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At least 19 recordsLinked to original sources
PubMed1992

Neuropeptide Y1 subtype pharmacology of a recombinantly expressed neuropeptide receptor.

Neuropeptide Y (NPY) is an important central and peripheral modulator of neural and endocrine functions. This neuropeptide interacts with at least two pharmacologically distinct receptors, termed Y1 and Y2. At Y1 receptors, the NPY analog [Leu31,Pro34] NPY, but not the carboxyl-terminal fragment NPY-(18-36), displaces radiolabeled NPY and the sequence-related peptide YY, whereas Y2 receptors exhibit the opposite selectivity. We have used cultured mammalian 293 cells for the high level transient expression of a previously cloned putative neuropeptide receptor of rat brain. We report that this receptor displays the ligand binding properties and selectivity of a Y1 receptor, with a single high affinity site for 125I-NPY (Kd, 0.7 +/- 0.2 nM). The functionality of the recombinantly expressed receptor was demonstrated by an inhibition of adenylyl cyclase and a concomitant mobilization of intracellular Ca2+.

Amino Acid Sequence↗
PubMed1998

Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists.

Neuropeptides, including mammalian bombesin-like peptides, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. These signaling peptides exert their characteristic effects on cellular processes by binding to specific G protein-coupled receptors (GPCR) on the surface of their target cells. Typically, the binding of a neuropeptide to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades is an important early response to neuropeptides. An emerging theme in signal transduction is that these agonists also induce rapid and coordinate tyrosine phosphorylation of cellular proteins including the nonreceptor tyrosine kinase p125fak and the adaptor proteins p130cas and paxillin. This tyrosine phosphorylation pathway depends on the integrity of the actin cytoskeleton and requires functional Rho. The purpose of this article is to review recent advances in unraveling the pathways that play a role in transducing mitogenic and migratory responses induced by G protein-coupled neuropeptide receptor agonists.

Animals↗
PubMed1995

Dual organisation of the Drosophila neuropeptide receptor NKD gene promoter.

Neuropeptide function in the peripheral and central nervous systems has been described in mammals as well as in insects. We previously reported the cloning of the neuropeptide receptor NKD, a Drosophila melanogaster homologue of the mammalian tachykinin receptors. This receptor is expressed during Drosophila embryonic development and in the adult fly. Use of the NKD promoter region to drive beta-galactosidase expression in transgenic flies reveals a bipartite promoter organisation: the distal region controls NKD expression in neurosecretory cells of the central nervous system during late embryogenesis, whereas the proximal region is responsible for transient expression in peripheral nervous system during late embryogenesis, whereas the proximal region is responsible for transient expression in peripheral nervous system precursor cells early in development. This early NKD expression, first restricted to the sensory organ precursor cell, an atonal positive cell, is abolished in the ato1 mutant. In addition, we show that the proneural protein atonal, in association with daughterless, transactivates the NKD promoter in Schneider S2 cells via the proximal E box NKDE2. Furthermore, heterodimers of atonal and daughterless interact with this E box in gel shift assay.

Amino Acid Sequence↗
PubMed2004

A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.

BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism.

Autistic Disorder↗
PubMed1996

Local up-regulation of neuropeptide receptors in host blood vessels around human colorectal cancers.

BACKGROUND & AIMS: Neuropeptide receptors, expressed at high density by neoplastic cells, can be instrumental for diagnosis and therapy. However, little is known about neuropeptides and neuropeptide receptors in the tumor bed. The aim of this study was to study the expression of two neuropeptide receptors in peritumoral blood vessels. METHODS: Somatostatin and substance P receptors were measured using in vitro receptor autoradiography in well-defined submucosal and subserosal vessels located in the immediate surroundings of human colorectal carcinomas or in normal colon taken at increasing distances from the tumor. RESULTS: Both receptors were 3-5-fold overexpressed in the host veins within a 2-cm-wide area surrounding human primary colorectal carcinomas compared with veins located at 5-10-cm distance in normal gut tissue. The expression of peritumoral vascular somatostatin receptor and substance P receptor appears independent of receptor expression in the tumor, of tumor stage, and of the grade of local inflammation. CONCLUSIONS: These biochemical alterations of veins in the immediate vicinity of tumors represent a novel tumor-related site of expression for the two receptors and may point to a new biological principle of host-tumor interaction. Thus, vascular regulatory mechanisms in the tumor bed may be important for tumor development and metastasis and may be used as a target for tumor therapy.

