scholarly journals Data Supporting a New Physiological Role for Brain Apelin in the Regulation of Hypothalamic Oxytocin Neurons in Lactating Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (9) ◽  
pp. 3492-3503 ◽  
Author(s):  
Laurence Bodineau ◽  
Christopher Taveau ◽  
Hong-Hanh Lê Quan Sang ◽  
Guillaume Osterstock ◽  
Isabelle Queguiner ◽  
...  
Keyword(s):  
Direct Action ◽  
Physiological Role ◽  
Double Immunofluorescence ◽  
Endogenous Ligand ◽  
Electrophysiological Measurements ◽  
Apelin Receptor ◽  
Immunofluorescence Labeling ◽  
G Protein Coupled

Apelin is a bioactive peptide identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ in 1998. The present data show that apelin modulates the activity of magnocellular and parvocellular oxytocin (OXY) neurons in the lactating rat. A combination of in situ hybridization and immunohistochemistry demonstrated the presence of apelin receptor mRNA in hypothalamic OXY neurons. Double immunofluorescence labeling then revealed the colocalization of apelin with OXY in about 20% of the hypothalamic OXY-positive neurons. Intracerebroventricular apelin administration inhibited the activity of magnocellular and parvocellular OXY neurons, as shown by measuring the c-fos expression in OXY neurons or by direct electrophysiological measurements of the electrical activity of these neurons. This effect was correlated with a decrease in the amount of milk ejected. Thus, apelin inhibits the activity of OXY neurons through a direct action on apelin receptors expressed by these neurons in an autocrine and paracrine manner. In conclusion, these findings highlight the inhibitory role of apelin as an autocrine/paracrine peptide acting on OXY neurons during breastfeeding.

The calcitonin receptor regulates osteocyte lacunae acidity during lactation in mice

2021 ◽  
Vol 249 (1) ◽  
pp. 31-41
Author(s):  
Rachel A Davey ◽  
Michele V Clarke ◽  
Suzanne B Golub ◽  
Patricia K Russell ◽  
Jeffrey D Zajac
Keyword(s):  
Gene Expression ◽  
Direct Action ◽  
Physiological Role ◽  
Calcitonin Receptor ◽  
Ph Indicator ◽  
Osteocyte Lacunae ◽  
Osteocytic Osteolysis ◽  
Indicator Dye

The physiological role of calcitonin, and its receptor, the CTR (or Calcr), has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated two- to three-fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls. This was associated with an increase in osteoclast activity evidenced by increases in osteoclast surface/bone surface and Dcstamp gene expression. To investigate the mechanism by which the CTR inhibits osteocytic osteolysis, in vivo acidification of the osteocyte lacunae during lactation (P14 days) was assessed using a pH indicator dye. A lower pH was observed in the osteocyte lacunae of lactating Global-CTRKOs compared to controls and was associated with an increase in the gene expression of ATPase H+ transporting V0 subunit D2 (Atp6v0d2) in whole bone of Global-CTRKOs at the end of lacation (P21). To determine whether the CTR is required for the replacement of mineral within the lacunae post-lactation, lacunar area was determined 3 weeks post-weaning. Comparison of the largest 20% of lacunae by area did not differ between Global-CTRKOs and controls post-lactation. These results provide evidence for CTR activation to inhibit osteocytic osteolysis during lactation being mediated by regulating the acidity of the lacunae microenvironment, whilst the CTR is dispensable for replacement of bone mineral within lacunae by osteocytes post-lactation.

scholarly journals GPR55: a new promising target for metabolism?

