diabetic neuropathy, but metabolic intervention in chronic diabetic neuropathy produces only limited acute clinical response. The residual, metabolically unresponsive neurological deficits have never been rigorously defined in terms of either persistent metabolic derangements or irreversible structural defects because human nerve tissue is rarely accessible for anatomical and biochemical study and experimentally diabetic animals do not develop the structural hallmarks of human diabetic neuropathy. Detailed neuroanatomical-functional-biochemical correlation was therefore undertaken in long-term spontaneously diabetic BB-Wistar rats that functionally and structurally model human diabetic neuropathy. Vigorous insulin replacement in chronically diabetic BB rats essentially normalized both the sural nerve fiber caliber spectrum and the decreased sciatic nerve myo-inositol and (Na,K)-ATPase levels generally associated with conduction slowing in diabetic animals; yet, nerve conduction was only partially restored toward normal. Morphometric analysis revealed a striking disappearance of paranodal axo-glial junctional complexes that was not corrected by insulin replacement. Loss of these strategic junctional complexes, which are thought to limit lateral migration of axolemmal Na channels away from nodes of Ranvier, correlates with and can account for the diminished nodal Na permeability and resultant nodal conduction delay characteristic of chronic diabetic neuropathy in this animal model.
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PMID:Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat. 300 60

(Na+ + K+)ATPase-like immunoreactivity along the axolemma of sensory and motor neurons and the plasmalemma of Schwann cells from spinal roots of dystrophic mice (129 ReJ Dy/Dy) was determined using polyclonal antibodies specific for guinea pig renal (Na+ + K+)ATPase (GP-17), along with polyclonal (439-2) and monoclonal (9A5) antibodies specific for rat renal (Na+ + K+)ATPase. In normal and dystrophic mice, (Na+ + K+)ATPase-like immunoreactivity was observed along the axolemma at nodes of Ranvier using GP-17 and 439-2, each of which binds to isozymes of (Na+ + K+)ATPase composed of the alpha and alpha + forms of the catalytic subunit. Staining was not seen along the nodal axolemma with 9A5, a preparation that binds to the alpha form of the catalytic subunit. The terminal processes and microvilli of Schwann cells were stained using all three antibody probes. The axolemma of unensheathed axons in dystrophic mice was continuously and uniformly labelled with GP-17 and 439-2, but not 9A5. Concentrations of (Na+ + K+)ATPase-like immunoreactivity along Schwann cell processes were observed most often in areas adjacent to unensheathed axolemma. At heminodes, staining abruptly decreased along Schwann cell processes in areas that were separated from the unensheathed axolemma by other intervening Schwann cell processes. It was concluded from these data that in dystrophic mice (Na+ + K+)ATPase is uniformly distributed along unensheathed portions of axons without evidence of detectable focal concentrations of the enzyme, and that the catalytic subunit of (Na+ + K+)ATPase along unensheathed axons is distinct from the alpha form found in Schwann cells and other organs. In addition, (Na+ + K+)ATPase is concentrated along the plasmalemma of Schwann cells in regions of close apposition to axolemmal areas associated with large ionic fluxes.
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PMID:The distribution of (Na+ + K+)ATPase is continuous along the axolemma of unensheathed axons from spinal roots of 'dystrophic' mice. 304 Sep 17

The ability of digoxin and a 4-aminocardenolide, ASI-222, to alter atrioventricular nodal refractory period (AVRP) was determined as a function of the maximum subarrhythmic dose (MSAD) in the dog anesthetized with morphine-pentobarbital. ASI-222, a highly polar and potent inhibitor of Na+, K+-adenosine triphosphatase produces a cardiotoxicity in dogs prominently involving atrioventricular nodal blockade rather than ventricular premature ectopic beats and tachycardia seen with digoxin. AVRP was assessed with trains of electrically isolated stimuli of decreasing pulse interval delivered to the right atria. Digoxin and ASI-222 were infused i.v. at rates which produced cardiac arrhythmias in about 100 min in dogs either: 1) with intact nerves, 2) pretreated with atropine, 3) without reflex receptors (without vagus and carotid sinus nerves, 4) without cardiac sympathetic nerves and adrenals or 5) pretreated with metoprolol. In dogs with intact nerves, ASI-222 produced greater increases in AVRP than digoxin at fractions of the MSAD; however, both glycoside produced a similar elevation at the MSAD (approximately equal to 30% increase). Atropine did not alter the AVRP response to ASI-222 but prevented the lengthening due to digoxin except for that which occurred near the MSAD. Removal of reflex receptor afferents (and vagi) had an effect similar to atropine on the AVRP response to digoxin, but completely prevented any response to ASI-222. Prior sympathectomy or beta adrenergic blockade abolished the AVRP response to ASI-222 but did not alter the responses to digoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of an aminocardenolide and digoxin upon atrioventricular refractory period in the dog. 407 25