Aged↗
PubMed2006

Modeling of neuropeptide receptors Y1, Y4, Y5, and docking studies with neuropeptide antagonist.

Neuropeptide Y (NPY), receptors belong to the G-protein coupled receptor superfamily. NPY mediates several physiological responses, such as blood pressure, food intake, sedation. These actions of NPY are mediated by six receptor subtypes denoted as Y1-Y5 and y6. Modeling of receptor subtypes and binding site identification is an important step in developing new therapeutic agents. We have attempted to model the three NPY receptor types, Y1, Y4, and Y5 using homology modeling and threading methods. The models are consistent with previously reported experimental evidence. To understand the interaction and selectivity of NPY analogues with different neuropeptide receptors, docking studies of two neuropeptide analogues (BVD10 and BVD15) with receptors Y1 and Y4 were carried out. Results of the docking studies indicated that the interaction of ligands BVD10 and BVD15 with Y1 and Y4 receptors are different. These results were evaluated for selectivity of peptide analogues BVD10 and BVD15 towards the receptors.

Amino Acid Sequence↗
PubMed1998

G protein-coupled receptors in gastrointestinal physiology. II. Regulation of neuropeptide receptors in enteric neurons.

Neuropeptides exert their diverse biological effects by interacting with G protein-coupled receptors (GPCRs). In this review we address the question, What regulates the ability of a target cell, in particular a neuron, to respond to a neuropeptide? Available evidence from studies of many GPCRs in reconstituted systems and transfected cell lines indicates that much of this regulation occurs at the level of the receptor and serves to alter the capacity of the receptor to bind ligands with high affinity and to couple to heterotrimeric G proteins. Although some of the knowledge gained from these studies is applicable to the regulation of neuropeptide receptors on neurons, at present there are far more questions than answers.

Animals↗
PubMed1990

Molecular cloning of a novel G protein-coupled receptor that may belong to the neuropeptide receptor family.

A novel cDNA encoding a putative G protein-coupled receptor was isolated from a rat forebrain cDNA library by homology screening. Sequence comparison demonstrates that the encoded polypeptide containing seven transmembrane domains shows highest homology with tachykinin receptors, particularly in the transmembrane domains and the first intracellular loop. The mRNA for this new receptor seems specifically expressed in brain and is prominently localized in specific nuclei of the rat brain, including thalamus, cerebral cortex and hippocampus. We speculate that a neuropeptide may be the natural ligand of this novel G protein-coupled receptor.

Amino Acid Sequence↗
PubMed1992

The structure of neuropeptide receptors.

Recently, the primary structures of 17 different receptors for neuropeptides and small peptide hormones have been elucidated by molecular cloning. All but one belong to the superfamily of G-protein coupled receptors which share a topography consisting of seven transmembrane domains. Comparison of primary structures shows that two classes of peptide receptors exist. One referred to as the 'neurokinin-type receptors', possesses many of the typical, conserved amino acid sequence motifs of the aminergic transmitter receptors (e.g. beta-adrenoceptor). The other, referred to the 'secretin-type receptors', displays unrelated and distinctly different sequence motifs which are conserved between the three presently known members of this class. These are the secretin, calcitonin and parathyroid hormone/parathyroid hormone-like polypeptide receptors. One may speculate that many other peptides with a core of biological activity in the N-terminal or middle region may have receptors of the secretin-type.

Amino Acid Sequence↗
PubMed1995

Distribution of neuropeptide receptors. New views of peptidergic neurotransmission made possible by antibodies to opioid receptors.

