Journal of Receptors and Signal Transduction最新文献

{"title":"Anti-COVID-19 and antidiabetic activities of new oleanane and ursane-type triterpenoids from <i>Salvia grossheimii</i>: an <i>in-silico</i> approach.","authors":"Somayeh Zare,&nbsp;Somayeh Pirhadi,&nbsp;Hesham R El Seedi,&nbsp;Amir Reza Jassbi","doi":"10.1080/10799893.2022.2072891","DOIUrl":"https://doi.org/10.1080/10799893.2022.2072891","url":null,"abstract":"<p><p><i>Salvia grossheimii</i> is a perennial herb with antidiabetic and cytotoxic constituents. In continuation of our study on <i>S. grosshiemii</i> to identify the bioactive phytochemicals, we have reported the characterization of seven undescribed triterpenoids. The aerial parts of the plant were extracted in dichloromethane and its constituents were isolated using chromatography techniques. The structures of compounds were identified using 1D, 2D NMR, and ESI-MS spectral data. Seven new oleanane- and ursane-type triterpenoids (<b>1</b>-<b>7</b>) were identified in <i>S. grossheimii</i>. The structures of <b>1</b>-<b>7</b> were characterized as; 2<i>α</i>-hydroxy-3<i>β</i>-acetoxy-olean-9(11),12-diene (<b>1</b>), 2<i>α</i>-acetoxy-3<i>β</i>-hydroxy-olean-9(11),12-diene (<b>2</b>), 3<i>β</i>-acetoxy-olean-18-ene,2<i>α</i>,11<i>α</i>-diol (<b>3</b>), 2<i>α</i>-hydroxy-3<i>β</i>-acetoxy-urs-9(11),12-diene (<b>4</b>), 2<i>α</i>-acetoxy-3<i>β</i>-hydroxy-urs-9(11),12-diene (<b>5</b>), 2<i>α</i>,3<i>β</i>-diacetoxy-urs-12-ene-11<i>α</i>,20<i>β</i>-diol (<b>6</b>), 2<i>α</i>,3<i>β</i>-diacetoxy-urs-9(11),12-diene-20<i>β</i>-ol (<b>7</b>). Triterpenoids (<b>2</b>, <b>5</b>, and <b>7</b>) were intramolecular transesterification or dehydration products of their corresponding isomers or allylic alcohol in the C rings, respectively, produced <i>in-situ</i> during NMR spectroscopy. Virtual screening of <b>1</b>-<b>7</b> was performed with molecular docking analysis to identify the potential SARS-CoV-2 and <i>α</i>-glucosidase inhibitors using the smina molecular docking algorithm. The best binding energy values (kcal/mol) against COVID-19 main protease M^pro were calculated for <b>6</b> (-8.77) and <b>7</b> (-8.68), and the higher binding affinities toward human <i>α</i>-glucosidase were obtained for <b>2</b> (-9.39) and <b>6</b> (-8.63). This study suggests <i>S. grossheimii</i> as a rich source of bioactive triterpenoids and introduces new natural compounds. Considering the high binding energy values of <b>2</b>, <b>6</b>, and <b>7</b>, these structures could be candidates for anti-COVID-19 and antidiabetic drug development in the future.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"540-548"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10327690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QSAR study of indole derivatives as active agents against <i>Candida albicans</i>: a DFT calculation.","authors":"Hanie Aminaee,&nbsp;Sharieh Hosseini,&nbsp;Asghar Davood,&nbsp;Elham Askarizadeh","doi":"10.1080/10799893.2022.2140166","DOIUrl":"https://doi.org/10.1080/10799893.2022.2140166","url":null,"abstract":"<p><p>Indole and its derivatives are common heterocyclic compounds in nature that have a wider range of medicinal activities such as antifungal, anti-inflammatory, and anti-seizure. Virtually all indole derivatives showed outstanding antifungal activity against <i>Candida albicans</i>. The aim of this study was to QSAR modeling of indole derivatives and the design of new drugs that have antifungal activity. In this study, 52 compounds were selected. All optimized compounds and quantum descriptors were obtained using Gaussian software and DFT/B3LYP computational method with 6-31 G (d) basis set al, so other descriptors were determined using Dragon software. To examine the relationship between these descriptors and the activity of these compounds, the MLR linear correlation method was used, and the QSAR equation with R² = 0.7884 and <i>R</i> = 0.8879 was obtained for it. Likewise, MSE = 0.1897, RMSE = 0.2848, and Q² = 0.68663 approve the acceptability of the obtained model. The obtained equation reveals that the activity of these compounds is related to the negative coefficient of GATS8p, R7e +, and G2e, which means that with increasing the values ​​of these description nodes, the amount of activity declines. On the other hand, the activity of these compounds depended on the positive coefficients of HATS3p, MATS5e, and RDF045, i.e. with increasing these values, the activity of these compounds also increases, and a good correlation was obtained between the experimental and predicted activity values.