DOCSLIB.ORG

A Potential Role of Apelin-13 Against Hepatic Injury and Metabolic Disorders in Preeclampsia Induced by L-NAME

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Potential Role of Apelin-13 Against Hepatic Injury and Metabolic Disorders in Preeclampsia Induced by L-NAME coatings Article A Potential Role of Apelin-13 against Hepatic Injury and Metabolic Disorders in Preeclampsia Induced by L-NAME Reham Z. Hamza 1,* , Abdel Aziz A. Diab 2, Mansour H. Zahra 2, Mai S. Attia 2, Suzan M. M. Moursi 3 and Najah M. Al-Baqami 4 1 Biology Department, Faculty of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia 2 Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt 3 Medical Physiology Department, Faculty of medicine, Zagazig University, Zagazig 44519, Egypt 4 Department of Biological Sciences, Zoology, King Abdulaziz University, Jeddah 21589, Saudi Arabia * Correspondence: [email protected] or [email protected] or [email protected] Abstract: Background: Hypertensive disorders of pregnancy, gestational hypertension, and preeclamp- sia (PE) are exceptionally challenging, as their pathologies and therapeutic management simulta- neously influence the mother and embryo, sometimes putting their well-beings at odds with each other. Dysregulated lipid and glucose metabolism may be related to some cases of preeclampsia. Fluctuations in serum apelin levels may be attributed to changes in the serum levels of multiple interrelated factors such as insulin, insulin resistance, inflammatory cytokines, and nephritic dam- age. Previous studies demonstrated that apelin is an endogenous active peptide with vasodilatory and antioxidative-stress capabilities. Objective: We investigated the relationships among hepatic, nephrotic, and metabolic injuries in different preeclampsia-like mouse models and the potential effect Citation: Hamza, R.Z.; Diab, A.A.A.; of exogenous apelin administration on hepatic and nephrotic injuries and metabolic disorders in Zahra, M.H.; Attia, M.S.; Moursi, an N-nitro-L-arginine methyl ester (L-NAME) preeclampsia-like Sprague Dawley (SD) rat model. S.M.M.; Al-Baqami, N.M. A Potential Materials and methods: Forty-three adult female and ten adult male SD rats were involved in this Role of Apelin-13 against Hepatic study. The male rats were used to induce pregnancy. The female rats were randomly divided into Injury and Metabolic Disorders in four equal groups: a non-pregnant group, a normal pregnant group, a group treated with L-NAME Preeclampsia Induced by L-NAME. to induce preeclampsia, and a group treated with L-NAME and apelin. In all the groups, maternal Coatings 2021, 11, 391. https:// blood was collected on the 21st day of gestation, and serum samples were used for the determina- doi.org/10.3390/coatings11040391 tion of systolic blood pressure; the serum uric acid, creatinine, nitric oxide (NO), xanthine oxidase, myeloperoxidase, insulin, glucose, cholesterol, triglyceride (TG), aspartate aminotransferase (AST) Academic Editors: Diana Anderson and alanine aspartate aminotransferase (ALT) levels; and the HOMA-insulin resistance (HOMA-IR). and El-Sayed Abd El-Aziz Results: In rats with pre-eclampsia, the systolic blood pressure; the concentrations of serum uric acid, Received: 6 March 2021 creatinine, nitric oxide (NO), xanthine oxidase, myeloperoxidase, blood glucose, serum cholesterol, Accepted: 26 March 2021 triglycerides, AST, and ALT; and the calculated HOMA-IR were significantly increased compared Published: 30 March 2021 to those in the rats in the other groups. Additionally, apelin treatment significantly improved these parameters in the apelin-treated group. Conclusion: This study examined the potential mechanisms Publisher’s Note: MDPI stays neutral whereby apelin may act as a curative candidate to reduce hepatic injury and inhibit kidney damage with regard to jurisdictional claims in and the development of metabolic disorders in an experimental model of preeclampsia. published maps and institutional affil- iations. Keywords: preeclampsia; apelin; kidney diseases; hepatic diseases and metabolism Copyright: © 2021 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. Preeclampsia (PE) is a dangerous and potentially life-threatening disease for both the This article is an open access article mother and fetus, so it is very important to improve the standard diagnostic approach distributed under the terms and with complementary treatment to address this problem and develop future treatment conditions of the