The cloning of receptors for neuropeptides made possible studies that identified the neurons that utilize these receptors. In situ hybridization can detect transcripts that encode receptors and thereby identify the cells responsible for their expression, whereas immunocytochemistry enables one to determine the region of the plasma membrane where the receptor is located. We produced antibodies to portions of the predicted amino acid sequences of delta, mu, and kappa opioid receptors and used them in combination with antibodies to a variety of neurotransmitters in multicolor immunofluorescence studies visualized by confocal microscopy. Several findings are notable: First, the cloned delta opioid receptor appears to be distributed primarily in axons, and therefore most likely functions in a presynaptic manner. Second, the cloned mu and kappa opioid receptors are found associated with neuronal plasma membranes of dendrites and cell bodies and therefore most likely function in a postsynaptic manner. However, in certain, discrete populations of neurons, mu and kappa opioid receptors appear to be distributed in axons. Third, enkephalin-containing terminals are often found in close proximity (although not necessarily synaptically linked) to membranes containing either the delta or mu opioid receptors, whereas dynorphin-containing terminals are often found in proximity to kappa opioid receptors. Finally, a substantial mismatch between opioid receptors and their endogenous ligands was observed in some brain regions. However, this mismatch was characterized by complementary zones of receptor and ligand, suggesting underlying principles of organization that underlie long-distance, nonsynaptic neurotransmission.

Afferent Pathways↗
PubMed1997

Structure-based design in drug discovery--the application of a peptoid drug design strategy for the development of non-peptide neuropeptide receptor ligands.

Over the last decade the increasing availability of metabolically- stable non-peptide antagonists targeted at neuropeptide receptors has led directly to a more thorough understanding of the role of neuropeptides in mammalian physiology. By far the majority of these non-peptide neuropeptide receptor antagonists thus far disclosed have been developed from leads identified from broad screening of company compound files or natural product collections, and may thus bear little obvious structural resemblance to the endogenous peptide ligand. This review will focus on an alternative structure-based approach to non-peptide neuropeptide receptor ligand design, referred to as the 'peptoid' drug design strategy, in which an appreciation of the structure of the neuropeptide is the key to the success of this approach. The development and current clinical progress of peptoid cholecystokinin and tachykinin receptor ligands that have thus far resulted from this process will be highlighted and used to exemplify the importance of this novel approach.

Journal Article↗
PubMed1985

Strategies in neuropeptide receptor binding research.

Strategies and general approaches used in neuropeptide receptor binding assays are described. Special attention is given to the nature of the ligand, its physical and chemical stability and the demonstration of an appropriate ligand selectivity pattern. Examples are given to illustrate critical aspects of neuropeptide receptor binding assays. Strong correlation between binding and bioassay data is also stressed.

Animals↗
PubMed2001

Localization and characterization of neuropeptide receptors in human colon.

Information about the expression of neuropeptide receptors is limited in human peripheral tissues, such as the gastrointestinal tract, as compared to the brain. A detailed evaluation of binding sites for gastrin-releasing peptide (GRP), neuropeptide Y, vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP), gastrin/cholecystokinin, neurotensin, substance P and somatostatin was therefore undertaken in human colon using in vitro receptor autoradiography and subtype characterization with receptor-selective ligands. GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensinl and sst2 receptors were abundantly expressed in the myenteric plexus. Y2, neurotensinl and sst2 receptors were also strongly expressed in the submucosal plexus. Furthermore, expression of GRP receptors, neurokinin (NK)1 receptors, VIP type2-receptors and sst2 receptors was found in the mucosa-directed margin of the circular smooth muscle where the interstitial cells of Cajal are located. A variable and complementary expression of GRP receptors, VIP/PACAP receptors, Y2 neurotensinl, NK1 and somatostatin receptors was found in the circular and longitudinal smooth muscle. NK1 and Y1 receptors were often detected in arteries and veins, while VIP/PACAP and sst2 receptors were found in lymphoid follicles. Y2, VIP type, and sst2 receptors were present in the colonic mucosa. Y2 was strongly expressed in the muscularis mucosae. This study shows that neuropeptide receptors are expressed in high amounts and in highly specific patterns in distinct targets in the human colon, suggesting a major physiological role for these peptides. The data represent the molecular basis to investigate the regulation by neuropeptides of colonic functions and to develop neuropeptide drugs aimed at interacting with these receptors in colonic diseases, such as Hirschsprung's and Crohn's diseases.

Autoradiography↗
PubMed2000

Mechanisms of initiation and termination of signalling by neuropeptide receptors: a comparison with the proteinase-activated receptors.

