Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of pergolide, an N-propylergoline derivative, has been tested for stimulation of central dopaminergic receptors. Binding to dopamine receptors shows that pergolide acts as an agonist with respect to these receptors. GTP decreases the potencies of dopamine agonists and of pergolide, but not of bromocriptine, to displace [3H]spiroperidol ([3H]Spi) from striatal membrane sites. The GTP-sensitive site labeled by [3H]Spi seems to be localized on intrastriatal dopamine receptors. The potency of dopamine agonists and of pergolide to displace [3H]Spi from striatal receptor sites is reduced in membranes exposed to higher temperatures. Pergolide, but not hitherto-tested dopaminergic ergots, stimulates dopamine-sensitive adenylate cyclase in striatal homogenates. Thus, pergolide, unlike other dopaminergic ergots, acts as an agonist on GTP-sensitive components of [3H]Spi binding and stimulates dopamine receptors linked to dopamine-sensitive adenylate cyclase. The drug also induces turning behavior in rats with 6-OH-dopamine lesions and relieves tremor in monkeys with ventromedial tegmental lesions for a longer time at a lower dose than other tested dopaminergic ergots. Other studies have shown that it is effective in the treatment of patients with advanced parkinsonism.
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PMID:Interaction of pergolide with central dopaminergic receptors. 693 44

Botulinum C3 exoenzyme specifically ADP-ribosylates a group of ras-related small molecular weight GTP-binding proteins, rho, and inhibits their biological activity. Using this enzyme, we examined the function of rho in PMA-induced activation of lymphocyte function-associated antigen-1 (LFA-1) in a B lymphoblastoid cell line, JY. Northern blot analysis revealed that among the three rho genes, rhoA mRNA was predominantly expressed in JY cells. Consistently, only one [32P]ADP-ribosylated band was found when the lysate of the cells was subjected to ADP ribosylation by C3 exoenzyme. When the cells were cultured with C3 exoenzyme, this substrate was ADP-ribosylated in situ in a time- and concentration-dependent manner. Concomitant with this ADP ribosylation, PMA-induced LFA-1/intercellular adhesion molecule (ICAM)-1-dependent aggregation of JY cells was inhibited. This inhibition was blocked by prior treatment of the enzyme with an anti-C3 monoclonal antibody, and overcome by stimulation with higher concentrations of PMA. The C3 exoenzyme-induced inhibition was not affected by shaking of the cell suspension, while inhibition of aggregation by cytochalasin B was abolished by this procedure, suggesting that the inhibitory effect of the C3 exoenzyme treatment was not due to decrease in cell motility. The C3 exoenzyme treatment affected neither protein phosphorylation in JY cells before and after PMA stimulation, nor affected surface expression of LFA-1 and ICAM-1. These results suggest that rhoA protein works downstream of protein kinase C activation linking PMA stimulation to LFA-1 activation and aggregation in JY cells.
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PMID:Inhibition of PMA-induced, LFA-1-dependent lymphocyte aggregation by ADP ribosylation of the small molecular weight GTP binding protein, rho. 768 Jun 58

Beta-adrenoceptors are members of a large family of hormone and neurotransmitter receptors that initiate their biological function by coupling to GTP-binding regulatory proteins. beta-Adrenoceptors can be subdivided into two main subgroups, designated beta1 and beta2. Atypical beta-adrenoceptors or beta3-adrenoceptors, which are present on adipocytes, have been demonstrated pharmacologically. Their function in adipose tissue is currently being investigated. Beta2-adrenoceptor agonists have played a key role in the treatment of asthma for some 30 years, being used for the relief and prophylaxis of symptoms. There is, however, no evidence that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. In neuropsychiatry, beta-adrenoceptor antagonists have been used for the treatment of acute stress reactions and generalised anxiety, essential tremor and prophylaxis of migraine. In general, they are effective in anxiety disorders if the somatic symptoms are not extreme. For prophylactic treatment of migraine, beta-adrenoceptor antagonists such as propranolol, metoprolol, nadolol and atenolol are the drugs of first choice. In cardiology, beta-adrenoceptor antagonists are an important class for the treatment of high blood pressure, arrhythmias and angina pectoris, and for prevention of myocardial infarction. With chronic treatment, they reduce mortality in hypertension and prolong survival in patients with coronary heart disease.
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PMID:Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. 955 98

A 26 year old woman with dopa responsive dystonia and cytogenetically confirmed Turner's syndrome had bilateral globus pallidus hypointensity on brain MRI. Among the living members of a five generation pedigree the patient's mother and the mother's sister also had dopa responsive dystonia; a maternal grandfather had senile parkinsonism, his niece isolated postural tremor. No other family member had Turner's syndrome. A new missense mutation in exon I of the gene of GTP-cyclohydrolase I was found in the three family members with dopa responsive dystonia. With levodopa substitution the patients with dopa responsive dystonia improved clinically as well as in quantitative tests on hand tapping, verbal and performance IQ, concept formation, and set shifting abilities.
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PMID:Dopa responsive dystonia with Turner's syndrome: clinical, genetic, and neuropsychological studies in a family with a new mutation in the GTP-cyclohydrolase I gene. 964 18

