scholarly journals Proton Sensitivity of Corticotropin-Releasing Hormone Receptor 1 Signaling to Proopiomelanocortin in Male Mice

Endocrinology ◽  
2018 ◽  
Vol 160 (2) ◽  
pp. 276-291 ◽  
Author(s):  
Hiraku Kameda ◽  
Masaaki Yamamoto ◽  
Yukiko Tone ◽  
Masahide Tone ◽  
Shlomo Melmed
Keyword(s):  
Ligand Binding ◽  
Low Ph ◽  
Pituitary Cells ◽  
Dependent Protein Kinase ◽  
Ectopic Acth ◽  
Primary Mouse ◽  
Dependent Protein ◽  
Acidic Conditions ◽  
Mouse Pituitary ◽  
The Impact

Abstract Because an acidic cellular microenvironment is engendered by inflammation and may determine cell differentiation, we elucidated the impact of acidic conditions on induction of proopiomelanocortin (POMC) expression. Here, we demonstrate mechanisms for proton sensitivity of CRH receptor 1 (CRHR1) signaling to POMC and ACTH production. Low pH (6.8) resulted in doubling of POMC expression and ACTH production in pituitary cell line AtT-20 and in primary mouse pituitary cells. Using CRISPR knockout, we show that CRHR1 is necessary for acid-induced POMC expression, and this induction is mediated by CRHR1 histidine residues and calmodulin-dependent protein kinase II in both pituitary corticotroph cells and in nonpituitary cell lines expressing ectopic ACTH. In contrast, CRH ligand binding affinity to CRHR1 was decreased with acidic pH, implying that proton-induced POMC expression prevails in acidic conditions independently of CRH ligand binding. The results indicate that proton-induced CRHR1 signaling regulates ACTH production in response to an acidic microenvironment.

P6344Volume overload-triggered pathological myocardial remodeling occurs in the absence of calcium/calmodulin-dependent protein kinase type II delta

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Elkenani ◽  
B A Mohamed ◽  
E Buchholz ◽  
D Lbik ◽  
M Schnelle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Heart Weight ◽  
Type Ii ◽  
Myocardial Remodeling ◽  
Dependent Protein Kinase ◽  
Mortality Pattern ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
The Impact

Abstract Background Calcium/calmodulin-dependent protein kinase type II delta (CamKIIδ), the predominant cardiac CaMKII isoform, has been implicated in the progression of myocardial infarction- and pressure overload-induced pathological remodeling and heart failure, but its role in volume overload (VO) has not been defined. We have previously reported an activation of CamKII during transition to HF in VO. Purpose Here, we analyzed the impact of CamKIIδ deletion in VO-triggered myocardial remodeling and heart failure development. Methods CaMKIIδ knockout (CaMKIIδ-KO) and wild-type (WT) littermates were exposed to aorto-caval shunt-induced VO, and the progression of myocardial remodeling was assessed by serial echocardiography, histological and molecular analyses. Results CaMKIIδ-KO and WT littermates exhibited similar mortality pattern in response to VO. Serial echocardiographic measurements showed a comparable eccentric myocardial remodeling, altered left ventricle geometry and perturbed ventricular function after shunt. At 12 weeks post-shunt both CaMKIIδ-KO and WT mice experienced comparable increases in relative heart weight, cardiomyocyte diameter, cardiac apoptosis, and hypertrophic genes expression. Conclusion We therefore conclude that CaMKIIδ signaling is dispensable for the progression of pathological cardiac remodeling induced by VO. This should be considered before CaMKII inhibition is approved therapeutically for HF treatment.

scholarly journals Use of kinase inhibitors against schistosomes to improve and broaden praziquantel efficacy

Parasitology ◽  
2020 ◽  
Vol 147 (13) ◽  
pp. 1488-1498
Author(s):  
Sujeevi S. K. Nawaratna ◽  
Donald P. McManus ◽  
Robin B. Gasser ◽  
Paul J. Brindley ◽  
Glen M. Boyle ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Lethal Dose ◽  
Alternative Therapies ◽  
Potential Drug ◽  
Dependent Protein Kinase ◽  
Drug Of Choice ◽  
Dependent Protein ◽  
The Impact

AbstractPraziquantel (PZQ) is the drug of choice for schistosomiasis. The potential drug resistance necessitates the search for adjunct or alternative therapies to PZQ. Previous functional genomics has shown that RNAi inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) gene in Schistosoma adult worms significantly improved the effectiveness of PZQ. Here we tested the in vitro efficacy of 15 selective and non-selective CaMK inhibitors against Schistosoma mansoni and showed that PZQ efficacy was improved against refractory juvenile parasites when combined with these CaMK inhibitors. By measuring CaMK activity and the mobility of adult S. mansoni, we identified two non-selective CaMK inhibitors, Staurosporine (STSP) and 1Naphthyl PP1 (1NAPP1), as promising candidates for further study. The impact of STSP and 1NAPP1 was investigated in mice infected with S. mansoni in the presence or absence of a sub-lethal dose of PZQ against 2- and 7-day-old schistosomula and adults. Treatment with STSP/PZQ induced a significant (47–68%) liver egg burden reduction compared with mice treated with PZQ alone. The findings indicate that the combination of STSP and PZQ dosages significantly improved anti-schistosomal activity compared to PZQ alone, demonstrating the potential of selective and non-selective CaMK/kinase inhibitors as a combination therapy with PZQ in treating schistosomiasis.