Creative Commons strategies [1]. Attribution (CC BY) license (https:// The cause of preeclampsia remains incompletely clarified due to the heterogeneous creativecommons.org/licenses/by/ nature of the disease [2]. This ailment is difficult for obstetricians, as there are no compelling 4.0/). Coatings 2021, 11, 391. https://doi.org/10.3390/coatings11040391 https://www.mdpi.com/journal/coatings Coatings 2021, 11, 391 2 of 12 ways to treat or prevent it, and the antenatal considerations include a troublesome harmony between the danger to the woman of continuing the pregnancy and the danger to the infant from preterm birth [3]. Despite the serious health, social, and economic costs of preeclampsia, no treatments are available to prevent, stabilize, or cure the disease. The only treatment is to end preg- nancy by delivery of the baby and placenta, which itself is related to dangers associated with premature birth [4]. Liver disorders of PE may be increased liver enzymes, low platelets (HELLP), acute fatty liver, hyperemesis gravidarum, intrahepatic cholestasis, and autoimmune liver [5]. In addition to control the mother’s metabolism, adipocytokines have been involved in pregnancy difficulties, including PE [6]. Apelin is a peptide hormone acting on Angiotensin II receptor-like - 1 (APJ) which is expressed in multiple tissues including the liver [7]. Apelin has been recognized as a novel adipocytokine, discharged in significant amounts by adipose tissue in a directed way. In this regard, apelin is upregulated by obesity and hyperinsulinemia in people and mice [8]. Apelin causes endothelium dependent vasorelaxation by setting off the release of NO, and it increases myocardial contractility [9,10]. In view of its angiogenic action, apelin discharged by adipocytes is likely to stimulate blood vessel growth, leading to increase growth of adipose tissue [8,11]. The hyperproduction of apelin observed in obesity has been proposed to be an adap- tive response that attempts to prevent the onset of obesity related disorders. Thus, research has focused on the potential link of apelin with obesity related insulin resistance [12,13]. APJ mRNA expression was identified in regions of the brain critical for the control of fluid homeostasis, so apelin may play a role in the regulation of water balance [7]. Sörhede Winzell et al. [14] reported that apelin inhibited insulin secretion in pancreatic islets in mice, suggesting a link with glucose homeostasis. A 14-day apelin treatment in mice was shown to regulate adiposity and to increase uncoupling protein expression [15], proposing a role of apelin in energy metabolism. Some studied documented also that apelin has anti-inflammatory effects by decreasing the mRNA level of IL- 6 and TNF- α [16]. It addi- tionally inhibits release of ROS in adipocytes and promotes an expression of antioxidative enzymes [17]. Notably, Zhou et al. [18] found that Fc-apelin greatly reduced macrophage infiltration and liver tissue injury by histology, which is in agreement with the observed reduction of serum ALT. Therefore, we designed this study to explore the possible effects of apelin-13 (a 13- amino-acid oligopeptide that is the ligand for the apelin receptor (also known as the APJ receptor) on renal functions in an L-NAME-induced rat model of preeclampsia and to identify the possible involved mechanisms. 2. Materials and Methods This study was carried out in the Faculty of Medicine, Zagazig University and in- volved 60 healthy adult albino rats (50 healthy females and 10 adult males for fertiliza- tion), which were obtained from the animal house of the Faculty of Veterinary Medicine, Zagazig University. Rats were kept in steel cages under hygienic conditions, fed a commer- cial diet with free access to water, and kept at room temperature on a 12 h light/dark cycle. The experimental methodology was conducted in accordance with the guidelines for the care and use of experimental animals and was reviewed and approved by the ZU-IACUC committee (approval number ZU-IACUC/1/F/78/2019). Induction of pregnancy: The estrous cycles of rats were investigated for 2 consecutive weeks. Unstained vaginal secretions were directly viewed every morning under a light microscope at 40× magnification, and the phases of the estrus cycle were detected by investigating the vaginal cytology. The estrus phase was determined by increasing the number of cornified or irregular-shaped epithelial cells in the vaginal smear. Rats in estrous stage were placed