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)

Previous investigations have suggested that changes in platelet activity may play a key role in the pathophysiology of migraine via mechanisms involving the nitric oxide (NO) pathway. Changes in platelet response and nitrite levels have recently been demonstrated during migraine attacks, while there is considerable uncertainty about NO activity in headache-free periods. A reactive oxidant produced from NO and superoxide anion at the site of inflammation, peroxynitrite (ONOO-) has effects including changes in membrane activity and fluidity. The aim of the present study was to determine ONOO- levels in the platelets of patients suffering from migraine during the headache-free period. Nitric oxide synthase (eNOS and iNOS) expression in platelets and the effects of ONOO- on membrane Na+/K+-ATPase activity and membrane fluidity were also evaluated. Subjects were 57 patients suffering from migraine without aura and 35 controls. Blood samples were collected in the headache-free period. Platelet ONOO- levels were determined using dichlorofluorescein acetate with steady-state fluorescence. Platelets were then probed for induction of eNOS and iNOS expression by western immunoblotting. Membrane Na+/K+-ATPase activity and fluidity were determined with the fluorescent probes TMA-DPH and DPH. In the presence of extracellular l-arginine(100 micromol/l), ONOO- production was significantly greater in patients' platelets than in those of controls (P < 0.001). Western immunoblotting of platelet proteins evidenced higher iNOS expression in patients than in controls. In addition, platelet membrane Na+/K+-ATPase activity and membrane fluidity evaluated by TMA-DPH were significantly lower in patients (P < 0.001). In conclusion, migraine patients show intercritic changes in platelet membrane fluidity and activity that may be related to the oxidative stress caused by increased ONOO- levels.
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PMID:Platelet membrane fluidity and peroxynitrite levels in migraine patients during headache-free periods. 1583 50

Familial hemiplegic migraine type 2, an autosomal dominant form of migraine with aura, has been associated with four distinct mutations in the alpha2-subunit of the Na+,K+-ATPase. We have introduced these mutations in the alpha2-subunit of the human Na+,K+-ATPase and the corresponding mutations in the Bufo marinus alpha1-subunit and studied these mutants by expression in Xenopus oocyte. Metabolic labeling studies showed that the mutants were synthesized and associated with the beta-subunit, except for the alpha2HW887R mutant, which was poorly synthesized, and the alpha1BW890R, which was partially retained in the endoplasmic reticulum. [3H]ouabain binding showed the presence of the alpha2HR689Q and alpha2HM731T at the membrane, whereas the alpha2HL764P and alpha2HW887R could not be detected. Functional studies with the mutants of the B. marinus Na+,K+-ATPase showed a reduced or abolished electrogenic activity and a low K+ affinity for the alpha1BW890R mutant. Through different mechanisms, all these mutations result in a strong decrease of the functional expression of the Na+,K+-pump. The decreased activity in alpha2 isoform of the Na+,K+-pump expressed in astrocytes seems an essential component of hemiplegic migraine pathogenesis and may be responsible for the cortical spreading depression, which is one of the first events in migraine attacks.
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PMID:Functional effects of Na+,K+-ATPase gene mutations linked to familial hemiplegic migraine. 1597 Jun 28

Migraine is a recurrent neurovascular disease. Its two most common forms-migraine without aura (MO) and migraine with aura (MA)-both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na(+)/K(+)-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [c.520G>A (p.E174 K) and c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM-mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na(+)/K(+)-ATPases, 4) the functional effect of C515Y, and 5) the involvement of ATP1A2 in a monogenic form of migraine.
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PMID:Rare missense variants in ATP1A2 in families with clustering of common forms of migraine. 1611 Apr 94

Although migraine is characterised by an abnormal cortical excitability level, whether the central nervous system is hyper- or hypo-excitable in migraine still remains an unsolved problem. The aim of our study was to compare the somatosensory evoked potential (SEP) recovery cycle, a marker of the somatosensory system's excitability, in a group of 15 children suffering from migraine without aura (MO) (mean age 11.7+/-1.6 years, five males, 10 females) and 10 control age-matched subjects (CS) (mean age 10.9+/-2.1 years, six males, four females). We calculated the SEP's latency and amplitude modifications after paired electrical stimuli at 5, 20 and 40 ms interstimulus intervals (ISIs), comparing it with a single stimulus condition assumed as the baseline. In MO patients, the amplitudes of the cervical N13 and of the cortical N20, P24 and N30 responses at 20 and 40 ms ISIs showed a higher recovery than in CS (two-way ANOVA, P<0.05). Since, the SEP recovery cycle depends on the inhibitory interneuron function, our findings suggest that a somatosensory system disinhibition takes place in migraine. This is a generalized phenomenon, not limited to the cerebral cortex, but concerning also the cervical grey matter. The SEP recovery cycle reflects the intracellular concentration of Na(+), therefore, the shortened recovery cycle in our MO patients suggests a high level of intracellular Na(+) and a consequent depolarized resting membrane potential, possibly due to an impaired Na(+) -K(+) ATPase function in migraine.
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PMID:Multilevel somatosensory system disinhibition in children with migraine. 1620 23

