Receptor-effector coupling by G proteins

Conscious rats were infused via a jugular vein catheter with 5 x 10-6 g/kg/h caerulein for periods up to 24 h. On macroscopic inspection a progressive interstitial oedema is seen to develop in the pancreas, from one hour of infusion on and is most marked at twelve hours. This oedema is largely reabsorbed after 24 h treatment, but the pancreas is considerably indurated by this time. Serum amylase levels increase consistently to reach a tenfold elevation above controls after three, six or twelve hours infusion. Premature fusion of condensing vacuoles and secretory granules leads to formation of large vacuoles in the cytoplasm of exocrine pancreatic cells. These vacuoles fuse with the lateral and basal plasma membrane and realease their content into the extracellular space. Regular discharge of zymogen granules at the cell apex into the duct system does not occur. Vacuole formation is associated with cytoplasmic destruction of the pancreatic cells. The rate of protein synthesis decreases consistently as a result of these structural alterations and this change corresponds largely to a reduction of cellular respiration. Release of amylase from isolated pancreatic lobules of caerulein infused animals shows a progressive increase of unstimulated discharge, while in vitro stimulation with 5 x 10-6M carbamylcholine gives secretion patterns of wash-out kinetics. Stimulated discharge of labeled secretory proteins indicates a progressive reduction in the in vitro sensitivity of the pancreatic cells to secretagogues. After 24 h infusion of 5 x 10-6 g/kg/h caerulein the pancreatic lobules are totally insensitive to the in vitro effect of carbamylcholine or caerulein.

Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue.

Distribution of vasoactive intestinal polypeptide in the rat and mouse brain

The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB1), the gastrin-releasing peptide (GRP) receptor (BB2), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB3). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB3 has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions.

https://pharmrev.aspetjournals.org/content/pharmrev/60/1/1.full.pdf

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

Bombesin (BBS) is a tetradecapeptide originally isolated from amphibian skin1. BBS-like irnmunoactivity is widely distributed in mammalian gut2–5, and plasma levels have been shown to rise sharply following feeding (ref. 6 and V. Erspamer, personal communication). The physiological actions of BBS are unknown. We have previously shown that the classic gut hormone cholecystokinin (CCK) is a powerful and specific suppressor of food intake7–9. Although CCK and BBS lack common amino acid sequences, they have certain common actions on gut viscera10,11. We have now shown that BBS also suppresses food intake, and we compare its action with that of CCK.

Bombesin suppresses feeding in rats.

1
The interaction of the vasoactive intestinal peptide family of hormones with synaptic membranes from guinea pig brain was examined using 125I-labeled vasoactive intestinal peptide as a tracer molecule. Binding of this peptide was rapid and temperature-dependent, as well as reversible and saturable. Scatchard plots were compatible with the existence of two classes of binding sites, the first class with an apparent Kd of 36 nM and a low binding capacity (4 pmol vasoactive intestinal peptide/mg membrane protein) and a second class of binding sites with a lower affinity (apparent Kd of 285 nM) and a higher capacity (20 pmol vasoactive intestinal peptide/mg membrane protein).

2
The specificity of binding sites for vasoactive intestinal peptide was established from the fact that binding of the 125I-labeled peptide was inhibited by the unlabeled peptide and by higher concentrations of unlabeled secretin but not by the parent hormone glucagon or by the neuropeptides somatiostatin, bombesin, C-terminal octapeptide of pancreozymin, Leu-enkephalin, and substance P.

3
Na+, K+, Ca2+, Mg2+ and EDTA reduced the amount of 125I-labeled vasoactive intestinal peptide bound at equilibrium. The monovalent and divalent cations decreased the binding rate constant, whereas EDTA increased the dissociation rate constant of binding.

4
Nucleoside triphosphates and diphosphates decreased binding of the 125I-labeled peptide at equilibrium and increased the rate constant of dissociation of membrane-bound vasoactive intestinal peptide. Guanyl nucleotides were the most potent and in this class of nucleotides GTP was 6-fold more potent than guanosine 5′-[β,γ-imido]triphosphate.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1978.tb12585.x

Specific Binding of Vasoactive Intestinal Peptide to Brain Membranes from the Guinea Pig

Bombesin (a tetradecapeptide), the C-terminal nonapeptide of bombesin (bombesin-NP), and litorin (a parent nonapeptide), each stimulated amylase secretion from rat pancreatic fragments. These responses were not affected by atropine. The concentrations that produced half-maximal stumulation of secretion were 0.25 nM for bombesin, 0.30 nM for bombesin-NP, and 0.07 nM for litorin, as compared to 0.12 nM for caerulein and 0.80 muM for the cholinergic agent carbamylcholine. When used at maximal concentrations, bombesin, bombesin-NP, and litorin showed no action on cyclic AMP levels in the presence of 5 mM theophylline. By contrast, caerulein and secretin increased cyclic AMP levels by 27 and 208%, respectively. Bombesin, bombesin-NP, and litorin did not activate adenylate cyclase in a purified pancreatic plasma membrane preparation, whereas caerulein and secretin increased this activity 20 and 16-times, respectively...

/pdf/in-vitro-action-of-bombesin-and-bombesin-like-peptides-on-1vq12m4kwc.pdf

In vitro action of bombesin and bombesin-like peptides on amylase secretion, calcium efflux, and adenylate cyclase activity in the rat pancreas: a comparison with other secretagogues.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2877%2980645-5

Characterization of VIP-sensitive adenylate cyclase in guinea pig brain

KoRBERECHT, P., M. DESCHODT-LANCKMAN, J. CAMUS, J. BRUYLANDS, AND J. CHRISTOPHE. Rat pancreatic hydrolases from birth to weaning and dietary adaptation cfter weaning. Am. J. Physi~l. 221(l): 376-381. 197 1 .-Within 2-4 days after birth, there was a marked depletion of cr-amylase and chymotrypsinogen in the rat pancreas. During the period 14-2 1 days, a-amylase, lipase, trypsins, and chymotrypsin increased in the small intestine, the three first corresponding levels of (pro) enzymes in the pancreas doing the same, but less evidently. After weaning (21 days) enzyme activities in the pancreas were modified by the nature of the diet. Amylase was markedly augmented by increasing the dietary intake of starch, lipase by lard, and trypsinogens by casein. The most important modifications, already manifested after 2 days, were a twofold increase in the specific activity of amylase on starch diet and a fourfold increase in the specific activity of lipase and trypsinogens, on lard and casein diets, respectively. Comparison of enzyme activities in pancreas and in small and large intestines indicates that rates of biosynthesis and secretion were not the sole factors determining intestinal activities in weanling rats. This was confirmed by a study of the in vitro stability of hydrolases in the washings of the small intestine, indicating that the stability of trypsins and amylase was reduced by 4 days of high-casein or high-lard diets. L

Deschodt-Lanckman M

Papers

Specific Binding of Vasoactive Intestinal Peptide to Brain Membranes from the Guinea Pig

In vitro action of bombesin and bombesin-like peptides on amylase secretion, calcium efflux, and adenylate cyclase activity in the rat pancreas: a comparison with other secretagogues.

Characterization of VIP-sensitive adenylate cyclase in guinea pig brain

Rat pancreatic hydrolases from birth to weaning and dietary adaptation after weaning.

VIP activation of rat anterior pituitary adenylate cyclase