with a mature male rat in a separate cage. After mating, female rats were isolated to confirm copulation in the next morning by the presence of Coatings 2021, 11, 391 3 of 12 a copulation plug or sperms in the vaginal smear. The presence of sperms indicates the first day of gestation [19]. Seven rats from the forty did not get pregnant and have been excluded from the study. Forty three pregnant rats were randomly divided into four groups: Group 1 (normal non pregnant group; n = 10): Rats have been injected with saline solution (0.5 mL/kg body weight) subcutaneously daily. Group 2 (normal pregnant group; n = 10): Rats have been injected subcutaneously with saline as placebo from day 9 to 20 of gestation. Group 3 (PE-induced group; n = 12): Rats were injected subcutaneously with L-NAME (Sigma Aldrich Co.,
Load more

Recommended publications
  • Synthetic Nanobodies As Angiotensin Receptor Blockers
    Synthetic nanobodies as angiotensin receptor blockers Conor McMahona,1, Dean P. Stausb,c,1, Laura M. Winglerb,c,1,2, Jialu Wangc, Meredith A. Skibaa, Matthias Elgetid,e, Wayne L. Hubbelld,e, Howard A. Rockmanc,f, Andrew C. Krusea,3, and Robert J. Lefkowitzb,c,g,3 aDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; bHoward Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; cDepartment of Medicine, Duke University Medical Center, Durham, NC 27710; dJules Stein Eye Institute, University of California, Los Angeles, CA 90095; eDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; fDepartment of Cell Biology, Duke University Medical Center, Durham, NC 27710; and gDepartment of Biochemistry, Duke University Medical Center, Durham, NC 27710 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved July 13, 2020 (received for review May 6, 2020) There is considerable interest in developing antibodies as functional a need for more broadly applicable methodologies to discover modulators of G protein-coupled receptor (GPCR) signaling for both antibody fragments explicitly directed to the membrane- therapeutic and research applications. However, there are few an- embedded domains with limited surface exposure. tibody ligands targeting GPCRs outside of the chemokine receptor The angiotensin II type 1 receptor (AT1R) is a GPCR that group. GPCRs are challenging targets for conventional antibody dis- exemplifies the opportunities and the challenges surrounding an- covery methods, as many are highly conserved across species, are tibody drug development. Both the endogenous peptide agonist of biochemically unstable upon purification, and possess deeply buried the AT1R (angiotensin II) and small-molecule inhibitors (angio- ligand-binding sites.
    [Show full text]
  • Acute Restraint Stress Induces Cholecystokinin Release Via Enteric
    Neuropeptides 73 (2019) 71–77 Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep Acute restraint stress induces cholecystokinin release via enteric apelin T ⁎ Mehmet Bülbüla, , Osman Sinena, Onur Bayramoğlua, Gökhan Akkoyunlub a Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey b Department of Histology and Embryology, Akdeniz University, Faculty of Medicine, Antalya, Turkey ARTICLE INFO ABSTRACT Keywords: Stress increases the apelin content in gut, while exogenous peripheral apelin has been shown to induce chole- Apelin cystokinin (CCK) release. The present study was designed to elucidate (i) the effect of acute stress on enteric Restraint stress production of apelin and CCK, (ii) the role of APJ receptors in apelin-induced CCK release depending on the Cholecystokinin nutritional status. CCK levels were assayed in portal vein blood samples obtained from stressed (ARS) and non- APJ receptor stressed (NS) rats previously injected with APJ receptor antagonist F13A or vehicle. Duodenal expressions of Fasting apelin, CCK and APJ receptor were detected by immunohistochemistry. ARS increased the CCK release which was abolished by selective APJ receptor antagonist F13A. The stimulatory effect of ARS on CCK production was only observed in rats fed ad-libitum. Apelin and CCK expressions were upregulated by ARS. In addition to the duodenal I cells, APJ receptor was also detected in CCK-producing myenteric neurons. Enteric apelin appears to regulate the stress-induced changes in GI functions through CCK. Therefore, apelin/APJ receptor systems seem to be a therapeutic target for the treatment of stress-related gastrointestinal disorders. 1. Introduction for APJ in rodents (De Mota et al., 2000; Medhurst et al., 2003).