Recent advances in genetic analysis of migraine headache are reviewed. Point mutations of P/Q -type Ca2+ channel alpha1 subunit(CACNA1A) gene and Na-K ATPase, alpha2 (ATP1A2) gene have been identified in the familial hemiplegic migraine (FHM-1 and FHM-2, respectively). Mutations in notch-3 gene cause the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an autosomal dominant inherited disorder often accompanying with migraine like headache. Serotonin (5-HT) related genes, dopamine D2 receptors (DRD2) gene, methylenetetrahydrofolate reductase (MTHFR) gene, and angiotensin converting enzyme (ACE) gene have been noticed as the susceptible genes for migraine pathogenesis. Genetic study of migraine is promising and will provide further understanding of the migraine pathophysiology. Discovery of the responsible or susceptible genes will open an avenue to develop new therapeutic strategy.
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PMID:[Genetic analysis of migraine headache: a review]. 1621 82

In Cerro de Pasco (CP), Peru (altitude 4338 m) 24% of men have migraine with aura. We studied 30 men. Twenty CP natives, examined in CP, were rated using a chronic mountain sickness (CMS) score to separate controls (10) from those with CMS (10), a maladaptation syndrome in natives to altitude which includes severe, recurring headache. We collected white cells in CP and, from the same men, within 1 h of arrival in Lima (150 m above sea level). Ten normal US men volunteered white cells for comparison. After RNA extraction we assessed gene expression by reverse transcription-polymerase chain reaction. Low ATP1A1 subunit of the ATPase gene mRNA expression in CP was correlated with headache (P=0.002), acral paraesthesias (P=0.004) and CMS score (P<0.001). ATP1A1 subunit expression was increased in all Andeans in Lima (P<0.001). There were no differences between Andean controls in Lima and US controls. Manipulation of Na+/K+ATPase could offer relief for migraineurs at sea level.
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PMID:Migraine in the Andes and headache at sea level. 1630

Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine, in which hemiparesis occurs during the aura. The majority of the families carry mutations in the CACNA1A gene on chromosome 19p13 (FHM1). About 20% of FHM families is linked to chromosome 1q23 (FHM2), and has mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na,K-ATPase. Mutation analysis in a Dutch and a Turkish family with pure FHM revealed two novel de novo missense mutations, R593W and V628M, respectively. Cellular survival assays support the hypothesis that both mutations are disease-causative. The identification of the first de novo mutations underscores beyond any doubt the involvement of the ATP1A2 gene in FHM2.
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PMID:Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine. 1653 23

Migraine is the most frequent primary headache disorder. It is a neurovascular disorder in which the primary abnormality is thought to be a neuronal excitability underlined by a complex genetic susceptibility. Epidemiogenetic studies have shown that migraine without aura and migraine with aura are polygenic conditions. The three known migraine genes have been identified by the study of the unique monogenic variety of migraine, i.e. familial hemiplegic migraine. These genes all encode ion transporters: the P/Q type calcium channel, a calcium/potassium ATPase and a sodium channel. According to the latter hypothesis about the mechanisms of migraine attacks, poorly known triggers initiate a cortical wave of depolarisation that is responsible for the transient aura symptoms. This cortical spreading depression induces several biochemical changes which, by diffusion through the extracellular space, stimulate the trigeminovascular fibres. These fibres release vasoactive neuropeptides that initiate the neurogenic inflammation. Trigeminovascular fibres transmit nociceptive information centrally via the brainstem. The trigeminovascular fibres also activate the parasympathetic system that is responsible for the persistence of vasodilation in meningeal vessels.
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PMID:[Mechanisms and genetics of migraine]. 1684 22

Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound and head movement. There is a clear familial tendency to migraine, which has been well defined in a rare autosomal dominant form of familial hemiplegic migraine (FHM). FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca(2+) channel), ATP1A2 (N(+)-K(+)-ATPase) and SCN1A (Na(+) channel) genes. Physiological studies in humans and studies of the experimental correlate--cortical spreading depression (CSD)--provide understanding of aura, and have explored in recent years the effect of migraine preventives in CSD. Therapeutic developments in migraine have come by targeting the trigeminovascular system, with the most-recent being the proof-of-principle study of calcitonin gene-related peptide (CGRP) receptor antagonists in acute migraine. To understand the basic pathophysiology of migraine, brain imaging studies have firmly established reproducible changes in the brainstem in regions that include areas that are involved in sensory modulation. These data lead to the view that migraine is a form of sensory dysmodulatio--a system failure of normal sensory processing.
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PMID:Recent advances in understanding migraine mechanisms, molecules and therapeutics. 1714 70

Na,K-ATPase (NKA) is well known for its role as a maintainer of electrolyte and fluid balance in cells, organs and whole body. Exciting new findings have revealed additional fundamental roles for NKA as a signal transducer and modulator of growth, apoptosis, cell adhesion and motility. The signal transduction function can be triggered by the binding of ouabain, the mammalian analogue of digitalis to NKA. The catalytic subunit of NKA exists in different forms and mutations in two of the forms that are expressed in brain can give rise to migraine, epilepsy and Parkinsonism-like symptoms. This review will present these new aspects of NKA and their clinical implications.
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PMID:New roles for an old enzyme: Na,K-ATPase emerges as an interesting drug target. 1722 67


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