Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of chloride conductance in basolateral membranes of proximal tubule is controversial. We measured 36Cl uptake in basolateral membranes loaded with KCl and suspended in a K(+)-free solution to create a positive intravesicular potential difference. Under these conditions, 36Cl uptake was maximal at 1 min, remained stable for at least 10 min and decreased to equilibrium levels by 60-120 min. Collapse of the voltage by valinomycin decreased 36Cl uptake by 46%, indicating the presence of K(+)-gradient-dependent chloride uptake. The chloride channel inhibitor diphenylamine-2-carboxylic acid inhibited 36Cl uptake in a dose-dependent fashion. 36Cl uptake was inhibited equally by unlabeled chloride, iodide and nitrate but not by sulfate or gluconate, indicating that the basolateral anion conductance is relatively selective. 36Cl uptake was pH independent but was calcium dependent. Phosphorylation of basolateral membranes with ATP significantly decreased 36Cl uptake, but the inhibitory effect of ATP was not further altered by exogenous cyclic AMP or the active phorbol ester PMA. These data demonstrate the presence of a relatively selective basolateral anion conductance which is regulated by pH, calcium and ATP.
 ...
PMID:Anion channel in basolateral cortical membranes of the rabbit kidney. 133 46

The gamma-aminobutyric acid (GABA) is one of the most important inhibitory transmitter in the CNS. When GABA is released in the synaptic cleft, it can act on two types of receptors, type A (GABAA-R) and type B. The GABAA-R is an ionotropic receptor whose subunits form a chloride channel. It contains specific binding sites at least for GABA, benzodiazepines, picrotoxin, barbiturates, anesthetic steroids, divalent cations such as Zn2+ and other compounds. Neurotransmitters and neuropeptides that regulate intracellular second messengers may modulate the responses of GABAA-R in the post-synaptic membrane and thus affect the synaptic plasticity. While consensus sites for several kinases are present on many subunit-subtypes, the functional consequences of these phosphorylations are unclear. However, the maintenance of normal GABA currents required the activity of a unique kinase specific for the GABAA-R. This intracellular regulation site might be involved in synaptic plasticity and considered as a site of vulnerability for epileptogenesis. The generation of epileptic discharge, synchronized burst firing and interictal spikes, can be subsequent to the alteration of GABAA-R function. A consequence of GABAergic disinhibition is the formation of new polysynaptic pathways leading to a network of neurons that were previously not connected. Cell loss and plasticity are currently observed in most patients with temporal lobe epilepsy. CA1 pyramidal cells are missing and mossy fibers of dentate granule cells project back through the granule cell layer to form recurrent terminals on granule cell dendrites. This mossy fiber sprouting leads to the destruction of most dentate hilar somatostatine interneurons. Nevertheless, local circuit neurons containing glutamic acid decarboxylase survive in this layer and in all regions of the sclerotic hippocampus. A decrease of the GABA release has been proposed as a basis for disinhibition temporal-lobe epilepsy is partially characterized by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters. A molecular reorganization of GABAA-R subunits has been suggested in the kindling model of temporal lobe epilepsy because the zinc released from abberantly sprouted mossy fiber terminals is responsible for a collapse of augmented inhibition by GABA. These results support the concept of a loss of inhibition in chronic epilepsy models and probably in human epilepsies.
 ...
PMID:[Intervention of GABAergic neurotransmission in partial epilepsies]. 968 48