2017 ◽  
Vol 58 (3) ◽  
pp. R191-R202 ◽  
Author(s):  
Eva Tudurí ◽  
Monica Imbernon ◽  
Rene Javier Hernández-Bautista ◽  
Marta Tojo ◽  
Johan Fernø ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Preclinical Models ◽  
Endogenous Ligand ◽  
Peripheral Tissues ◽  
Promising Target ◽  
Nutrient Partitioning ◽  
G Protein Coupled ◽  
Biological Actions

GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.

scholarly journals Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice

2006 ◽  
Vol 191 (1) ◽  
pp. 197-205 ◽  
Author(s):  
Takaharu Maruyama ◽  
Kenichi Tanaka ◽  
Jun Suzuki ◽  
Hiroyuki Miyoshi ◽  
Naomoto Harada ◽  
...  
Keyword(s):  
Bile Acid ◽  
G Protein ◽  
Physiological Role ◽  
Wild Type ◽  
Fat Accumulation ◽  
Acid Receptor ◽  
Bile Acid Receptor ◽  
The Impact ◽  
G Protein Coupled

G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for bile acid. Tissue distribution and cell-type specificity of Gpbar1 mRNA suggest a potential role for the receptor in the endocrine system; however, the precise physiological role of Gpbar1 still remains to be elucidated. To investigate the role of Gpbar1 in vivo, the Gpbar1 gene was disrupted in mice. In homozygous mice, total bile acid pool size was significantly decreased by 21–25% compared with that of the wild-type mice, suggesting that Gpbar1 contributes to bile acid homeostasis. In order to assess the impact of Gpbar1 deficiency in bile acid homeostasis more precisely, Gpbar1 homozygous mice were fed a high-fat diet for 2 months. As a result, female Gpbar1 homozygous mice showed significant fat accumulation with body weight gain compared with that of the wild-type mice. These findings were also observed in heterozygous mice to the same extent. Although the precise mechanism for fat accumulation in female Gpbar1 homozygous mice remains to be addressed, these data indicate that Gpbar1 is a potential new player in energy homeostasis. Thus, Gpbar1-deficient mice are useful in elucidating new physiological roles for Gpbar1.

Structure–activity relationship of novel macrocyclic biased apelin receptor agonists

2017 ◽  
Vol 15 (2) ◽  
pp. 449-458 ◽  
Author(s):  
Alexandre Murza ◽  
Xavier Sainsily ◽  
Jérôme Côté ◽  
Laurent Bruneau-Cossette ◽  
Élie Besserer-Offroy ◽  
...  
Keyword(s):  
G Protein ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
G Protein Coupled Receptor ◽  
Endogenous Ligand ◽  
Structure Activity ◽  
Apelin Receptor ◽  
Relationship Of ◽  
G Protein Coupled ◽  
Cardiovascular Functions

Apelin is the endogenous ligand for the G protein-coupled receptor APJ and exerts a key role in regulating cardiovascular functions.

Calcium pools, calcium entry, and cell growth

1996 ◽  
Vol 16 (2) ◽  
pp. 139-157 ◽  
Author(s):  
Donald L. Gill ◽  
Richard T. Waldron ◽  
Krystyna E. Rys-Sikora ◽  
Carmen A. Ufret-Vincenty ◽  
Matthew N. Graber ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Morphological Analysis ◽  
Essential Fatty Acids ◽  
Physiological Role ◽  
Wide Distribution ◽  
Short Term ◽  
Growth State

The Ca2+ pump and Ca2+ release functions of intracellular Ca2+ pools have been well characterized. However, the nature and identity of Ca2+ pools as well as the physiological implications of Ca2+ levels within them, have remained elusive. Ca2+ pools appear to be contained within the endoplasmic reticulum (ER); however, ER is a heterogeneous and widely distributed organelle, with numerous other functions than Ca2+ regulation. Studies described here center on trying to determine more about subcellular distribution of Ca2+ pools, the levels of Ca2+ within Ca2+ pools, and how these intraluminal Ca2+ levels may be physiologically related to ER function. Experiments utilizing in situ high resolution subcellular morphological analysis of ER loaded with ratiometric fluroescent Ca2+ dyes, indicate a wide distribution of inositol 1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pools within cells, and large changes in the levels of Ca2+ within pools following InsP3-mediated Ca2+ release. Such changes in Ca2+ may be of great significance to the translation, translocation, and folding of proteins in ER, in particular with respect to the function of the now numerously described luminal Ca2+-sensitive chaperonin proteins. Studies have also focussed on the physiological role of pool Ca2+ changes with respect to cell growth. Emptying of pools using Ca2+ pump blockers can result in cells entering a stable quiescent G0-like growth state. After treatment with the irreversible pump blocker, thapsigargin, cells remain in this state until they are stimulated with essential fatty acids whereupon new pump protein is synthesized, functional Ca2+ pools return, and cells reenter the cell cycle. During the Ca2+ pool-depleted growth-arrested state, cells express a Ca2+ influx channel that is distinct from the store-operated Ca2+ influx channels activated after short-term depletion of Ca2+ pools. Overall, these studies indicate that significant changes in intraluminal ER Ca2+ do occur and that such changes appear linked to alteration of essential ER functions as well as to the cell cycle-state and the growth of cells.