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"614-622"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10335676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CBLC inhibits the proliferation and metastasis of breast cancer cells via ubiquitination and degradation of CTTN.","authors":"Weiwei Li,&nbsp;Ting Lei,&nbsp;Xiaoyu Song,&nbsp;Chun Deng,&nbsp;Jingrun Lu,&nbsp;Wenwu Zhang,&nbsp;Zhenzhan Kuang,&nbsp;Yongyin He,&nbsp;Quan Zhou,&nbsp;Zhaoxun Luo,&nbsp;Fei Mo,&nbsp;Hanlin Yang,&nbsp;Jianfeng Hang,&nbsp;Bin Xiao,&nbsp;Linhai Li","doi":"10.1080/10799893.2022.2116049","DOIUrl":"https://doi.org/10.1080/10799893.2022.2116049","url":null,"abstract":"<p><p>The E3 ubiquitin ligase is an important regulator of cell signaling and proteostasis and is tightly controlled in many diseases, including cancer. Our study aimed to investigate the biological role of the E3 ubiquitin ligase CBLC in breast cancer and elucidate the specific mechanistic network underlying CBLC-mediated target substrate degradation, cell proliferation and metastasis. Here, we showed that CBLC expression was higher in breast cancer tissues and cells than that in normal tissues and cells. Higher expression of CBLC predicted a better prognosis for breast cancer patients. CBLC inhibited the proliferation, migration and invasion of breast cancer cells. Co-IP and immunofluorescence co-localization assays demonstrated that CBLC interacted with CTTN in the cytoplasm. CBLC promoted the degradation of CTTN through the ubiquitin-proteasome pathway without affecting its mRNA level. The inhibitory effect of CBLC on breast cancer cell proliferation, migration and invasion could partly be reversed by CTTN. Taken together, our study clarified the biological role of CBLC as a tumor suppressor and discovered its functional substrate, providing a molecular basis for CBLC/CTTN as a potential therapeutic target in breast cancer.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"588-598"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10396474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In silico</i> screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 as potential MDR reversal agents.","authors":"Fatemeh Moosavi, Tahereh Damghani, Somayeh Ghazi, Somayeh Pirhadi","doi":"10.1080/10799893.2022.2086988","DOIUrl":"10.1080/10799893.2022.2086988","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using <i>in silico</i> studies.</p><p><strong>Methods: </strong>Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations.</p><p><strong>Results: </strong>Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results.</p><p><strong>Conclusion: </strong>We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"549-561"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10702327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gαs and Gαq/11 protein coupling bias of two AVPR2 mutants (R68W and V162A) that cause nephrogenic diabetes insipidus.","authors":"Beril Erdem Tuncdemir","doi":"10.1080/10799893.2022.2102651","DOIUrl":"https://doi.org/10.1080/10799893.2022.2102651","url":null,"abstract":"<p><p>Loss-of-function mutations of the arginine vasopressin receptor 2 gene (AVPR2) cause Nephrogenic diabetes insipidus (NDI). AVPR2 is a kind of G protein coupled receptor (GPCR) and mainly couples with Gαs protein leading to cAMP accumulation in the cell as a secondary messenger. Recent studies showed that some AVPR2 mutations could cause biased Gαq/11 protein coupling rather than Gαs. Investigation into the characterization of biased receptors may give insights into the relationship between the conformational change of the receptor because of the mutation and related downstream signaling. In this study, R68W and V162A were analyzed to whether they show a bias to Gαs or Gαq/11 proteins. Their functionality in terms of cAMP production <i>via</i> Gαs protein coupling was decreased compared to the wild-type receptor. On the other hand, they showed the ability to couple with Gαq/11 protein and make Ca²⁺ mobilization at different levels in the cell. R68W showed bias to coupling with Gαq/11 protein rather than V162A and wild-type receptor. Studies about the Gα protein coupling bias of mutant AVPR2s may broaden our understanding of the relationship between the changed conformation of the receptor and consequently activated signaling pathways, and also may shed light on the development of more effective new therapeutics.