Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cultured hippocampal neurons, transient receptor potential 5 (TRPC5) channels are translocated and inserted into plasma membranes of hippocampal neurons to generate nonselective cation (NSC) currents. We investigated whether TRPC5 channel translocation also contributes to the generation of NSC currents underlying the afterdepolarizations and plateau potentials (PPs) in hippocampal pyramidal cells that are induced by muscarinic receptor activation. Using a biotinylation assay to quantify the change in surface membrane proteins in acute hippocampal slices, we found that muscarinic stimulation significantly enhanced the levels of TRPC5 protein on the membrane surface but not those of TRPC1 or TRPC4 channels. We then investigated the pharmacological sensitivity of the cation current observed during muscarinic stimulation to determine if a component could be due to TRPC5 channels. The TRPC channel antagonists 2-APB and SKF96365 strongly depressed the generation of PPs, the underlying tail currents (I(tail)) and the associated dendritic Ca(2+) influx induced by muscarinic receptor activation in pyramidal neurons. High intracellular concentrations of ATP, which specifically inhibit TRPC5 channels, depressed I(tail). In addition, pretreatment with the calmodulin (CaM) inhibitor W-7, which depresses recombinant TRPC5 currents, inhibited both the cation current (I(tail)) and the surface insertion of TRPC5 channels. Finally, the phosphatidylinositide 3-kinase (PI(3)K) inhibitor wortmannin, which blocks translocation of TRPC5 channels in cell culture, also inhibited both the I(tail) and the surface insertion of TRPC5 channels. Therefore, we conclude that insertion of TRPC5 channels contributes to the generation of the prolonged afterdepolarizations following muscarinic stimulation. This altered plasma membrane expression of TRPC5 channels in pyramidal neurons may play an important role in the generation of prolonged neuronal depolarization and bursting during the epileptiform seizure discharges of epilepsy.
 ...
PMID:Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons. 2086 44

Canonical transient receptor potential channels (TRPCs) are receptor-operated cation channels that are activated in response to phospholipase C signaling. Although TRPC1 is ubiquitously expressed in the brain, TRPC4 expression is the most restrictive, with the highest expression level limited to the lateral septum. The subunit composition of neuronal TRPC channels remains uncertain because of conflicting data from recombinant expression systems. Here we report that the large depolarizing plateau potential that underlies the epileptiform burst firing induced by metabotropic glutamate receptor agonists in lateral septal neurons was completely abolished in TRPC1/4 double-knockout mice, and was abolished in 74% of lateral septal neurons in TRPC1 knockout mice. Furthermore, neuronal cell death in the lateral septum and the cornu ammonis 1 region of hippocampus after pilocarpine-induced severe seizures was significantly ameliorated in TRPC1/4 double-knockout mice. Our data suggest that both TRPC1 and TRPC4 are essential for an intrinsic membrane conductance mediating the plateau potential in lateral septal neurons, possibly as heteromeric channels. Moreover, excitotoxic neuronal cell death, an underlying process for many neurological diseases, is not mediated merely by ionotropic glutamate receptors but also by heteromeric TRPC channels activated by metabotropic glutamate receptors. TRPC channels could be an unsuspected but critical molecular target for clinical intervention for excitotoxicity.
 ...
PMID:Heteromeric canonical transient receptor potential 1 and 4 channels play a critical role in epileptiform burst firing and seizure-induced neurodegeneration. 2214 71

Seizures are the manifestation of highly synchronized burst firing of a large population of cortical neurons. Epileptiform bursts with an underlying plateau potential in neurons are a cellular correlate of seizures. Emerging evidence suggests that the plateau potential is mediated by neuronal canonical transient receptor potential (TRPC) channels composed of members of the TRPC1/4/5 subgroup. We previously showed that TRPC1/4 double-knockout (DKO) mice lack epileptiform bursting in lateral septal neurons and exhibit reduced seizure-induced neuronal cell death, but surprisingly have unaltered pilocarpine-induced seizures. Here, we report that TRPC5 knockout (KO) mice exhibit both significantly reduced seizures and minimal seizure-induced neuronal cell death in the hippocampus. Interestingly, epileptiform bursting induced by agonists for metabotropic glutamate receptors in the hippocampal CA1 area is unaltered in TRPC5 KO mice, but is abolished in TRPC1 KO and TRPC1/4 DKO mice. In contrast, long-term potentiation is greatly reduced in TRPC5 KO mice, but is normal in TRPC1 KO and TRPC1/4 DKO mice. The distinct changes from these knockouts suggest that TRPC5 and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Furthermore, the reduced seizure and excitotoxicity and normal spatial learning exhibited in TRPC5 KO mice suggest that TRPC5 is a promising novel molecular target for new therapy.
 ...
PMID:Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. 2318 15

The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and investment before we can reap the rewards of highly potent and selective pharmacological modulators.
...
PMID:In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels -- mirage or pot of gold? 2376 62

Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research.
...
PMID:The role of canonical transient receptor potential channels in seizure and excitotoxicity. 2472 70

The TRPC1 ion channel was the first mammalian TRP channel to be cloned. In humans, it is encoded by the TRPC1 gene located in chromosome 3. The protein is predicted to consist of six transmembrane segments with the N- and C-termini located in the cytoplasm. The extracellular loop connecting transmembrane segments 5 and 6 participates in the formation of the ionic pore region. Inside the cell, TRPC1 is present in the endoplasmic reticulum, plasma membrane, intracellular vesicles, and primary cilium, an antenna-like sensory organelle functioning as a signaling platform. In human and rodent tissues, it shows an almost ubiquitous expression. TRPC1 interacts with a diverse group of proteins including ion channel subunits, receptors, and cytosolic proteins to mediate its effect on Ca(2+) signaling. It primarily functions as a cation nonselective channel within pathways controlling Ca(2+) entry in response to cell surface receptor activation. Through these pathways, it affects basic cell functions, such as proliferation and survival, differentiation, secretion, and cell migration, as well as cell type-specific functions such as chemotropic turning of neuronal growth cones and myoblast fusion. The biological role of TRPC1 has been studied in genetically engineered mice where the Trpc1 gene has been experimentally ablated. Although these mice live to adulthood, they show defects in several organs and tissues, such as the cardiovascular, central nervous, skeletal and muscular, and immune systems. Genetic and functional studies have implicated TRPC1 in diabetic nephropathy, Parkinson's disease, Huntington's disease, Duchenne muscular dystrophy, cancer, seizures, and Darier-White skin disease.
...
PMID:TRPC1. 2475 1

Human canonical transient receptor potential channel 5 (TRPC5) has been cloned from the Xq23 region on chromosome X as a suspect in nonsyndromic mental retardation. TRPC5 is a Ca(2+)-permeable cation channel predominantly expressed in the CNS, including the hippocampus, cerebellum, amygdala, sensory neurons, and retina. It also shows more restricted expression in the periphery, notably in the kidney and cardiovascular system. Homotetrameric TRPC5 channels are primarily activated by receptors coupled to Gq and phospholipase C and/or Gi proteins, but TRPC5 channels may also gate in a store-dependent manner, which requires other partner proteins such TRPC1, STIM1, and Orai1. There is an impressive array of other activators of TRPC5 channels, such as nitric oxide, lysophospholipids, sphingosine-1-phosphate, reduced thioredoxin, protons, lanthanides, and calcium, and many can cause its direct activation. Moreover, TRPC5 shows constitutive activity, and it is responsive to membrane stretch and cold. Thus, TRPC5 channels have significant potential for synergistic activation and may serve as an important focal point in Ca(2+) signalling and electrogenesis. Moreover, TRPC5 functions in partnership with about 60 proteins, including TRPC1, TRPC4, calmodulin, IP3 receptors, NHERF, NCS-1, junctate, stathmin 2, Ca(2+)-binding protein 1, caveolin, and SESTD1, while its desensitisation is mediated by both protein kinases A and C. TRPC5 has a distinct voltage dependence shared only with its closest relative, TRPC4. Its unique N-shaped activation curve underlined by intracellular Mg(2+) block seems to be perfectly "shaped" to trigger action potential discharge, but not to grossly interfere with the action potential shape. The range of biological functions of TRPC5 channels is also impressive, from neurotransmission to control of axon guidance and vascular smooth muscle cell migration and contractility. Recent studies of Trpc5 gene knockouts begin to uncover its roles in fear, anxiety, seizures, and cold sensing.
...
PMID:TRPC5. 2475 5

Transient receptor potential canonical (TRPC) channels are calcium permeable, non-selective cation channels with wide tissue-specific distribution. Among 7 TRPC channels, TRPC 1/4/5 and TRPC3/6/7 are subdivided based on amino acid sequence homology. TRPC4 and TRPC5 channels exhibit cationic current with homotetrameric form, but they also form heterotetrameric channel such as TRPC1/4 or TRPC1/5 once TRPC1 is incorporated. The expression of TRPC1 is ubiquitous whereas the expressions of TRPC4 and TRPC5 are rather focused in nervous system. With the help of conditional knock-out of TPRC1, 4 and/or 5 genes, TRPC channels made of these constituents are reported to be involved in various pathophysiological functions such as seizure, anxiety-like behaviour, fear, Huntington's disease, Parkinson's disease and many others. In heterologous expression system, many issues such as activation mechanism, stoichiometry and relative cation permeabilites of homomeric or heteromeric channels have been addressed. In this review, we discussed the role of TRPC1 channel per se in plasma membrane, role of TRPC1 in heterotetrameric conformation (TRPC1/4 or TRPC1/5) and relationship between TRPC1/4/5 channels, calcium influx and voltage-gated calcium channels.
 ...
PMID:TRPC1 as a negative regulator for TRPC4 and TRPC5 channels. 3122 90