scholarly journals Exploring a role for heteromerization in GPCR signalling specificity

2010 ◽  
Vol 433 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Raphael Rozenfeld ◽  
Lakshmi A. Devi
Keyword(s):  
Physiological Role ◽  
Therapeutic Effects ◽  
Receptor Ligands ◽  
Physiological Processes ◽  
Downstream Effectors ◽  
Signal Specificity ◽  
G Protein Coupled ◽  
Intracellular Milieu ◽  
Formation Of Complexes

The critical involvement of GPCRs (G-protein-coupled receptors) in nearly all physiological processes, and the presence of these receptors at the interface between the extracellular and the intracellular milieu, has positioned these receptors as pivotal therapeutic targets. Although a large number of drugs targeting GPCRs are currently available, significant efforts have been directed towards understanding receptor properties, with the goal of identifying and designing improved receptor ligands. Recent advances in GPCR pharmacology have demonstrated that different ligands binding to the same receptor can activate discrete sets of downstream effectors, a phenomenon known as ‘ligand-directed signal specificity’, which is currently being explored for drug development due to its potential therapeutic advantage. Emerging studies suggest that GPCR responses can also be modulated by contextual factors, such as interactions with other GPCRs. Association between different GPCR types leads to the formation of complexes, or GPCR heteromers, with distinct and unique signalling properties. Some of these heteromers activate discrete sets of signalling effectors upon activation by the same ligand, a phenomenon termed ‘heteromer-directed signalling specificity’. This has been shown to be involved in the physiological role of receptors and, in some cases, in disease-specific dysregulation of a receptor effect. Hence targeting GPCR heteromers constitutes an emerging strategy to select receptor-specific responses and is likely to be useful in achieving specific beneficial therapeutic effects.

Demonstration and characterization of motilin-binding sites in the rabbit cerebellum

1997 ◽  
Vol 272 (5) ◽  
pp. G994-G999 ◽  
Author(s):  
I. Depoortere ◽  
T. L. Peeters
Keyword(s):  
Binding Sites ◽  
Molecular Layer ◽  
Physiological Role ◽  
Scatchard Analysis ◽  
Affinity Binding ◽  
Lower Affinity ◽  
Erythromycin A ◽  
G Protein Coupled

This is the first report on central motilin receptors. Autoradiography on cerebellar slices revealed specific motilin-binding sites in the molecular layer of the cortex. Scatchard analysis of cold saturation studies showed the existence of a high-(pKd,hi = 9.07 +/- 0.09, where pKd is the negative logarithm of the dissociation constant) and a low-affinity binding site (pKd,lo = 6.56 +/- 0.09). Similar affinities were found with rabbit motilin and with the porcine (po) antagonist [Phe3, Leu13]po-motilin. Feline and canine motilin had a markedly lower affinity for the low-affinity site (pKd,lo = 5.29 and 4.58, respectively); chicken motilin had a lower affinity for both sites (pKd,hi = 8.36, pKd,lo = 3.97). Erythromycin A and its derivative N-trimethyl erythromycin A cnol ether also bound to cerebellar motilin receptors (pKd,hi = 7.29 and 8.91, respectively). Structure-activity studies with motilin fragments and the potency ranking of agonists suggest that a novel subtype receptor of motilin may exist in the brain. Guanosine 5'-O-(3-thiotriphosphate) (0.1 mM) reduced the number and the affinity for the high-affinity binding sites, which is evidence for G protein-coupled receptors. Our findings open new perspectives for the study of the physiological role of motilin.