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"573-579"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10359783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel mycocompounds as inhibitors of PI3K/AKT/mTOR pathway against RCC.","authors":"Ravi Prakash Yadav,&nbsp;Srilagna Chatterjee,&nbsp;Arindam Chatterjee,&nbsp;Dilip Kumar Pal,&nbsp;Sudakshina Ghosh,&nbsp;Krishnendu Acharya,&nbsp;Madhusudan Das","doi":"10.1080/10799893.2022.2123515","DOIUrl":"https://doi.org/10.1080/10799893.2022.2123515","url":null,"abstract":"<p><p>PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from <i>Astraeus hygrometricus</i> against key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"599-607"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10411097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ozone protects cardiomyocytes from myocardial ischemia-reperfusion injury through miR-200c/FOXO3 axis.","authors":"Lian Zhang,&nbsp;Xingping Men,&nbsp;Shenglong Yu,&nbsp;Huizhuang Guo,&nbsp;Yi Luo,&nbsp;Hanwei Chen,&nbsp;Shaohua Mi","doi":"10.1080/10799893.2022.2060259","DOIUrl":"https://doi.org/10.1080/10799893.2022.2060259","url":null,"abstract":"<p><strong>Purpose: </strong>Myocardial ischemia-reperfusion injury (I/R) is a detrimental process contributing to the pathological progression of coronary artery diseases. Studies indicate that miRNAs are implicated in ischemic heart disease, and ozone therapy could protect the heart from ischemic heart disease. In this study, we investigated the effect of ozone on miR-200c expression and the potential role of miR-200c in an I/R myocardial injury model.</p><p><strong>Methods: </strong>A myocardial cellular model of I/R was established to detect the expression of miR-200c. Cardiomyocytes with I/R induction were treated with ozone as a cellular model to detect miR-200 expression and investigate its functional roles. The downstream target of miR-200c was predicted with Starbase online tools and validated by dual luciferase reporter assay. The function of miR-200c/FOXO3 axis in I/R was examined by CCK-8 proliferation and apoptotic assays.</p><p><strong>Results: </strong>miR-200c was upregulated in primary cardiomyocytes of the I/R model. In cardiomyocyte cells, cell proliferation in the I/R group was significantly impaired, which could be partially rescued by miR-200c inhibitor or ozone treatment. Cell death detected by LDH release and apoptosis assay in the I/R model could also be inhibited by miR-200c inhibitor or ozone treatment. FOXO3 was identified as a downstream target of miR-200c, which was induced by ozone treatment and suppressed by miR-200c. Silencing FOXO3 abrogated the protective effect of ozone treatment on the I/R cell model.</p><p><strong>Conclusion: </strong>Overall, our results suggest that ozone plays a cardio-protective role in I/R through regulating miR-200/FOXO3 axis, and indicate that targeting miR-200/FOXO3 axis could potentially alleviate I/R.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"531-539"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10817490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylglyoxal enhances the proliferation of vascular smooth muscle cells via Akt phosphorylation.","authors":"Mustafa Kırça","doi":"10.1080/10799893.2022.2098328","DOIUrl":"https://doi.org/10.1080/10799893.2022.2098328","url":null,"abstract":"<p><p>Methylglyoxal (MGO) is predominantly produced as a by-product of the glycolysis pathway. The glyoxalase system effectively removes it in a healthy organism. However, this process is impaired, and MGO level is elevated in people with diabetes. MGO's effects on proliferation were mostly studied in cancer cells, and the data in other cell types are limited. This study inspected the proliferative capacity of MGO in vascular smooth muscle cells (VSMCs), which have a crucial role in atherosclerosis and restenosis. The roles of ERK1/2 MAPK and Akt phosphorylations in proliferation were determined. Telmisartan, irbesartan, and NF-κB inhibitor JSH-23's roles in protecting the cells from MGO-induced proliferation were also investigated. Primary VSMCs were isolated from the rat aorta. The proliferation was spectrophotometrically measured by using a tetrazolium salt (Wst-1). The cells were cultured in standard