    [Show full text]
  • A Metabolically Stable Apelin-17 Analog Decreases AVP-Induced Antidiuresis and Improves Hyponatremia
    ARTICLE https://doi.org/10.1038/s41467-020-20560-y OPEN A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia Adrien Flahault 1,3, Pierre-Emmanuel Girault-Sotias 1,3, Mathilde Keck1, Rodrigo Alvear-Perez1, ✉ Nadia De Mota1, Lucie Estéoulle2, Sridévi M. Ramanoudjame2, Xavier Iturrioz1, Dominique Bonnet 2 & ✉ Catherine Llorens-Cortes 1 1234567890():,; Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inap- propriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In col- lecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment. 1 Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM, Unit U1050, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7241, Collège de France, Paris, France. 2 Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
    [Show full text]
  • Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin
    nutrients Review Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance Iwona Kojta, Marta Chaci ´nskaand Agnieszka Błachnio-Zabielska * Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Jana Kili´nskiego1, 15-089 Bialystok, Poland; [email protected] (I.K.); [email protected] (M.C.) * Correspondence: [email protected] Received: 1 April 2020; Accepted: 30 April 2020; Published: 3 May 2020 Abstract: Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. The exact mechanism by which adipose tissue induces insulin resistance is still unclear. It has been demonstrated that obesity is associated with the adipocyte dysfunction, macrophage infiltration, and low-grade inflammation, which probably contributes to the induction of insulin resistance. Adipose tissue synthesizes and secretes numerous bioactive molecules, namely adipokines and cytokines, which affect the metabolism of both lipids and glucose. Disorders in the synthesis of adipokines and cytokines that occur in obesity lead to changes in lipid and carbohydrates metabolism and, as a consequence, may lead to insulin resistance and type 2 diabetes. Obesity is also associated with the accumulation of lipids. A special group of lipids that are able to regulate the activity of intracellular enzymes are biologically active lipids: long-chain acyl-CoAs, ceramides, and diacylglycerols. According to the latest data, the accumulation of these lipids in adipocytes
    [Show full text]
  • The Effects of Apelin on Hypothalamic–Pituitary–Adrenal Axis
    123 The effects of apelin on hypothalamic–pituitary–adrenal axis neuroendocrine function are mediated through corticotrophin- releasing factor- and vasopressin-dependent mechanisms Michael J F Newson, Emma M Roberts, George R Pope, Stephen J Lolait and Anne-Marie O’Carroll Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK (Correspondence should be addressed to A-M O’Carroll; Email: [email protected]) Abstract The apelinergic system has a widespread expression in the (V1bR KO). Administration of pGlu-apelin-13 (1 mg/kg central nervous system (CNS) including the paraventricular i.c.v.) resulted in significant increases in plasma ACTH and nucleus, supraoptic nucleus and median eminence, and corticosterone (CORT), which were significantly reduced isolated cells of the anterior lobe of the pituitary. This pattern by pre-treatment with a-helical CRF9–41, indicating the of expression in hypothalamic nuclei known to contain involvement of a CRF-dependent mechanism. Additionally, corticotrophin-releasing factor (CRF) and vasopressin (AVP) pGlu-apelin-13-mediated increases in both plasma ACTH and to co-ordinate endocrine responses to stress has and CORT were significantly attenuated in V1bR KO generated interest in a role for apelin in the modulation of animals when compared with wild-type controls, indicating stress, perhaps via the regulation of hormone release from a role for the vasopressinergic system in the regulation of the pituitary. In this study, to determine whether apelin the effects of apelin on neuroendocrine function. Together, has a central role in the regulation of CRF and AVP these data confirm that the in vivo effects of apelin on neurones, we investigated the effect of i.c.v.
