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American Journal of Physiology.... Jan 2005Glucose-dependent insulinotropic polypeptide (GIP) regulates glucose homeostasis and high-fat diet-induced obesity and insulin resistance. Therefore, elucidating the...
Glucose-dependent insulinotropic polypeptide (GIP) regulates glucose homeostasis and high-fat diet-induced obesity and insulin resistance. Therefore, elucidating the mechanisms that regulate GIP release is important. GIP is produced by K cells, a specific subtype of small intestinal enteroendocrine (EE) cell. Bombesin-like peptides produced by enteric neurons and luminal nutrients stimulate GIP release in vivo. We previously showed that PMA, bombesin, meat hydrolysate, glyceraldehyde, and methylpyruvate increase hormone release from a GIP-producing EE cell line (GIP/Ins cells). Here we demonstrate that bombesin and nutrients additively stimulate hormone release from GIP/Ins cells. In various cell systems, bombesin and PMA regulate cell physiology by activating PKD signaling in a PKC-dependent fashion, whereas nutrients regulate cell physiology by inhibiting AMPK signaling. Western blot analyses of GIP/Ins cells using antibodies specific for activated and/or phosphorylated forms of PKD and AMPK and one substrate for each kinase revealed that bombesin and PMA, but not nutrients, activated PKC, but not PKD. Conversely, nutrients, but not bombesin or PMA, inhibited AMPK activity. Pharmacological studies showed that PKC inhibition blocked bombesin- and PMA-stimulated hormone release, but AMPK activation failed to suppress nutrient-stimulated hormone secretion. Forced expression of constitutively active vs. dominant negative PKDs or AMPKs failed to perturb bombesin- or nutrient-stimulated hormone release. Thus, in GIP/Ins cells, PKC regulates bombesin-stimulated hormone release, whereas nutrients may control hormone release by regulating the activity of AMPK-related kinases, rather than AMPK itself. These results strongly suggest that K cells in vivo independently respond to neuronal vs. nutritional stimuli via two distinct signaling pathways.
Topics: Adenylate Kinase; Bombesin; Carcinogens; Cells, Cultured; Drug Synergism; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Humans; Insulin; Protein Hydrolysates; Protein Kinase C; Signal Transduction; Tetradecanoylphorbol Acetate
PubMed: 15383372
DOI: 10.1152/ajpendo.00346.2004 -
Current Opinion in Endocrinology,... Feb 2008Mammalian bombesin-related peptides, gastrin-releasing peptide and neuromedin B actions are mediated by two receptors (BB1-receptor, BB2-receptor), which are closely... (Review)
Review
PURPOSE OF REVIEW
Mammalian bombesin-related peptides, gastrin-releasing peptide and neuromedin B actions are mediated by two receptors (BB1-receptor, BB2-receptor), which are closely related to the orphan receptor BRS-3 (BB3-receptor). The purpose of this review is to highlight advances in the understanding of these peptides in physiology/disease states.
RECENT FINDINGS
Pharmacologic/receptor-knockout studies show involvement of these receptors in a number of new processes/diseases. Neuromedin B/BB1-receptor is an important physiological regulator of pituitary-thyroid function; in mediating behavior, especially feas/anxiety; in mediating satiety through different cascades than gastrin-releasing peptide/BB2 receptors and for its autocrine tumor-growth effects. Gastrin-releasing peptide/BB2-receptor plays important roles in mediating signals for pruritus, lung development/injury, small intestinal mucosal defense, and central nervous system processes such as learning/memory. The signaling mechanisms of its potent growth effects are being elucidated and their possible therapeutic targets identified. BB3-receptor knockout mice provided insights for their obesity/glucose intolerance and demonstrated that this receptor may be important in the lung response to injury, tumor growth and gastrointestinal motility. Each receptor is frequently overexpressed in human tumors and has potent growth effects. This effect is being explored to develop new antitumor treatments, such as bombesin-receptor ligands conjugated to cytotoxic agents.
SUMMARY
This receptor family is involved in an increasing number of central nervous system/peripheral processes physiologically and in disease states, and increased understanding of its role may lead to novel treatments.