scholarly journals Engineering of chimeric peptides as antagonists for the G protein-coupled receptor, RXFP4

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Praveen Praveen ◽  
Ross A. D. Bathgate ◽  
Mohammed Akhter Hossain
Keyword(s):  
Physiological Role ◽  
Disulfide Bridges ◽  
Antagonist Activity ◽  
Partial Agonism ◽  
Relaxin Family ◽  
Specific Antagonist ◽  
Chimeric Peptides ◽  
Further Development ◽  
G Protein Coupled

AbstractInsulin-like peptide 5 (INSL5) is a very important pharma target for treating human conditions such as anorexia and diabetes. However, INSL5 with two chains and three disulfide bridges is an extremely difficult peptide to assemble by chemical or recombinant means. In a recent study, we were able to engineer a simplified INSL5 analogue 13 which is a relaxin family peptide receptor 4 (RXFP4)-specific agonist. To date, however, no RXFP4-specific antagonist (peptide or small molecule) has been reported in the literature. The focus of this study was to utilize the non-specific RXFP3/RXFP4 antagonist ΔR3/I5 as a template to rationally design an RXFP4 specific antagonist. Unexpectedly, we demonstrated that ΔR3/I5 exhibited partial agonism at RXFP4 when expressed in CHO cells which is associated with only partial antagonism of INSL5 analogue activation. In an attempt to improve RXFP4 specificity and antagonist activity we designed and chemically synthesized a series of analogues of ΔR3/I5. While all the chimeric analogues still demonstrated partial agonism at RXFP4, one peptide (Analogue 17) exhibited significantly improved RXFP4 specificity. Importantly, analogue 17 has a simplified structure which is more amenable to chemical synthesis. Therefore, analogue 17 is an ideal template for further development into a specific high affinity RXFP4 antagonist which will be an important tool to probe the physiological role of RXFP4/INSL5 axis.

scholarly journals Glycodelin mRNA is expressed in the genital tract of male and female rats (Rattus norvegicus)

1999 ◽  
Vol 23 (1) ◽  
pp. 57-66 ◽  
Author(s):  
C Keil ◽  
B Husen ◽  
J Giebel ◽  
G Rune ◽  
R Walther
Keyword(s):  
Epithelial Cells ◽  
Reproductive Tract ◽  
In Situ Hybridisation ◽  
Physiological Role ◽  
Reproductive Organs ◽  
Female Rats ◽  
Male And Female Rats ◽  
First Time

In the present study we demonstrate for the first time the expression of glycodelin mRNA in the female and male genital tracts of rats using non-radioactive in situ hybridisation. Glycodelin fragment 1 (+41 to +141) shares 100% homology with the human gene sequence. In the ovary, glycodelin mRNA was restricted to granulosa cells. In the uterus, glycodelin mRNA was expressed in all epithelial cells of the endometrium. In the male reproductive tract, glycodelin mRNA was distributed in all epithelial cells of the epididymis, the prostate and the seminal vesicle. However, in the testis, glycodelin mRNA was predominantly found in spermatogonia and in spermatocytes of the seminiferous epithelium. The expression in several reproductive organs of rats offers an excellent tool to study further the physiological role of glycodelin, which is so far thought to act as an immunosuppressive factor.

Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release

2007 ◽  
Vol 292 (1) ◽  
pp. E7-E15 ◽  
Author(s):  
Annabelle Reaux-Le Goazigo ◽  
Rodrigo Alvear-Perez ◽  
Philippe Zizzari ◽  
Jacques Epelbaum ◽  
Marie-Thérèse Bluet-Pajot ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Cellular Localization ◽  
Physiological Role ◽  
Nerve Fibers ◽  
Male Rat ◽  
Stimulatory Action ◽  
Receptor Mrna ◽  
Apelin Receptor ◽  
Acth Release

Apelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 ± 0.3%) and to a much lower extent in somatotropes (3.2 ± 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10−6 M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10−6 M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K+-evoked ACTH release, with maximal increase being observed for a 10−6 M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions.

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