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Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists [4434 cells]

ABSTRACT: Our aim is to compare whole-genome expression profiles of partially reprogrammed 4434 melanoma murine cells after induction of stem cell related genes (+ dox vs -dox)

ORGANISM(S): Mus musculus

PROVIDER: GSE122402 | GEO | 2020/02/21

REPOSITORIES: GEO

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Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists

Project description:Our aim is to compare whole-genome expression profiles of partially reprogrammed C790 melanoma murine cells after induction of stem cell related genes (+ dox vs -dox)

2020-02-21 | GSE122763 | GEO

Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists [C790 cells]

Project description:Our aim is to compare whole-genome expression profiles of partially reprogrammed C790 melanoma murine cells ( - dox vs + dox) after treatment with trametinib, in order to identify potential candidates related with drug resistance.

2020-02-21 | GSE122399 | GEO

Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists

Project description:Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists

| PRJNA506248 | ENA

Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists [4434 cells]

Project description:Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists [4434 cells]

| PRJNA504899 | ENA

Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists [C790 cells]

Project description:Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to calcium channel antagonists [C790 cells]

| PRJNA504897 | ENA

A Partial Calcium-Free Linker Confers Flexibility to Inner-Ear Protocadherin-15.

Project description:Tip links of the inner ear are protein filaments essential for hearing and balance. Two atypical cadherins, cadherin-23 and protocadherin-15, interact in a Ca2+-dependent manner to form tip links. The largely unknown structure and mechanics of these proteins are integral to understanding how tip links pull on ion channels to initiate sensory perception. Protocadherin-15 has 11 extracellular cadherin (EC) repeats. Its EC3-4 linker lacks several of the canonical Ca2+-binding residues, and contains an aspartate-to-alanine polymorphism (D414A) under positive selection in East Asian populations. We present structures of protocadherin-15 EC3-5 featuring two Ca2+-binding linker regions: canonical EC4-5 linker binding three Ca2+ ions, and non-canonical EC3-4 linker binding only two Ca2+ ions. Our structures and biochemical assays reveal little difference between the D414 and D414A variants. Simulations predict that the partial Ca2+-free EC3-4 linker exhibits increased flexural flexibility without compromised mechanical strength, providing insight into the dynamics of tip links and other atypical cadherins.

| S-EPMC5363953 | biostudies-literature

Antagonists of the TMEM16A calcium-activated chloride channel modulate airway smooth muscle tone and intracellular calcium.

Project description:BackgroundPerioperative bronchospasm refractory to β agonists continues to challenge anesthesiologists and intensivists. The TMEM16A calcium-activated chloride channel modulates airway smooth muscle (ASM) contraction. The authors hypothesized that TMEM16A antagonists would relax ASM contraction by modulating membrane potential and calcium flux.MethodsHuman ASM, guinea pig tracheal rings, or mouse peripheral airways were contracted with acetylcholine or leukotriene D4 and then treated with the TMEM16A antagonists: benzbromarone, T16Ainh-A01, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid, or B25. In separate studies, guinea pig tracheal rings were contracted with acetylcholine and then exposed to increasing concentrations of isoproterenol (0.01 nM to 10 μM) ± benzbromarone. Plasma membrane potential and intracellular calcium concentrations were measured in human ASM cells.ResultsBenzbromarone was the most potent TMEM16A antagonist tested for relaxing an acetylcholine -induced contraction in guinea pig tracheal rings (n = 6). Further studies were carried out to investigate the clinical utility of benzbromarone. In human ASM, benzbromarone relaxed either an acetylcholine- or a leukotriene D4-induced contraction (n = 8). Benzbromarone was also effective in relaxing peripheral airways (n = 9) and potentiating relaxation by β agonists (n = 5 to 10). In cellular mechanistic studies, benzbromarone hyperpolarized human ASM cells (n = 9 to 12) and attenuated intracellular calcium flux from both the plasma membrane and the sarcoplasmic reticulum (n = 6 to 12).ConclusionTMEM16A antagonists work synergistically with β agonists and through a novel pathway of interrupting ion flux at both the plasma membrane and sarcoplasmic reticulum to acutely relax human ASM.

| S-EPMC4543527 | biostudies-literature

Phe369(7.38) at human 5-HT(7) receptors confers interspecies selectivity to antagonists and partial agonists.

Project description:Background and purposeHuman and rat 5-HT(7) receptors were studied with a particular emphasis on the molecular interactions involved in ligand binding, searching for an explanation to the interspecies selectivity observed for a set of compounds. We performed affinity studies, molecular modelling and site-directed mutagenesis, with special focus on residue Phe(7.38) of the human 5-HT(7) receptor [Cys(7.38) in rat].Experimental approachCompetition binding studies were performed for seven 5-HT(7) receptor ligands at three different 5-HT(7) receptors. The functional behaviour was evaluated by measuring 5-carboxytryptamine-stimulated cAMP production. Computational simulations were carried out to explore the structural bases in ligand binding observed for these compounds.Key resultsCompetition experiments showed a remarkable selectivity for the human receptor when compared with the rat receptor. These results indicate that mutating Cys to Phe at position 7.38 profoundly affects the binding affinities at the 5-HT(7) receptor. Computational simulations provide a structural interpretation for this key finding. Pharmacological characterization of compounds mr25020, mr25040 and mr25053 revealed a competitive antagonistic behaviour. Compounds mr22423, mr22433, mr23284 and mr25052 behaved as partial agonists.Conclusions and implicationsWe propose that the interspecies difference in binding affinities observed for the compounds at human and rat 5-HT(7) receptors is due to the nature of the residue at position 7.38. Our molecular modelling simulations suggest that Phe(7.38) in the human receptor is integrated in the hydrophobic pocket in the central part of the binding site [Phe(6.51)-Phe(6.52)] and allows a tighter binding of the ligands when compared with the rat receptor.

| S-EPMC2839265 | biostudies-literature

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

Project description:A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 ?M with an apparent terminal half-life of 3.0 ± 1.1 h.

| S-EPMC4007914 | biostudies-literature

Discovery of 4,4-Disubstituted Quinazolin-2-ones as T-Type Calcium Channel Antagonists.

Project description:A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervous system efficacy in epilepsy and tremor models, as well as significant effects on rat active wake as measured by electrocorticogram.

| S-EPMC4007971 | biostudies-literature

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