Topics: Animals; Antineoplastic Agents; Bombesin; Cell Proliferation; Humans; Neoplasms; Peptide Fragments; Receptors, Bombesin
PubMed: 18185064
DOI: 10.1097/MED.0b013e3282f3709b -
The Yale Journal of Biology and Medicine 1997Since ancient times, bile secretion has been considered vital for maintaining health. One of the main functions of bile secretion is gastric acid neutralization with... (Review)
Review
Since ancient times, bile secretion has been considered vital for maintaining health. One of the main functions of bile secretion is gastric acid neutralization with biliary bicarbonate during a meal or Pavlovian response. Although the liver has many extrinsic and intrinsic nerve innervations, the functional role of these nerves in biliary physiology is poorly understood. To understand the role of neural regulation in bile secretion, our recent studies on the effect of bombesin, a neuropeptide, on bile secretion and its underlying mechanisms will be reviewed. Using isolated perfused rat livers (IPRL) from both normal and 2 week bile duct ligated rats, as well as hepatocyte couplets and isolated bile duct units (IBDU) from normal rat livers, bombesin was shown to stimulate biliary bicarbonate and fluid secretion from bile ducts. Detailed pH studies indicated that bombesin stimulated the activity of Cl-/HCO3- exchanger, which was counterbalanced by a secondary activation of electrogenic Na+/HCO3- symport. Quantitative videomicroscopic studies showed that bombesin-stimulated fluid secretion in IBDU was dependent on Cl- and HCO3- in the media, anion exchanger(s), Cl- and K+ channels, and carbonic anhydrase, but not on the microtubular system. Furthermore, this bombesin response is inhibited by somatostatin but not substance P. Finally, studies of secondary messengers in isolated cholangiocytes and IBDU indicated that bombesin had no effect on intracellular cAMP, cGMP, or Ca++ levels in cholangiocytes. These results provide evidence that neuropeptides such as bombesin can directly stimulate fluid and bicarbonate secretion from cholangiocytes by activating luminal Cl-/HCO3- exchange, but by different mechanisms from those established for secretin. These findings, in turn, suggest that neuropeptides may play an important regulatory role in biliary transport and secretion. Thus, this neuropeptidergic regulation of bile secretion may provide a plausible mechanism for the bicarbonate-rich choleresis seen with meals or Pavlovian response.
Topics: Animals; Antiporters; Bicarbonates; Bile; Bile Ducts; Bombesin; Carrier Proteins; Chloride-Bicarbonate Antiporters; Humans; In Vitro Techniques; Ion Transport; Liver; Perfusion; Rats; Sodium-Bicarbonate Symporters
PubMed: 9626761
DOI: No ID Found -
Digestion 2013The gastrointestinal tract has a major role in digestion and absorption of nutrients while playing a leading role in defense of the body. It forms a shield against the... (Review)
Review
The gastrointestinal tract has a major role in digestion and absorption of nutrients while playing a leading role in defense of the body. It forms a shield against the invasion of various microorganisms or their products (e.g. antigens, toxins) and therefore it is important to establish its integrity and functionality. That depends on the route of administration and the composition of the artificial nutrition. This study concentrates on the influences of different kinds of artificial nutrition in the functionality of the intestinal mucosal barriers. It seems that full macromolecular solutions of enteral nutrition ensure an adequate mucous immune response, while a lack of nutritional stimulus in the lumen leads rapidly to a dysfunction of gastric-associated lymphatic tissue and mucosal immune system. This dysfunction renders the patients susceptible to infections in distant organs, hospital pneumonia, and multiorgan failure of non-infectious etiology. In patients with indication of total parenteral nutrition administration, addition of bombesin or glutamine preserves mucosal immune response and may limit the adverse effects.
Topics: Bacterial Translocation; Bombesin; Enteral Nutrition; Food, Formulated; Glutamine; Humans; Immunity, Mucosal; Intestinal Mucosa; Multiple Organ Failure; Neurotransmitter Agents; Parenteral Nutrition Solutions; Parenteral Nutrition, Total; Systemic Inflammatory Response Syndrome
PubMed: 24247113
DOI: 10.1159/000353603 -
International Journal of Molecular... Feb 2023Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic... (Review)
Review
Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical, and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby, the recent advances in the field of applications of various nanoplatforms that are able to reach the GRPR-expressing cells are reviewed.