    [Show full text]
  • Apelin-13 Regulates Vasopressin-Induced Aquaporin-2 Expression and Trafficking in Kidney Collecting Duct Cells
    Cellular Physiology Cell Physiol Biochem 2019;53:687-700 DOI: 10.33594/00000016510.33594/000000165 © 2019 The Author(s).© 2019 Published The Author(s) by and Biochemistry Published online: online: 4 4October October 2019 2019 Cell Physiol BiochemPublished Press GmbH&Co. by Cell Physiol KG Biochem 687 Press GmbH&Co. KG, Duesseldorf BoulkerouaAccepted: 25 et September al.: Effect 2019 of Apelin-13 on Kidney Collectingwww.cellphysiolbiochem.com Duct Cells This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Interna- tional License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Original Paper Apelin-13 Regulates Vasopressin-Induced Aquaporin-2 Expression and Trafficking in Kidney Collecting Duct Cells Chahrazed Boulkerouaa Houda Ayaria Taoufik Khalfaouia Mylène Lafrancea Élie Besserer-Offroya Nadia Ekindib Robert Sabbaghc,d Robert Dumainea,d Olivier Lesurd,e Philippe Sarreta,d Ahmed Chraibia,d aDepartment of Pharmacology & Physiology, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC, Canada, bDepartment of Pathology, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC, Canada, cDepartment of Surgery, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC, Canada, dResearch Center of the Centre Hospitalier Universitaire de Sherbrooke (CR-CHUS), Sherbrooke University, Sherbrooke, QC, Canada, eDepartment of Medicine, Faculty of Medicine and Health Sciences, Sherbrooke University, QC, Canada Key Words Kidney • Aquaporin • Apelin • Vasopressin • Confocal microscopy • PCR • mpkCCD Abstract Background/Aims: Apelin and its G protein-coupled receptor APJ (gene symbol Aplnr) are strongly expressed in magnocellular vasopressinergic neurons suggesting that the apelin/APJ system plays a key role at the central level in regulating salt and water balance by counteracting the antiduretic action of vasopressin (AVP).
    [Show full text]
  • Adipokines in the Skin and in Dermatological Diseases
    International Journal of Molecular Sciences Review Adipokines in the Skin and in Dermatological Diseases Dóra Kovács 1 , Fruzsina Fazekas 1, Attila Oláh 2 and Dániel Tör˝ocsik 1,* 1 Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98., 4032 Debrecen, Hungary; [email protected] (D.K.); [email protected] (F.F.) 2 Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98., 4032 Debrecen, Hungary; [email protected] * Correspondence: [email protected]; Tel.: +36-52-255-602 Received: 31 October 2020; Accepted: 25 November 2020; Published: 28 November 2020 Abstract: Adipokines are the primary mediators of adipose tissue-induced and regulated systemic inflammatory diseases; however, recent findings revealed that serum levels of various adipokines correlate also with the onset and the severity of dermatological diseases. Importantly, further data confirmed that the skin serves not only as a target for adipokine signaling, but may serve as a source too. In this review, we aim to provide a complex overview on how adipokines may integrate into the (patho) physiological conditions of the skin by introducing the cell types, such as keratinocytes, fibroblasts, and sebocytes, which are known to produce adipokines as well as the signals that target them. Moreover, we discuss data from in vivo and in vitro murine and human studies as well as genetic data on how adipokines may contribute to various aspects of the homeostasis of the skin, e.g., melanogenesis, hair growth, or wound healing, just as to the pathogenesis of dermatological diseases such as psoriasis, atopic dermatitis, acne, rosacea, and melanoma.