We reported previously that Go-deficient mice develop severe neurological defects that include hyperalgesia, a generalized tremor, lack of coordination, and a turning syndrome somewhat reminiscent of unilateral lesions of the dopaminergic nigro-striatal pathway. By using frozen coronal sections of serially sectioned brains of normal and Go-deficient mice, we studied the ability of several G protein coupled receptors to promote binding of GTPgammaS to G proteins and the ability of GTP to promote a shift in the affinity of D2 dopamine receptor for its physiologic agonist dopamine. We found a generalized, but not abolished reduction in agonist-stimulated binding of GTPgammaS to frozen brain sections, with no significant left-right differences. Unexpectedly, the ability of GTP to regulate the binding affinity of dopamine to D2 receptors (as seen in in situ [(35)S]sulpiride displacement curves) that was robust in control mice, was absent in Go-deficient mice. The data suggest that most of the effects of the Gi/Go-coupled D2 receptors in the central nervous system are mediated by Go instead of Gi1, Gi2, or Gi3. In agreement with this, the effect of GTP on dopamine binding to D2 receptors in double Gi1 plus Gi2- and Gi1 plus Gi3-deficient mice was essentially unaffected.
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PMID:Most central nervous system D2 dopamine receptors are coupled to their effectors by Go. 1124 20

The authors report a kindred in which GTP-CH deficiency resulted in a myoclonus-dystonia syndrome. The proband, a 17-year-old boy, presented with early-onset myoclonus and later, dystonia and bradykinesia. Blood prolactin was increased and CSF homovanillic acid, 5-hydroxyindoleacetic acid, and biopterin were all reduced. L-Dopa/carbidopa administration resulted in clinical improvement. In the paternal branch, the grandfather and three relatives had myoclonus-dystonia and resting or postural tremor of limbs. The authors found a missense mutation in the exon 6 of GCH-1 gene (K224R).
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PMID:Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome. 1239 38

Recent studies have examined the changes in the activity of cannabinoid signaling system in multiple sclerosis (MS), as a way to explain the efficacy of cannabinoid compounds to alleviate spasticity, pain, tremor and other signs of this autoimmune disease. In the present study, we have further explored this issue by examining density, mRNA expression and activation of GTP-binding proteins for the cannabinoid CB1 receptor subtype in several brain structures of mice with chronic relapsing experimental allergic encephalomyelitis (CREAE), a chronic model of MS that reproduces many of the pathological hallmarks of the human disease. CREAE animals were used at different phases in the progression of the disease (acute, remission and chronic) and compared to control mice. We observed several changes in the status of CB1 receptors that were region-specific and mainly circumscribed to motor-related regions, which is compatible with the symptomatology described for these animals that is preferentially of motor nature. We found a moderate decrease in the density of CB1 receptors in the caudate-putamen during the acute phase of CREAE. These reductions disappeared during the remission phase, but they were again observed, to a more marked extent, in the chronic phase. The same pattern for CB1 receptor density was observed in the cerebellum which, in this case, was accompanied by a progressive decrease in the capability of these receptors to activate GTP-binding proteins that was maximal in the chronic phase. The decrease in the density of CB1 receptors in the acute phase was also found in the globus pallidus but, in this case, the reduction was maintained during the further phases. No changes were observed in CB1 receptor-mRNA levels in any of the different regions examined. Finally, by contrast with the observations in motor structures, the status of CB1 receptors remained unaltered in cognition-related regions, such as the cerebral cortex and the hippocampus, during the different phases of CREAE. In summary, CB1 receptors were affected by the development of CREAE in mice exhibiting always down-regulatory responses that were circumscribed to motor-related regions and that were generally more marked during the acute and chronic phases. These observations may explain the efficacy of cannabinoid agonists to improve motor symptoms (spasticity, tremor, ataxia) typical of MS in both humans and animal models.
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PMID:Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice. 1682 88