Topics: Humans; Bombesin; Nanomedicine; Neoplasms; Receptors, Bombesin; Theranostic Nanomedicine
PubMed: 36834867
DOI: 10.3390/ijms24043455 -
The Journal of International Medical... 2012Increased understanding of prostate cancer biology has led to new treatment strategies and promising new agents for treating prostate cancer, in particular peptide-based... (Review)
Review
Increased understanding of prostate cancer biology has led to new treatment strategies and promising new agents for treating prostate cancer, in particular peptide-based agonists and antagonists. In this review article, new therapy modalities and potential approaches for the treatment of advanced prostate cancer are discussed, including agonists and antagonists of luteinizing hormone-releasing hormone, antagonists of bombesin/gastrin-releasing peptide, and growth hormone-releasing hormone and somatostatin analogues. Though the prognosis of patients with prostate cancer is much improved by some of these treatment approaches, including combination treatment methods, extensive side-effects are still reported. These include sexual dysfunction, functional lesions of the liver and renal system, osteoporosis, anaemia and diarrhoea. Future studies should focus on new treatment agents and treatment approaches that can eliminate side-effects and improve quality of life in patients with prostate cancer on the basis of potent treatment efficacy.
Topics: Animals; Antineoplastic Agents, Hormonal; Bombesin; Clinical Trials as Topic; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Octreotide; Oligopeptides; Peptide Fragments; Prostatic Neoplasms; Sermorelin
PubMed: 22971474
DOI: 10.1177/147323001204000401 -
Proceedings of the National Academy of... Feb 2023Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including...
Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Phe, β-Ala, Phe, Nle] Bn (6-14), in complex with G heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and G proteins signaling of GRPR, which are expected to accelerate the structure-based design of GRPR antagonists and agonists for the treatments of cancer and pruritus.
Topics: Male; Humans; Mice; Animals; Receptors, Bombesin; Cryoelectron Microscopy; Bombesin; Gastrin-Releasing Peptide; Neoplasms; Pruritus
PubMed: 36724251
DOI: 10.1073/pnas.2216230120 -
Journal of Neurophysiology Nov 2014Intrathecal administration of the neurotoxin bombesin-saporin reduces or abolishes pruritogen-evoked scratching behavior. We investigated whether spinal neurons that...
Intrathecal administration of the neurotoxin bombesin-saporin reduces or abolishes pruritogen-evoked scratching behavior. We investigated whether spinal neurons that respond to intradermal (ID) injection of pruritogens also respond to spinal superfusion of bombesin and vice versa. Single-unit recordings were made from superficial lumbar spinal dorsal horn neurons in anesthetized mice. We identified neurons with three search strategies: 1) ID injection of the nonhistaminergic itch mediator chloroquine, 2) spinal superfusion of bombesin, and 3) noxious pinch. All units were tested with an array of itch mediators (chloroquine, histamine, SLIGRL, BAM8-22), algogens [capsaicin, allyl isothiocyanate (AITC)], and physical stimuli (brush, pinch, noxious heat, cooling) applied to the hindlimb receptive field. The vast majority of chloroquine-responsive units also responded to bombesin. Of 26 chloroquine-sensitive units tested, most responded to SLIGRL, half responded to histamine and/or BAM8-22, and most responded to capsaicin and/or AITC as well as noxious thermal and mechanical stimuli. Of 29 bombesin-responsive units, a large majority also responded to other itch mediators as well as AITC, capsaicin, and noxious thermal and mechanical stimuli. Responses to successive applications of bombesin exhibited tachyphylaxis. In contrast, of 36 units responsive to noxious pinch, the majority (67%) did not respond to ID chloroquine or spinal bombesin. It is suggested that chloroquine- and bombesin-sensitive spinal neurons signal itch from the skin.