    [Show full text]
  • Apelin‑13 Attenuates ER Stress‑Associated Apoptosis Induced by MPP+ in SH‑SY5Y Cells
    1732 INTERNATIONAL JOURNAL OF MOleCular meDICine 42: 1732-1740, 2018 Apelin‑13 attenuates ER stress‑associated apoptosis induced by MPP+ in SH‑SY5Y cells YUNLU JIANG1, HAIQING LIU2, BINGYUAN JI1, ZHENGWEN WANG1, CHUNMEI WANG1, CHUNQING YANG1, YANYOU PAN1, JING CHEN3, BAOHUA CHENG1 and BO BAI1 1Neurobiology Institute, Jining Medical University, Jining, Shandong 272067; 2Department of Physiology, Taishan Medical College, Taian, Shandong 271000, P.R. China; 3Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK Received October 12, 2017; Accepted May 31, 2018 DOI: 10.3892/ijmm.2018.3719 Abstract. Apelin-13, a neuropeptide that acts as a ligand for GRP78, CHOP and cleaved caspase-12 in MPP+-treated a putative receptor related to the angiotensin II type receptor, SH‑SY5Y cells, and significantly enhanced the expression elicits neuroprotective effects in numerous neurological condi- levels of phospho-ERK1/2. Taken together, the present results tions, such as Huntington's disease and cerebral ischemia. support a model in which apelin-13 inhibits MPP+-induced Parkinson's disease (PD), one of the most prevalent neuro- apoptosis of SH-SY5Y cells by decreasing the expression of degenerative diseases, is caused by damage to neurons in the GRP78, CHOP, and cleaved caspase-12, and by increasing the brain; however, the underlying mechanism remains unclear. expression of phospho-ERK1/2. The present findings suggest The present study explored the effects of apelin-13 on SH-SY5Y that apelin-13 may be useful for the treatment of PD. human neuroblastoma cells treated with 1-methyl-4-phenyl- pyridine (MPP+). Cell growth, cell viability, and apoptosis Introduction were measured by real-time cell analysis, the Cell Counting Kit-8 assay, and flow cytometry, respectively.
    [Show full text]
  • Cryo-EM Structures of PAC1 Receptor Reveal Ligand Binding Mechanism
    www.nature.com/cr www.cell-research.com ARTICLE OPEN Cryo-EM structures of PAC1 receptor reveal ligand binding mechanism Jia Wang 1, Xianqiang Song2, Dandan Zhang2, Xiaoqing Chen2, Xun Li2, Yaping Sun2, Cui Li2, Yunpeng Song2, Yao Ding2, Ruobing Ren3, Essa Hu Harrington4, Liaoyuan A. Hu 2, Wenge Zhong2, Cen Xu5, Xin Huang 6, Hong-Wei Wang 1 and Yingli Ma 2 The pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R) belongs to the secretin receptor family and is widely distributed in the central neural system and peripheral organs. Abnormal activation of the receptor mediates trigeminovascular activation and sensitization, which is highly related to migraine, making PAC1R a potential therapeutic target. Elucidation of PAC1R activation mechanism would benefit discovery of therapeutic drugs for neuronal disorders. PAC1R activity is governed by pituitary adenylate cyclase-activating polypeptide (PACAP), known as a major vasodilator neuropeptide, and maxadilan, a native peptide from the sand fly, which is also capable of activating the receptor with similar potency. These peptide ligands have divergent sequences yet initiate convergent PAC1R activity. It is of interest to understand the mechanism of PAC1R ligand recognition and receptor activity regulation through structural biology. Here we report two near-atomic resolution cryo-EM structures of PAC1R activated by PACAP38 or maxadilan, providing structural insights into two distinct ligand binding modes. The structures illustrate flexibility of the extracellular domain (ECD) for ligands with distinct conformations, where ECD accommodates ligands in different orientations while extracellular loop 1 (ECL1) protrudes to further anchor the ligand bound in the orthosteric site. By structure- guided molecular modeling and mutagenesis, we tested residues in the ligand-binding pockets and identified clusters of residues fi fi 1234567890();,: that are critical for receptor activity.