The membrane of the myelinated axon expresses a rich repertoire of physiologically active molecules: (1) Voltage-sensitive NA+ channels are clustered at high density (approximately 1,000/microns 2) in the nodal axon membrane and are present at lower density (< 25/microns 2) in the internodal axon membrane under the myelin. Na+ channels are also present within Schwann cell processes (in peripheral nerve) and perinodal astrocyte processes (in the central nervous system) which contact the Na+ channel-rich axon membrane at the node. In some demyelinated fibers, the bared (formerly internodal) axon membrane reorganizes and expresses a higher-than-normal Na+ channel density, providing a basis for restoration of conduction. The presence of glial cell processes, adjacent to foci of Na+ channels in immature and demyelinated axons, suggests that glial cells participate in the clustering of Na+ channels in the axon membrane. (2) "Fast" K+ channels, sensitive to 4-aminopyridine, are present in the paranodal or internodal axon membrane under the myelin; these channels may function to prevent reexcitation following action potentials, or participate in the generation of an internodal resting potential. (3) "Slow" K+ channels, sensitive to tetraethylammonium, are present in the nodal axon membrane and, in lower densities, in the internodal axon membrane; their activation produces a hyperpolarizing afterpotential which modulates repetitive firing. (4) The "inward rectifier" is activated by hyperpolarization. This channel is permeable to both Na+ and K+ ions and may modulate axonal excitability or participate in ionic reuptake following activity. (5) Na+/K(+)-ATPase and (6) Ca(2+)-ATPase are also present in the axon membrane and function to maintain transmembrane gradients of Na+, K+, and Ca2+. (7) A specialized antiporter molecule, the Na+/Ca2+ exchanger, is present in myelinated axons within central nervous system white matter. Following anoxia, the Na+/Ca2+ exchanger mediates an influx of Ca2+ which damages the axon. The molecular organization of the myelinated axon has important pathophysiological implications. Blockade of fast K+ channels and Na+/K(+)-ATPase improves action potential conduction in some demyelinated axons, and block of the Na+/Ca2+ exchanger protects white matter axons from anoxic injury. Modification of ion channels, pumps, and exchangers in myelinated fibers may thus provide an important therapeutic approach for a number of neurological disorders.
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PMID:Molecular dissection of the myelinated axon. 767 65

Exposure to acrylamide (ACR) monomer produces distal swelling and subsequent degeneration in central and peripheral myelinated axons of humans and laboratory animals. The molecular and cellular events leading to this type of axonopathy are currently unknown. Herein we describe a new mechanism of ACR axonopathy that represents a synthesis of recent research findings and prior hypotheses. According to this model, ion regulation in distal paranodal axon regions is compromised by diminished axolemmal Na/K-ATPase activity. It is suggested that decreased NA/K-ATPase activity is a consequence of aberrant cell body processing and/or deficient axonal transport. Reduced Na pump activity promotes membrane depolarization in conjunction with axoplasmic accumulation of Na and loss of K. Thermodynamically, this favors reverse operation of the Na/Ca-exchanger which permits axonal Ca entry in exchange for Na. The influx of Ca eventually overwhelms buffering mechanisms and leads to distal axon degeneration. Distal axons are predisposed to regulatory failure of this type due to a dependency on cell body output and the unique differential distribution of enzymes, ion channels and exchangers among nodal and internodal regions. This heuristic model might account for axon degeneration occurring as a result of exposure to other chemical neurotoxicants and following axotomy and other forms of mechanical injury.
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PMID:Acrylamide-induced distal axon degeneration: a proposed mechanism of action. 799 Dec 13