Topics: Animals; Bombesin; Capsaicin; Chloroquine; Histamine; Hot Temperature; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; Oligopeptides; Peptide Fragments; Posterior Horn Cells; Pruritus; Touch
PubMed: 25122701
DOI: 10.1152/jn.00409.2014 -
The Journal of Biological Chemistry Jul 2001Substance P analogues including [d-Arg1,d-Phe5,d-Trp7,9,Leu11]substance P (SpD) act as "broad spectrum neuropeptide antagonists" and are potential anticancer agents that...
Substance P analogues including [d-Arg1,d-Phe5,d-Trp7,9,Leu11]substance P (SpD) act as "broad spectrum neuropeptide antagonists" and are potential anticancer agents that inhibit the growth of small cell lung cancer cells in vitro and in vivo. However, their mechanism of action is controversial and not fully understood. Although these compounds block bombesin-induced mitogenesis and signal transduction, they also have agonist activity. The mechanism underlying this agonist activity was examined. SpD binds to the ligand-binding site of the bombesin/gastrin-releasing peptide receptor and blocks the bombesin-stimulated increase in [Ca2+]i within the same concentration range that causes sustained activation of c-Jun N-terminal kinase and extracellular signal-regulated protein kinase (ERK). The activation of c-Jun N-terminal kinase by SpD and bombesin is blocked by dominant negative inhibition of G(alpha12). The ERK activation by SpD is pertussis toxin-sensitive in contrast to ERK activation by bombesin, which is pertussis toxin-insensitive but dependent on epidermal growth factor receptor phosphorylation. SpD does not simply act as a partial agonist but differentially modulates the activation of the G-proteins G(alpha12), G(i), and G(q) compared with bombesin. This unique ability allows the bombesin receptor to couple to G(i) and at the same time block receptor activation of G(q). Our results provide direct evidence that SpD is acting as a "biased agonist" and that this has physiological relevance in small cell lung cancer cells. This validation of the concept of biased agonism has important implications in the development of novel pharmacological agents to dissect receptor-mediated signal transduction and of highly selective drugs to treat human disease.
Topics: 3T3 Cells; Animals; Binding Sites; Blotting, Western; Bombesin; COS Cells; Calcium; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; GTP-Binding Proteins; Genes, Dominant; Humans; Ligands; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Models, Theoretical; Pertussis Toxin; Phosphorylation; Protein Binding; Quinazolines; Rats; Receptors, Bombesin; Signal Transduction; Substance P; Time Factors; Tumor Cells, Cultured; Tyrphostins; Virulence Factors, Bordetella
PubMed: 11323408
DOI: 10.1074/jbc.M009772200 -
British Journal of Pharmacology Oct 1975The pharmacological activity of two natural bombesin-like peptides, alytesin and litorin, and 25 related synthetic peptides has been compared to that of bombesin. 2 The...
The pharmacological activity of two natural bombesin-like peptides, alytesin and litorin, and 25 related synthetic peptides has been compared to that of bombesin. 2 The minimum length of the amino acid chain required for the first appearance of bombesin-like effects was represented by the C-terminal heptapeptide, and the minimum length for maximal effects by the C-terminal nonapeptide. The latter possessed approximately the same activity as bombesin and may be considered a good substitute. 3 Both the tryptophan and histidine residues seemed to be essential for bombesin-like activity. 4 The C-terminal octapeptide was less active than either bombesin or the C-terminal nonapeptide and its action was more rapid in onset and less sustained. 5 Litorin apparently has an intermediate position between bombesin octapeptide and bombesin nonapeptide in the speed and duration of its effects. The relationship between structure and activity is discussed.
Topics: Animals; Blood Pressure; Bombesin; Cats; Dogs; Female; Gallbladder; Gastric Juice; Gastric Mucosa; Gastrins; In Vitro Techniques; Intestines; Muscle Contraction; Muscle, Smooth; Oligopeptides; Peptides; Rats; Structure-Activity Relationship; Time Factors; Urinary Bladder; Uterine Contraction
PubMed: 1201380
DOI: 10.1111/j.1476-5381.1975.tb07631.x