    [Show full text]
  • Chronic Central Administration of Apelin-13 Over 10 Days Increases Food Intake, Body Weight, Locomotor Activity and Body Temperature in C57BL/6 Mice
    Journal of Neuroendocrinology 20, 79–84 ORIGINAL ARTICLE ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd Chronic Central Administration of Apelin-13 Over 10 Days Increases Food Intake, Body Weight, Locomotor Activity and Body Temperature in C57BL/6 Mice A. Valle,* à N. Hoggard, A. C. Adams,à P. Roca* and J. R. Speakmanà *Grup de Metabolisme Energe`tic i Nutricio´, Departament de Biologia Fonamental i Cie`ncies de la Salut, Institut Universitari d’Investigacio´ en Cie`ncies de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain. Division of Obesity and Metabolic Health, Rowett Research Institute, Aberdeen Centre for Energy Regulation and Obesity (ACERO), Aberdeen, UK. àACERO, School of Biological Sciences, University of Aberdeen, Aberdeen, UK. Journal of The peptide apelin has been located in a wide range of tissues, including the gastrointestinal tract, stomach and adipose tissue. Apelin and its receptor has also been detected in the arcuate Neuroendocrinology and paraventricular nuclei of the hypothalamus, which are involved in the control of feeding behaviour and energy expenditure. This distribution suggests apelin may play a role in energy homeostasis, but previous attempts to discern the effects of apelin by acute injection into the brain have yielded conflicting results. We examined the effect of a chronic 10-day intracerebro- ventricular (i.c.v.) infusion of apelin-13 into the third ventricle on food intake, body temperature and locomotor activity in C57BL ⁄ 6 mice. Apelin-13 (1 lg ⁄ day) increased food intake significantly on days 3–7 of infusion; thereafter, food intake of treated and control individuals converged.
    [Show full text]
  • DIABETES PEPTIDES Peptides and Diabetes
    DIABETES PEPTIDES Peptides and Diabetes PEPTIDES FOR DIABETES RESEARCH In 2014, according to data from the WHO, 422 million adults (or 8.5% of the population) had diabetes mellitus, a chronic metabolic disorder characterized by hypergly- cemia, compared with 108 million (4.7%) in 1980. Diabe- tes mellitus can be divided into two main types, type 1 or insulin-dependent diabetes mellitus (IDDM) and type 2, or non insulin-dependent diabetes mellitus (NIDDM). The absolute lack of insulin, due to destruction of the insulin producing pancreatic β-cells, is the particular disorder in type 1 diabetes. Type 2 diabetes is mainly characterized by the inability of cells to respond to insulin. The condition affects mostly the cells of muscle and fat tissue, and re- sults in a condition known as „insulin resistance“. Introduction means ‘to flow through’. The adjective mel- Diabetes was already known in ancient litus, which comes from Latin and means times. The name of this disease was created ‘honey-sweet’, was added by the German by the Graeco-Roman physician Aretaeus physician Johann Peter Frank (1745-1821). of Cappadocia (approx. 80 - 130 AD) and is It was introduced in order to distinguish derived from the Greek word diabainein that diabetes mellitus, also called ‘sugar dia- betes’, from diabetes insipidus, where an excessive amount of urine is produced as a result of a disturbance of the hormonal control of reabsorption of water in the kid- neys. In 1889, pancreatic secretions were EFFECTS OF shown to control blood sugar levels. How- ever, it took another 30 years until insulin DIABETES was purified from the islets of Langerhans.
    [Show full text]
  • Helix 8 Is the Essential Structural Motif of Mechanosensitive Gpcrs
    ARTICLE https://doi.org/10.1038/s41467-019-13722-0 OPEN Helix 8 is the essential structural motif of mechanosensitive GPCRs Serap Erdogmus1,10, Ursula Storch1,2,10, Laura Danner1, Jasmin Becker1, Michaela Winter1, Nicole Ziegler3, Angela Wirth4,5, Stefan Offermanns4,6, Carsten Hoffmann 7, Thomas Gudermann1,8,9*& Michael Mederos y Schnitzler1,8* G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but 1234567890():,; also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology. 1 Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336 Munich, Germany. 2 Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Pettenkoferstr. 9, 80336 Munich, Germany. 3 Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany.
    [Show full text]