A comprehensive review of the literature has revealed that endothelins belong to a family of vasoactive peptides which are formed and released from the endothelium. By producing constriction of the coronary arteries and peripheral blood vessels, endothelins are known both to reduce coronary bloodflow and increase blood pressure and thus can be seen to affect heart function adversely. On the other hand, endothelins are capable of producing positive inotropic and chronotropic effects by directly affecting both the myocardium and nodal tissues. Prolonged actions of high concentrations of endothelins can be seen to induce relative hypoxia in the myocardium which will eventually result in heart dysfunction. The mechanisms of actions of endothelin on smooth muscle cells and cardiomyocytes include interaction with endothelin receptors on the cell surface, activation of phospholipase C through G-proteins, and increase in the intracellular concentration of Ca2+ through the increase in phosphoinositol turnover. Endothelins were found to exert no effects on sarcolemmal Na+,K(+)-ATPase, Na(+)-Ca2+ exchange and Ca2+ pump systems nor on the sarcoplasmic reticular Ca2+ pump system and myofibrillar ATPase activities in the rat heart. Marked elevation in the levels of plasma endothelins and down-regulation of endothelin receptors in ischemia-reperfusion injury, hypertension and chronic diabetes indicate a significant role of endothelins in the genesis of heart dysfunction under different pathological conditions.
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PMID:Role of endothelin in heart function in health and disease. 822 63

1. The hyperpolarization that follows tetanic stimulation was recorded intra-axonally from the internodal region of intramuscular myelinated motor axons. 2. The peak amplitude of the posttetanic hyperpolarization (PTH) that followed stimulation at 20-100 Hz for < or = 35 s increased with increasing train duration, reaching a maximum of 22 mV. PTH decayed over a time course that increased from tens to hundreds of seconds with increasing train duration. For a given frequency of stimulation the time integral of PTH was proportional to the number of stimuli in the train, averaging 3-4 mV.s per action potential. 3. Ouabain (0.1-1 mM) and cyanide (1 mM) depolarized the resting potential and abolished PTH. Tetanic stimulation in ouabain was followed by a slowly decaying depolarization (probably due to extra-axonal K+ accumulation) whose magnitude and duration increased as the duration of the train increased. 4. Axonal input resistance showed no consistent change during PTH in normal solution but increased during PTH in the presence of 3 mM Cs+ (which blocks axonal inward rectifier currents). 5. PTH was abolished when bath Na+ was replaced by Li+ or choline. PTH persisted after removal of bath Ca2+ and addition of 2 mM Mn2+. 6. Removal of bath K+ abolished the PTH recorded after brief stimulus trains and greatly reduced the duration of PTH recorded after longer stimulus trains. 7. A brief application of 10 mM K+, which normally depolarizes axons, produced a ouabain-sensitive hyperpolarization in axons bathed in K(+)-free solution. 8. These observations suggest that in these myelinated axons PTH is produced mainly by activation of an electrogenic Na(+)-K(+)-ATPase, rather than by changes in K+ permeability or transmembrane [K+] gradients. This conclusion is supported by calculations showing agreement between estimates of Na+ efflux/impulse based on PTH measurements and estimates of Na+ influx/impulse based on nodal voltage-clamp measurements. Pump activity also appears to contribute to the resting potential. 9. The stimulus intensity required to initiate a propagating action potential increased during PTH but decreased during the posttetanic depolarization recorded in ouabain. Thus changes in axonal excitability after tetanic stimulation correlate with changes in the posttetanic membrane potential. 10. Action potentials that propagated during PTH had a larger peak amplitude and were followed by a larger and longer depolarizing afterpotential than action potentials elicited at the resting potential. This enhancement of the depolarizing afterpotential is consistent with previous reports of an increased superexcitable period after action potentials evoked during PTH.
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PMID:Posttetanic hyperpolarization produced by electrogenic Na(+)-K+ pump in lizard axons impaled near their motor terminals. 829 60

We tried to demonstrate the electron microscopic histochemical localization of membrane Ca(2+)-ATPase activity in glutaraldehyde-fixed rat sciatic nerves. Although conventional glutaraldehyde fixatives containing impurities interfered with the reactivity of Ca(2+)-ATPase, this activity was successfully preserved in the tissues fixed with pure glutaraldehyde as well as in those fixed with paraformaldehyde. In unmyelinated nerve fibers, an ATPase activity depending on 10 mM CaCl2 was detected on the whole external surface of Schwann cell plasma membranes. In myelinated fibers, this activity was localized on the surface of Schwann cell outer loops at the paranodal region of Ranvier nodes and on the axonal membrane at the nodal region. Another activity depending on 0.1 mM CaCl2 was demonstrated on the axolemma of unmyelinated fibers. These results indicated that there may be two types of Ca(2+)-ATPase activities showing high and low affinity to calcium ions localized in peripheral nerve systems in a different manner between myelinated and unmyelinated fibers.
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PMID:Fine localization of low and high calcium dependent ATPase activities in the rat sciatic nerve. 865 27