media (SM, glucose conc. 5.5 mM) or high glucose media (HGM, glucose conc. 25 mM; an <i>in vitro</i> model of hyperglycemia). ERK1/2 MAPK and Akt phosphorylations were determined by the western blot method. MGO triggered the proliferation at 24, 48, and 72 hrs in SM and 48 and 72 hrs in HGM. Low doses of MGO such as 1-10 µM can induce proliferation. The phosphorylated ERK1/2 MAPK and Akt participated in MGO-induced proliferation. Telmisartan, irbesartan, and JSH-23 effectively alleviated the proliferation and Akt phosphorylation. MGO could proliferate VSMCs even at low doses. Moreover, hypertensive diabetic patients might benefit from a sartan family drug to protect VSMCs from MGO-induced proliferation.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"567-572"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10335788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between kisspeptin and gonadotropin-inhibitory hormone in the silence of puberty: preclinical evidence from a calcium signaling study.","authors":"Ferah Bulut,&nbsp;Emine Kacar,&nbsp;Batuhan Bilgin,&nbsp;Munevver Gizem Hekim,&nbsp;Muhammed Mirac Keleştemur,&nbsp;Zafer Sahin,&nbsp;Ahmet Ayar,&nbsp;Mete Ozcan","doi":"10.1080/10799893.2022.2125014","DOIUrl":"https://doi.org/10.1080/10799893.2022.2125014","url":null,"abstract":"<p><p>Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are among suggested neuroendocrine modulators of reproductive function. Intracellular calcium signaling is a critical component in the regulation of a variety of physiological and pathological processes including neurotransmitter release, and, therefore, can be used as signaling indicator for investigating the involvement of kisspeptin, GnIH, and gonadotropin-releasing hormone (GnRH) release. Hence, this study investigated the effects of kisspeptin and GnIH on calcium signaling using immortalized hypothalamic cells (rHypoE-8) as a model. Kisspeptin neurons were loaded with the ratiometric calcium dye (Fura-2 AM, 1 μmol) and intracellular free calcium ([Ca²⁺]_i) responses were quantified using digital fluorescence imaging system. Kisspeptin-10 (100, 300, and 1000 nM) caused a significant increase in [Ca²⁺]_i in rHypoE-8 cells (<i>n</i> = 58, <i>n</i> = 64, and <i>n</i> = 49, respectively, <i>p</i> < 0.001). The kisspeptin receptor antagonist, P234, inhibited the calcium responses to kisspeptin (<i>p</i> < 0.001, <i>n</i> = 32). GnIH (100 and 1000 nM), alone, did not cause any significant change in the mean basal [Ca²⁺]_i levels in kisspeptin cells, but GnIH attenuated the kisspeptin-evoked [Ca²⁺]_i transients (<i>n</i> = 47, <i>p</i> < 0.001). This novel findings of [Ca²⁺]_i signaling in <i>in vitro</i> setting implicate that kisspeptin and GnIH may exert their effects on hypothalamus-pituitary-gonadal (HPG) axis by modulating kisspeptin neurons. These results also implicate that kisspeptin neurons may have an autocrine regulation.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"608-613"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10336587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological characterization of the α_2A-adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency.","authors":"Joseph P Biggane, Ke Xu, Brianna L Goldenstein, Kylie L Davis, Elizabeth J Luger, Bethany A Davis, Chris W D Jurgens, Dianne M Perez, James E Porter, Van A Doze","doi":"10.1080/10799893.2022.2110896","DOIUrl":"10.1080/10799893.2022.2110896","url":null,"abstract":"<p><p>The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α₁, α₂, and other receptor subtypes. Correlation and slope of unity were found for the α_2A-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC₅₀) and relative efficacy (RE) were determined. Compared with NE (pEC₅₀, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC₅₀, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC₅₀, 7.94; RE, 37.9%), exhibited the highest potency (pEC₅₀). In contrast, the catecholamines, EPI (pEC₅₀, 6.95; RE, 120%) and α-methyl-NE (pEC₅₀, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α_2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α_2A-AR agonists that can cross the blood-brain barrier.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"42 6","pages":"580-587"},"PeriodicalIF":2.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10710878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10607954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}