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Vasoactive Intestinal Peptide: A Neural Modulator of Endocrine Function
Published in Craig A. Johnston, Charles D. Barnes, Brain-Gut Peptides and Reproductive Function, 2020
Willis K. Samson, Marc E. Freeman
As early as 1902 (Bayliss and Starling), descriptions of acid-extractable substances in gut tissue possessing a wide spectra of bioactivity hinted at the presence of peptides now known to comprise the secretin/vasoactive intestinal peptide (VIP) family of hormones. Originally called the Secretin Family, perhaps because the first of the two peptides characterized was the 27-amino acid secretin (Jorpes et al., 1962), it has become popular to refer to this group of structural homologs as the VIP Family. No doubt this reflects the explosion of literature on VIP which occurred from 1975 to the present (Said and Mutt, 1988).
Hindbrain Neuroactive Substances Controlling Gastrointestinal Function
Published in T. S. Gaginella, Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Zbigniew K. Krowicki, Pamela J. Hornby
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide of the VIP/glucagon/secretin family of peptides with a putative neurotransmitter/neuromodulator role,242 is widely distributed in the CNS, predominately as PACAP38, a 38 amino acid molecule.243 Specific PACAP binding sites have been identified in the rat and bovine brain.244, 245 Recent studies have demonstrated a distribution of PACAP-like immunoreactive cell bodies as well as various densities of fibers in rat medulla, including the DVC, raphe nuclei, and the NA.246 Preliminary experiments show that microinjection of PACAP38 into the DVC, NRO, and the NA in alpha-chloralose-anesthetized rats at doses of 1 to 100 pmol dose-dependently increased intragastric pressure.
Gastrointestinal physiology
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2015
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The secretin family of peptides include secretin, gastric inhibitory peptide and vasoactive intestinal peptide. Secretin, a 27 amino acid peptide, is synthesized and released from S cells in the duodenal mucosa. It is released in response to a low intraluminal pH in the duodenum. Secretin stimulates the release of about 80% of bicarbonate from cells lining the pancreatic and biliary duct, and the duodenal epithelial cells during normal digestion and absorption. Gastric inhibitory peptide is released from intestinal K cells in response to carbohydrates, fat and proteins in the meal. Its main function is to inhibit gastric acid secretion and enhance the release of insulin from the pancreas by glucose (incretin).
Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders
Published in Expert Opinion on Therapeutic Targets, 2018
Mahip K. Verma, Rajan Goel, Nandakumar Krishnadas, Kumar V. S. Nemmani
GIP is a 42 amino acid peptide secreted from the intestinal K-cells in response to the meal intake, regulating post-prandial glucose homeostasis [13]. Existence of the GIP mRNA and protein has been shown to be widely distributed in the rat brain, apart from the possibility of peripheral GIP entering the brain through BBB [14]. Further investigations confirmed the presence of GIP immunoreactivity in several brain regions, e.g. the hippocampus, olfactory bulb, cerebellar Purkinje cells, cerebral cortex, striatal dopaminergic neurons, substantia nigra, and lateral septal nucleus, suggestive of its potential roles as a neurotransmitter or as a neuromodulator [5,15]. Among other peptides of the glucagon-secretin family, GIP expression correlates with potentiation of the adult hippocampal cells by regulating the neural progenitor cell proliferation in the dentate gyrus of rat brain [14]. Apart from the CNS, GIP is expressed in rat spinal cord neurons, dorsal root ganglion (DRG), and sciatic nerve indicating regulatory roles in the peripheral nervous system [16]. GIP expression in DRG was detected in small, medium, and larger diameter neurons, with prominescense on the smaller diameter fibers [16]. Myelinating Schwann cells, satellite cells, and nonneuronal oligodendroglial and ependymal cells exhibit distinct GIP immunopositivity [16]. Human brain mapping revealed widespread expression of GIP and GIPR, with highest levels in nucleus acumbens, frontal cortex, and striatum [17].
Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions
Published in Expert Opinion on Drug Discovery, 2020
Andrey D. Bondarev, Misty M. Attwood, Jörgen Jonsson, Vladimir N. Chubarev, Vadim V. Tarasov, Helgi B. Schiöth
The aGPCR family is an evolutionarily ancient receptor family within the GPCR superfamily, encompassing 33 members in humans, divided into nine subfamilies [2,8]. The different main branches of the GPCR family are suggested to have originated from a common ancestor [9] supported with detailed analysis of the 7-transmembrane (7TM) domains. There is also considerable evidence that the well-known Secretin family, which includes drug targets mediating the effects of several hormones, has descended from the ancient aGPCR receptor branch [10]. Interestingly, the aGPCR family is also identified in the fungi, where it notably lacks the N-terminal domains [11].
Discovery and design of G protein-coupled receptor targeting antibodies
Published in Expert Opinion on Drug Discovery, 2023
Sean M. Peterson, Catherine J. Hutchings, Cameron F. Hu, Melina Mathur, Janelle W. Salameh, Fumiko Axelrod, Aaron K. Sato
Many antibodies have been described that act as G protein-coupled receptor antagonists. The secretin family B1 receptors have a large N-terminal domain that binds to an agonist that forms an alpha-helical rod (Figure 1B). We recently described a competitive antagonist antibody [16] called TB-001-003 against GLP-1 R, which is a Class B1 or a secretin family GPCR. This antibody was derived from our GPCR-directed antibody library that has GPCR ligands grafted into an extended complementary determining region 3 (CDR3). Thus, TB-001-003 is able to displace GLP-1 from GLP-1 R, in a similar way to the peptide antagonist avexitide (exendin-(9-39)). In contrast, the GLP-1 R antagonist antibody, Fab 3F52, was raised against the GLP-1 R large N-terminus and was shown by x-ray crystallography to inhibit GLP-1 binding via an allosteric inhibition mechanism [46]. Similar to TB-001-003, a GIPR antagonist antibody called Gipg013 was shown to displace the alpha-helical GIP peptide from the N-terminal domain of GIPR [47]. Regeneron had advanced crotedumab [48], another antagonist antibody for the secretin family GPCR called glucagon receptor (GCGR), to Phase 1 clinical trials for cardiometabolic disorders, but further development has been discontinued [49]. Crotedumab was generated using a humanized mouse immunization of GCGR [50]. REMD Biotherapeutics has advanced another GCGR antagonist antibody, volagidemab, to Phase 2 trials for the treatment of diabetes [51,52]. Finally, a nanobody antagonist was also developed against GCGR [53]. Very few antibodies targeting GPCRs have been clinically approved globally; one is called erenumab to treat migraine. Erenumab binds to the calcitonin gene-related peptide type 1 receptor (CALRL) complexed to a receptor activity-modifying protein 1 (RAMP1) [54]. The complex of CALRL and RAMP1 is called calcitonin gene-related peptide receptor (CGRPR) and erenumab was raised against an asymmetric Fc fusion of the RAMP1 and CALRL extracellular domains [55,56].