In the late 1980s, a loss-of-function mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel was identified to be the primary cause of cystic fibrosis (CF); a fatal multiple-organ disorder that mostly affects Caucasians. To date, approximately 2000 genetic mutations have been identified in the CFTR gene (http://www.genet.sickkids.on.ca/cftr/app). The most common cause of morbidity and mortality in persons with CF is a progressive deterioration in lung function leading ultimately to respiratory collapse. The median life expectancy of CF patients currently is estimated to be 39 years in the US. The most prevalent CFTR mutation, F508del, accounts for 70% of CF cases and causes a processing defect in the protein leading to premature endoplasmic reticulum-associated degradation (ERAD) and reduced F508del-CFTR delivery to the cell surface. A CF corrector is defined as a chemical chaperone that increases cell-surface levels of F508del-CFTR. A series of CF correctors have been developed, and VX-809 (lumacaftor) has been cited as the most effective symptomatic CF corrector to date. VX-809 improves the function of the mutant protein by approximately 15% in in vitro culture systems. However, this effect did not completely translate clinically, with only a marginal improvement observed in lung function of the F508del-homozygous patients undergoing the therapy. New studies revealed that even after successful ER retrieval, rescued F508del-CFTR (rF508del-CFTR) once at the cell surface does not function properly, exhibiting poor stability and channel gating and structural abnormalities. This becomes further complicated by the existence of genes termed CFTR modifiers, which can alter CFTR function to be additionally defective and exacerbate the CF phenotype while also alternatively suggested be potentially targeted to improve F508del-CFTR functional outcome. It is necessary to understand the biology of F508del-CFTR post-ER and at the plasma membrane where the protein might also confront the modifiers and how we can incorporate these components into CF therapeutics. Additionally, the notion that CF individuals would eventually benefit from more of a personalized medicine is becoming increasingly accepted. Here, we review how CF therapeutics may be simplified by understanding the complexities of rescued F508del-CFTR biology and eventually move toward more personalized medicine for patients suffering with CF.
 ...
PMID:Pharmacological Correction of Cystic Fibrosis: Molecular Mechanisms at the Plasma Membrane to Augment Mutant CFTR Function. 2664 81

The calcium-activated chloride channel (CaCC) TMEM16A plays crucial roles in regulating neuronal excitability, smooth muscle contraction, fluid secretion and gut motility. While opening of TMEM16A requires binding of intracellular Ca2+, prolonged Ca2+-dependent activation results in channel desensitization or rundown, the mechanism of which is unclear. Here we show that phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates TMEM16A channel activation and desensitization via binding to a putative binding site at the cytosolic interface of transmembrane segments (TMs) 3-5. We further demonstrate that the ion-conducting pore of TMEM16A is constituted of two functionally distinct modules: a Ca2+-binding module formed by TMs 6-8 and a PIP2-binding regulatory module formed by TMs 3-5, which mediate channel activation and desensitization, respectively. PIP2 dissociation from the regulatory module results in ion-conducting pore collapse and subsequent channel desensitization. Our findings thus provide key insights into the mechanistic understanding of TMEM16 channel gating and lipid-dependent regulation.
 ...
PMID:Molecular basis of PIP2-dependent regulation of the Ca2+-activated chloride channel TMEM16A. 3143 6

TMEM16A is a calcium-activated chloride channel that is associate with several diseases, including pulmonary diseases, hypertension, diarrhea and cancer. The CaCCinh-A01 (A01) is widely recognized as an efficient blocker of TMEM16A and has been used as a tool drug to inhibit TMEM16A currents in the laboratory. A01 also has excellent pharmacokinetic properties and can be developed as a drug to target TMEM16A. However, the molecular mechanism how A01 inhibits TMEM16A is still elusive, which slows down its drug development process. Here, calculations identified that the binding pocket of A01 was located above the pore, and it was also discovered that the binding of A01 to TMEM16A not only blocked the pore but also led to its collapse. The interaction model analysis predicted that R515/K603/E623 were crucial residues for the binding between TMEM16A and A01, and the site-directed mutagenesis studies confirmed the above results. The binding mode and quantum chemical calculations showed that the carboxyl and the amide oxygen atom of A01 were the key interaction sites between TMEM16A and A01. Therefore, our study proposed the inhibitory mechanism of TMEM16A current by A01 and revealed how A01 inhibits TMEM16A at the molecular level. These findings will shed light on both the development of A01 as a potential drug for TMEM16A dysfunction-related disorders and drug screening targeting the pocket.
 ...
PMID:Molecular mechanism of CaCCinh-A01 inhibiting TMEM16A channel. 3313 91