Biological responses to neuropeptides are rapidly attenuated by overlapping mechanisms that include peptide degradation by cell-surface proteases, receptor uncoupling from heterotrimeric G-proteins and receptor endocytosis. We have investigated the mechanisms that terminate the proinflammatory effects of the neuropeptide substance P (SP), which are mediated by the neurokinin 1 receptor (NK1R). Neutral endopeptidase degrades SP in the extracellular fluid and is one of the first mechanisms to terminate signalling. G-protein receptor kinases and second-messenger kinases phosphorylate the NK1R to permit interaction with beta-arrestins, which uncouple the receptor from G-proteins to terminate the signal. SP-induces NK1R endocytosis by a beta-arrestin-dependent mechanism, which also involves the GTPases dynamin and Rab5a. Endocytosis contributes to desensitization by depleting receptors from the cell surface. Disruption of these mechanisms results in uncontrolled stimulation and disease. Thus the deletion of neutral endopeptidase in mice exacerbates inflammation of many tissues. There are similarities and distinct differences in the mechanisms that regulate signalling by neuropeptide receptors and other G-protein-coupled receptors, in particular those that are activated irreversibly by proteolysis.

Animals↗
PubMed1995

Neuropeptide receptors in developing and adult rat spinal cord: an in vitro quantitative autoradiography study of calcitonin gene-related peptide, neurokinins, mu-opioid, galanin, somatostatin, neurotensin and vasoactive intestinal polypeptide receptors.

A number of neuroactive peptides including calcitonin gene-related peptide (CGRP), substance P, neurokinin B, opioids, somatostatin (SRIF), galanin, neurotensin and vasoactive intestinal polypeptide (VIP) have been localized in adult rat spinal cord and are considered to participate either directly and/or indirectly in the processing of sensory, motor and autonomic functions. Most of these peptides appear early during development, leading to the suggestion that peptides, in addition to their neurotransmitter/neuromodulator roles, may possibly be involved in the normal growth and maturation of the spinal cord. To provide an anatomical substrate for a better understanding of the possible roles of peptides in the ontogenic development of the cord, we investigated the topographical profile as well as variation in densities of [125I]hCGRP alpha, [125I]substance P/neurokinin-1 (NK-1), [125I]eledoisin/neurokinin-3 (NK-3), [125I]FK 33-824 ([D-Ala2, Me-Phe4, Met(O)ol5]enkephalin)/mu-opioid, [125I]galanin, [125I]T0D8-SRIF14 (an analog of somatostatin); [125I]neurotensin and [125I]VIP binding sites in postnatal and adult rat spinal cord using in vitro quantitative receptor autoradiography. Receptor binding sites recognized by each radioligand are found to be distributed widely during early stages of postnatal development and then to undergo selective modification to attain their adult profile of distribution during the third week of postnatal development. The apparent density of various receptor sites, however, are differently regulated depending on the lamina and the stage of development studied. For example, the density of mu-opioid binding sites, following a peak at postnatal day 4 (P4), declines gradually in almost all regions of the spinal cord with the increasing age of the animal. [125I]substance P/NK-1 binding sites, on the other hand, show very little variation until P14 and then subsequently decrease as the development proceeds. In the adult rat, most of these peptide receptor binding sites are localized in relatively high amounts in the superficial laminae of the dorsal horn. To varying extents, moderate to low density of various peptide receptor binding sites are also found to be present in the ventral horn, intermediolateral cell column and around the central canal. Taken together, these results suggest that each receptor-ligand system is regulated differently during development and may each uniquely be involved in cellular growth, differentiation and in maturation of the normal neural circuits of the spinal cord. Furthermore, the selective localization of various receptor binding sites in adult rat spinal cord over a wide variety of functionally distinct regions reinforces the neurotransmitter/modulator roles of these peptides in sensory, motor and autonomic functions associated with the spinal cord.

Aging↗
PubMed1995

A novel putative neuropeptide receptor expressed in neural tissue, including sensory epithelia.

We have used a homology based approach to identify G protein-coupled receptors preferentially expressed in retinal and taste cells. Rat and bovine sequences encoding a novel G protein-coupled receptor have been isolated. Analysis indicates that while the protein sequence is most similar to the receptors for somatostatin and opiates, it is unlikely to be a subtype of these receptors. Northern and RNase protection analysis indicates that the gene is preferentially expressed in neural and sensory tissues.

Amino Acid Sequence↗