scholarly journals The Impact of pH on Clostridioides difficile Sporulation and Physiology

2019 ◽  
Vol 86 (4) ◽  
Author(s):  
Daniela Wetzel ◽  
Shonna M. McBride
Keyword(s):  
Phenotypic Diversity ◽  
Toxin Production ◽  
Low Ph ◽  
Spore Morphology ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Alkaline Environments ◽  
Acidic Conditions ◽  
Ph Conditions ◽  
The Impact

ABSTRACT Clostridioides difficile is a pathogenic bacterium that infects the human colon to cause diarrheal disease. Growth of the bacterium is known to be dependent on certain bile acids, oxygen levels, and nutrient availability in the intestine, but how the environmental pH can influence C. difficile is mostly unknown. Previous studies indicated that C. difficile modulates the intestinal pH, and prospective cohort studies have found a strong association between a more alkaline fecal pH and C. difficile infection. Based on these data, we hypothesized that C. difficile physiology can be affected by various pH conditions. In this study, we investigated the impact of a range of pH conditions on C. difficile to assess potential effects on growth, sporulation, motility, and toxin production in the strains 630Δerm and R20291. We observed pH-dependent differences in sporulation rate, spore morphology, and viability. Sporulation frequency was lowest under acidic conditions, and differences in cell morphology were apparent at low pH. In alkaline environments, C. difficile sporulation was greater for strain 630Δerm, whereas R20291 produced relatively high levels of spores in a broad range of pH conditions. Rapid changes in pH during exponential growth impacted sporulation similarly among the strains. Furthermore, we observed an increase in C. difficile motility with increases in pH, and strain-dependent differences in toxin production under acidic conditions. The data demonstrate that pH is an important parameter that affects C. difficile physiology and may reveal relevant insights into the growth and dissemination of this pathogen. IMPORTANCE Clostridioides difficile is an anaerobic bacterium that causes gastrointestinal disease. C. difficile forms dormant spores which can survive harsh environmental conditions, allowing their spread to new hosts. In this study, we determine how intestinally relevant pH conditions impact C. difficile physiology in the two divergent strains, 630Δerm and R20291. Our data demonstrate that low pH conditions reduce C. difficile growth, sporulation, and motility. However, toxin production and spore morphology were differentially impacted in the two strains at low pH. In addition, we observed that alkaline environments reduce C. difficile growth, but increase cell motility. When pH was adjusted rapidly during growth, we observed similar impacts on both strains. This study provides new insights into the phenotypic diversity of C. difficile grown under diverse pH conditions present in the intestinal tract, and demonstrates similarities and differences in the pH responses of different C. difficile isolates.

Mechanisms for gonadotropin-releasing hormone potentiation of growth hormone rebound following norepinephrine inhibition in goldfish pituitary cells

2007 ◽  
Vol 292 (1) ◽  
pp. E203-E214 ◽  
Author(s):  
Anderson O. L. Wong ◽  
Maggie C. Y. Chuk ◽  
Hiu Chi Chan ◽  
Eric K. Y. Lee
Keyword(s):  
Growth Hormone ◽  
Adrenergic Receptors ◽  
Gonadotropin Releasing Hormone ◽  
Pituitary Cells ◽  
Adrenergic Stimulation ◽  
Dependent Protein Kinase ◽  
Releasing Hormone ◽  
Gh Secretion ◽  
Dependent Protein ◽  
Subsequent Activation

In the goldfish, norepinephrine (NE) inhibits growth hormone (GH) secretion through activation of pituitary α2-adrenergic receptors. Interestingly, a GH rebound is observed after NE withdrawal, which can be markedly enhanced by prior exposure to gonadotropin-releasing hormone (GnRH). Here we examined the mechanisms responsible for GnRH potentiation of this “postinhibition” GH rebound. In goldfish pituitary cells, α2-adrenergic stimulation suppressed both basal and GnRH-induced GH mRNA expression, suggesting that a rise in GH synthesis induced by GnRH did not contribute to its potentiating effect. Using a column perifusion approach, GnRH given during NE treatment consistently enhanced the GH rebound following NE withdrawal. This potentiating effect was mimicked by activation of PKC and adenylate cyclase (AC) but not by induction of Ca2+ entry through voltage-sensitive Ca2+ channels (VSCC). Furthermore, GnRH-potentiated GH rebound could be alleviated by inactivation of PKC, removal of extracellular Ca2+, blockade of VSCC, and inhibition of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII). Inactivation of AC and PKA, however, was not effective in this regard. These results, as a whole, suggest that GnRH potentiation of GH rebound following NE inhibition is mediated by PKC coupled to Ca2+ entry through VSCC and subsequent activation of CaMKII. Apparently, the Ca2+-dependent cascades are involved in GH secretion during the rebound phase but are not essential for the initiation of GnRH potentiation. Since GnRH has been previously shown to have no effects on cAMP synthesis in goldfish pituitary cells, the involvement of cAMP-dependent mechanisms in GnRH potentiation is rather unlikely.

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