There has been controversy for some time as to whether a posttraumatic influx of calcium ions occurs in stretch/nondisruptively injured axons within the central nervous system in both human diffuse axonal injury and a variety of models of such injury. We have used the oxalate/pyroantimonate technique to provide cytochemical evidence in support of such an ionic influx after focal axonal injury to normoxic guinea pig optic nerve axons, a model for human diffuse axonal injury. We present evidence for morphological changes within 15 min of injury where aggregates of pyroantimonate precipitate occur in nodal blebs at nodes of Ranvier, in focal swellings within axonal mitochondria, and at localized sites of separation of myelin lamellae. In parallel with these studies, we have used cytochemical techniques for localization of membrane pump Ca(2+)-ATPase and ecto-Ca-ATPase activity. There is loss of labelling for membrane pump Ca(2+)-ATPase activity on the nodal axolemma, together with loss of ecto-Ca-ATPase from the external aspect of the myelin sheath at sites of focal separation of myelin lamellae. Disruption of myelin lamellae and loss of ecto-Ca-ATPase activity becomes widespread between 1 and 4 h after injury. This is correlated with both infolding and retraction of the axolemma from the internal aspect of the myelin sheath to form periaxonal spaces which are characterized by aggregates of pyroantimonate precipitate, and the development of myelin intrusions into invaginations of the axolemma such that the regular profile of the axon is lost. There is novel labelling of membrane pump Ca(2+)-ATPase on the cytoplasmic aspect of the internodal axolemma between 1 and 4 h after injury. There is loss of an organized axonal cytoskeleton in a proportion of nerve fibres by 4-6 h after injury. We suggest that these changes demonstrate a progressive pathology linked to calcium ion influx after stretch (non-disruptive) axonal injury to optic nerve myelinated fibres. We posit that calcium influx, linked to or correlated with changes in Ca(2+)-ATPase activities, results in dissolution of the axonal cytoskeleton and axotomy between 4 and 6 h after the initial insult to axons.
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PMID:Cytochemical evidence for redistribution of membrane pump calcium-ATPase and ecto-Ca-ATPase activity, and calcium influx in myelinated nerve fibres of the optic nerve after stretch injury. 871 20

Nerve myo-inositol depletion, which has been implicated in the pathogenesis of acute experimental diabetic neuropathy, can be reproduced in normal rats by feeding diets enriched in L-fucose, a competitive inhibitor of sodium-dependent myo-inositol transport. Previously, we reported that L-fucose feeding for 6 weeks reproduces the effect of experimental diabetes on nerve Na+-K+-ATPase activity and conduction velocity, which can be prevented by simultaneous dietary myo-inositol supplementation. To further validate this model of myo-inositol depletion, we examined the effects of long-term (24-week) L-fucose feeding and dietary myo-inositol supplementation on nerve Na+-K+-ATPase, nerve conduction velocity, and myelinated nerve fiber pathology. After 24 weeks of L-fucose enriched (10 or 20%) diets, nerve myo-inositol levels and Na+-K+-ATPase activity decreased significantly (P < 0.05) and were associated with a 25-30% reduction in nerve conduction velocity, all of which were completely prevented by 1% dietary myo-inositol. Twenty percent L-fucose diet resulted in significant axonal atrophy, paranodal swelling (P < 0.001), and paranodal demyelination (P < 0.005), without increasing Wallerian degeneration or nerve fiber loss, a pattern qualitatively similar to that seen in early murine diabetic neuropathy. Dietary myo-inositol supplementation prevented these structural changes and increased nodal remyelination, supporting a role of myo-inositol depletion in the genesis of early diabetic neuropathy. The L-fucose model system may therefore serve as an experimental tool to elucidate the pathophysiological role of isolated myo-inositol depletion and its consequences in the multifactorial pathogenesis of diabetic neuropathy.
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PMID:Supplemental myo-inositol prevents L-fucose-induced diabetic neuropathy. 900 Jul 8


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