Parkinson's disease is the second most common age-related neurodegenerative disorder, typified by the progressive loss of substantia nigra pars compacta dopamine neurons and the consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms, with the most common affecting motor function and including resting tremor, rigidity, akinesia, bradykinesia and postural instability. Current pharmacological interventions are palliative and largely aimed at increasing dopamine levels through increased production and/or inhibition of metabolism of this key neurotransmitter. The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact. Consequently, as the number of substantia nigra dopamine neurons and striatal projections decrease, these treatments become less efficacious. Current translational research is focused on the development of novel disease-modifying therapies, including those utilizing gene therapeutic approaches. Herein we present an overview of current gene therapy clinical trials for Parkinson's disease. Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production; modulation of the neuronal phenotype; and neuroprotection. The first two therapies discussed in this article focus on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis (amino acid decarboxylase, tyrosine hydroxylase and GTP [guanosine triphosphate] cyclohydrolase 1). In an attempt to bypass the degenerating nigrostriatal pathway, a third clinical trial utilizes rAAV2 to deliver glutamic acid decarboxylase to the subthalamic nucleus, converting a subset of excitatory neurons to GABA-producing cells. In contrast, the final clinical trial is aimed at protecting the degenerating nigrostriatum by striatal delivery of rAAV2 harbouring the neuroprotective gene, neurturin. Based on preclinical studies, this gene therapeutic approach is posited to slow disease progression by enhancing neuronal survival. In addition, we discuss the outcome of each clinical trial and discuss the potential rationale for the marginal yet incremental clinical advancements that have thus far been realized for Parkinson's disease gene therapy.
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PMID:Gene therapy in Parkinson's disease: rationale and current status. 2015 94

The current cell oxygen paradigm shows some major gaps that have not yet been resolved. Something seems to be lacking for the comprehensive statement of the oxygen distribution in the cell, especially the low cytoplasmic oxygen level. The entrapment of oxygen in microtubules (MTs) resolves the latter observation, as well as the occurrence of an extensive cytoplasmic foam formation. It leads to a novel oxygen paradigm for cells. During the steady-state treadmilling, the mobile cavity would absorb oxygenated cytoplasm forward, entrap gas nuclei and concentrate them. A fluorescence method is described to confirm the in vitro load of oxygen in MTs during their periodic growths and shrinkages. The latter operating mechanism is called the gas dynamic instability (GDI) of MTs. Several known biosystems could rest on the GDI. (1) The GTP-cap is linked with the gas meniscus encountered in a tube filled with gas. The GTP hydrolysis is linked to the conformational change of the GTPase domain according to the bubble pressure, and to the shaking of protofilaments with gas particles (soliton-like waves). (2) The GDI provides a free energy water pump because water molecules have to escape from MT pores when foam concentrates within the MT. Beside ATP hydrolysis in motor proteins, the GDI provides an additional driving force in intracellular transport of cargo. The water streams flowing from the MT through slits organize themselves as water layers between the cargo and the MT surface, and break ionic bridges. It makes the cargo glide over a water rail. (3) The GDI provides a universal motor for chromosome segregation because the depolymerization of kinetochorial MTs is expected to generate a strong cytoplasmic foam. Chromosomes are sucked up according to the pressure difference (or density difference) applied to opposite sides of the kinetochore, which is in agreement with Archimedes' principle of buoyancy. Non-kinetochorial MTs reabsorb foam during GDI. Last, the mitotic spindle is imagined as a gas recycler. (4) The luminal particles within MTs (called MIPs) are imagined as a foam organizer, the luminal proteins being part of the borders and edges of identical bubbles. (5) Last, volatile anesthetics could destabilize MTs through anesthetic-induced bubble nucleation between protofilaments, and therefore causing shear stress and the opening of MT. The load of oxygen in MTs might provide a major advance in this area of research.
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PMID:Heuristic consequences of a load of oxygen in microtubules. 2452 90

The clinical diagnosis of Parkinson's Disease (PD) is not supported by Single Photon Emission Computed Tomography (SPECT) using dopamine transporter radioligand in 4-15 % of patients. It has been hypothesized that this phenomenon, named "Scans Without Evidence of Dopaminergic Deficiency" (SWEDD), may be an adult-onset dystonia. We investigated the hypothesis that these patients might be affected by Dopa-Responsive Dystonia (DRD). We enrolled eleven unrelated patients (8 F and 3 M) with clinical parkinsonism and normal [(123)I]FP-CIT SPECT. The GTP-cyclohydrolase1 (GCH1) gene was sequenced in all patients; urine biopterin and neopterin analysis was carried out in nine and oral phenylalanine (Phe) loading in seven. Neurological examination showed bradykinesia and resting/postural tremor in all patients, and rigidity in ten, suggesting a clinical diagnosis of PD. We detected mild dystonic signs in eight cases. In particular, five of them presented cranial dyskinesias. No mutation of the GCH1 gene was found. The results of the urine biopterin and neopterin analysis and the oral Phe loading did not reveal biochemical abnormalities suggestive of reduced GCH1 activity. We confirm that some clinical features, namely the presence of focal or segmental dystonia, suggest an adult-onset dystonia in SWEDD cases. However, we exclude DRD caused by GCH1 gene mutations in the present series.
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PMID:Screening for dopa-responsive dystonia in patients with Scans Without Evidence of Dopaminergic Deficiency (SWEDD). 2518 1


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