Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Information on the molecular biology of Alzheimer's disease (AD) pointing to new methods of diagnosis and drug therapies is explored. AD is the most common cause of dementia in the elderly and is characterized by senile plaques and neurofibrillary tangles in the brain and loss of cholinergic neurons in the basal forebrain. The disease has a strong genetic component. A definitive diagnosis can be made only by neuropathologic examination at autopsy or biopsy; however, the accuracy of diagnosis based on standard neuropsychological testing and inclusion criteria has improved considerably. Senile plaques consist of a central core of amyloid fibrils surrounded by dystrophic axons. The main component of senile plaque amyloid is a 39-to 42-amino-acid segment referred to as beta-amyloid, which is derived from amyloid precursor protein (APP). APP exists as multiple isoforms encoded by a single gene on chromosome 21. Factors that may influence APP metabolism include activation of phospholipase C, phosphorylation, and the cholinergic system. The microtubule-associated protein tau may contribute to the neurofibrillary tangles of AD. In AD all six adult isoforms of tau can become maximally phosphorylated and can, rather than binding to microtubules, bind to each other, destabilizing the neuronal cytoskeleton. One of the most important discoveries in AD research was the linking of apolipoprotein E phenotype to familial late-onset AD. Acetylcholinesterase inhibitors appear to improve cognitive function but may be limited in utility by adverse effects. Nicotinic agonists are also being investigated as symptomatic therapies. Other possible strategies include nerve growth factor, agents that potentiate the action of endogenous glutamate, antioxidants, nonsteroidal anti-inflammatory drugs, and estrogens. Research into the molecular biology of Alzheimer's disease has begun to point to possible causes of and treatments for this condition.
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PMID:Molecular basis of Alzheimer's disease. 880 75

Human immunodeficiency virus (HIV) infection may cause a dementing illness. HIV-mediated dementia is clinically and pathologically correlated with the infiltration of activated macrophages and elevated levels of tumor necrosis factor (TNF)-alpha, both of which occur in an environment of small numbers of infected cells. We examined the possibility that HIV protein Tat, which is released extracellularly from infected cells, may induce the production of TNF-alpha. Tat induced TNF-alpha mRNA and protein production dose-dependently, primarily in macrophages but also in astrocytic cells. The TNF-alpha induction was NF-kappaB-dependent and could be eliminated by inhibiting protein kinase A or protein tyrosine kinase activity. In addition, Tat-induced TNF-alpha release was also linked to phospholipase C activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link between HIV and macrophage/glial cell activation and suggest new therapeutic approaches for HIV dementia.
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PMID:The Tat protein of HIV-1 induces tumor necrosis factor-alpha production. Implications for HIV-1-associated neurological diseases. 927 85

HIV-1 protein Tat is neurotoxic and increases macrophage and microglia production of TNF-alpha, a cytopathic cytokine linked to the neuropathogenesis of HIV dementia. Others have shown that intracellular calcium regulates TNF-alpha production in macrophages, and we have shown that Tat releases calcium from inositol 1,4, 5-trisphosphate (IP3) receptor-regulated stores in neurons and astrocytes. Accordingly, we tested the hypothesis that Tat-induced TNF-alpha production was dependent on the release of intracellular calcium from IP3-regulated calcium stores in primary macrophages. We found that Tat transiently and dose-dependently increased levels of intracellular calcium and that this increase was blocked by xestospongin C, pertussis toxin, and by phospholipase C and type 1 protein kinase C inhibitors but not by protein kinase A or phospholipase A2 inhibitors. Xestospongin C, BAPTA-AM, U73122, and bisindolylmalemide significantly inhibited Tat-induced TNF-alpha production. These results demonstrate that in macrophages, Tat-induced release of calcium from IP3-sensitive intracellular stores and activation of nonconventional PKC isoforms play an important role in Tat-induced TNF-alpha production.
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PMID:Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages. 1084 12

Despite considerable efforts and successes investigating the function of the hippocampal formation in memory processes, there are still numerous elusive key issues. Some of them will be addressed in this review. We will argue that recent evidence supports hippocampal participation in several memory processes, such as encoding, short-term and long-term consolidation and retrieval. While some processes, for example encoding and short-term consolidation, have been the subject of detailed investigations, at least for specific and repeatedly used behavioural paradigms, there appears to be considerable lack of information with respect to other processes, for example long-term consolidation. Although the existence of long-term consolidation is not at debate here, there is only very fragmented information as to the cellular processes enabling long-term consolidation. Recent ample evidence now suggests a potential role in metabotropic glutamate receptors, and more specifically the phospholipase C-coupled receptor 5, in long-term consolidation. The hyperexpression of receptor protein was limited to CA1 indicating a specific role of this brain region in the consolidation of memories. Future work should further explore this important issue especially since long-term consolidation appears to be a necessity for permanent storage of information, and may thus engage memory mechanism that fail during ageing and dementia.
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PMID:Function of the hippocampus in memory formation: desperately seeking resolution. 1138 80

TRPM7 is a ubiquitously expressed nonselective cation channel fused to a C-terminal alpha kinase. TRPM7 current is typically small at physiological magnesium concentrations, but large outwardly rectifying currents develop in low-magnesium extracellular solution when cells are dialyzed with magnesium free solutions during whole-cell patch clamp recordings. In addition to regulation by magnesium, TRPM7 current is potentiated by low extracellular pH and inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)) during phospholipase C mediated signaling events. A diverse body of literature has implicated TRPM7 in fundamental cellular processes including death, survival, proliferation, cell cycle progression, magnesium homeostasis and responses to shear stress and oxidative stress. Global deletion of TRPM7 in mouse results in embryonic lethality and a thymocyte-restricted conditional knockout exhibits defective thymopoeisis, suggesting a role for TRPM7 in development and organogenesis. In disease states, TRPM7 has been linked to Guamanian amyotrophic lateral sclerosis and parkinsonian dementia (ALS/PD), various forms of neoplasia, hypertension and delayed neuronal death following cerebral ischemia.
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PMID:TRPM7, the Mg(2+) inhibited channel and kinase. 2129 Feb 95