Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G-protein-coupled receptor 100 (GPR100) was discovered by searching the human genome database for novel G-protein-coupled peptide receptors. Full-length GPR100 was amplified from a cDNA library of the neuroendocrine cell line BON, which is derived from a human pancreas carcinoid. The open-reading frame, present on a single exon, coded for a protein of 374 amino acids with highest sequence identity (43%) to the human orphan somatostatin- and angiotensin-like peptide receptor. The analysis of chromosomal localisation mapped the GPR100 gene to chromosome 1q21.2-q21.3. The stable expression of GPR100 in Chinese hamster ovary cells together with aequorin as calcium sensor and the promiscuous G-protein subunit alpha16 as signal transducer revealed bradykinin and kallidin as effectors to elicit a calcium response. Dose-response curves yielded EC50 values for both ligands in the low nanomolar range, while the respective analogues without arginine at the carboxy-terminus were inactive. Calcium mobilisation was inhibited by the phospholipase C blocker U73122, but not by pertussis toxin, suggesting the involvement of the G-protein subunit alphaq and not alphai or alphao in signal transduction. In line with the main function of kinins as peripheral hormones, we found that GPR100 was expressed predominantly in tissues like pancreas, heart, skeletal muscle, salivary gland, bladder, kidney, liver, placenta, stomach, jejunum, thyroid gland, ovary, and bone marrow, but smaller amounts were also detected in the brain and in cell lines derived from tumours of various origins.
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PMID:Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. 1453 Feb 18

The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHSR1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK- 293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3- dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels (store-operated calcium channels). Upon repeated administration, ghrelin showed a marked suppression of ghrelin-mediated elevations of intracellular calcium. This homologous desensitization represents an important physiological mechanism that modulates receptor responsiveness and acts as an information filter for intracellular signaling system. The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis.
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PMID:Regulation of ghrelin secretion and action. 1461 Feb 93

Urotensin II (U-II) is a disulfide-bridged undecapeptide recently identified as the ligand of an orphan G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. With the aim of elucidating the active conformation of hU-II, we have performed a spectroscopic analysis of hU-II minimal active fragment hU-II(4-11) in different environmental conditions. The analysis indicated that hU-II(4-11) was highly structured in the anisotropic membrane mimetic SDS solution, showing a type II' beta-turn structure, which is almost unprecedented for L-amino acid peptides. Micelle bound structure of hU-II(4-11) was then compared with those of four synthetic analogues recently synthesized in our lab, bearing modified Cys residues at position 5 and/or position 10 and characterized by different levels of agonist activity. The structures of the active compounds were found to be very similar to that of hU-II(4-11), while a barely active compound does not show any propensity to beta-turn formation. Furthermore, distances among putative pharmacophoric points in the structures of the active compounds obtained in SDS solution are in good agreement with those found in a recently described non-peptide agonist of the hU-II receptor. A type II' beta-turn structure was already found for the somatostatin analogue octreotide. On the basis of the similarity of the primary and 3D structures of U-II and somatostatin analogues and on the basis of the sequence homology between the GPR14/UT-II receptor and members of the somatostatin receptor family, a common evolutionary pathway for the signal transmission system activated by these peptide can be hypothesized.
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PMID:Unraveling the active conformation of urotensin II. 1502 56

The identification of a human homolog of urotensin-II (U-II) and a novel, specific G-protein-coupled receptor by Ames et al. in 1999 changed the perception that the U-II isopeptide family was an esoteric collection of 'somatostatin-like neuropeptides' present only in the nervous systems of an eclectic array of aquatic invertebrates, fish and amphibians. In this article, we review recent developments in the pharmacology of human U-II, focusing on the actions of this peptide in the mammalian cardiorenal system. The putative role of U-II in the etiology of hypertension, heart failure, renal dysfunction and diabetes is discussed, as are novel U-II receptor antagonists.
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PMID:From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function. 1510 93

The GoLoco motif is a short polypeptide sequence found in G-protein signaling regulators such as regulator of G-protein signaling proteins type 12 and 14 and activator of G-protein signaling protein type 3. A unique property of the GoLoco motifs from these three proteins is their preferential interaction with guanosine diphosphate (GDP)-bound Galpha(i1), Galpha(i3) and, sometimes, Galpha(i2) subunits over Galpha(o) subunits. This interaction prevents both spontaneous guanine nucleotide release and reassociation of Galpha(i)-GDP with Gbetagamma. We utilized this property of the GoLoco motif to examine dopamine (D2 and D3) and somatostatin receptor coupling to G-protein-regulated inwardly rectifying potassium (GIRK) channels in mouse AtT20 cells. GoLoco motif peptides had no effect on either basal channel activity or the initial responses to agonists, suggesting that the GoLoco motif cannot disrupt pre-formed G-protein heterotrimers. GoLoco motif peptides did, however, interfere with human D2((short)) receptor coupling to GIRK channels as demonstrated by the progressively diminished responses after repeated agonist application. This behavior is consistent with some form of compartmentalization of D2 receptors and GIRK channels such that Gbetagamma subunits, freed by local receptor activation and prevented from reforming a heterotrimeric complex, are not functionally constrained within the receptor-channel complex and thus are unable to exert a persistent activating effect. In contrast, GoLoco motif peptides had no effect on either D3 or somatostatin coupling to GIRK channels. Our results suggest that GoLoco motif-based peptides will be useful tools in examining the specificity of G-protein-coupled receptor-effector coupling.
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PMID:D2 dopamine receptor activation of potassium channels is selectively decoupled by Galpha-specific GoLoco motif peptides. 1574 59

Urotensin II is the most potent vasoconstrictor known. Paradoxically, urotensin II also possesses vasodilator activity in certain vascular beds. While much is still to be learnt regarding urotensin II's actions on vascular tone, it is now clear that it mediates its effects by interacting with a specific G-protein-coupled receptor. The presence of urotensin II and its receptor in both vertebrate and invertebrate species suggests an evolutionarily conserved role in normal physiology although evidence is mounting for both species-specific as well as disease-specific effects of this peptide. This somatostatin-like peptide was originally thought to reside solely in compartments of the central nervous system. However, recent evidence implicated urotensin II in the pathogenesis of a variety of disease processes ranging from hypertension to hepatic cirrhosis. Increased expression of this peptide has been noted in cardiac, renal and hepatic disease. While the contribution of urotensin II to these diseases remains unclear, the advent of urotensin II antagonists allows for not only the possibility of a new range of therapeutic drugs but also new avenues of investigation and further mechanistic insights into the pathophysiology of these disease processes.
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PMID:Urotensin II: a vascular mediator in health and disease. 1585 35

The accumulation of amyloid-beta peptide (Abeta), a physiological peptide, in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease (AD) and appears to be caused by an increase in the anabolic activity, as seen in familial AD cases or by a decrease in catabolic activity. Neprilysin is a rate-limiting peptidase involved in the physiological degradation of Abeta in the brain. As demonstrated by reverse genetics studies, disruption of the neprilysin gene causes elevation of endogenous Abeta levels in mouse brain in a gene-dose-dependent manner. Thus, the reduction of neprilysin activity will contribute to Abeta accumulation and consequently to AD development. Evidence that neprilysin in the hippocampus and cerebral cortex is down-regulated with aging and from an early stage of AD development supports a close association of neprilysin with the etiology and pathogenesis of AD. Therefore, the up-regulation of neprilysin represents a promising strategy for therapy and prevention. Recently, somatostatin, which acts via a G-protein-coupled receptor (GPCR), has been identified as a modulator that increases brain neprilysin activity, resulting in a decrease of Abeta levels. Thus, it may be possible to pharmacologically control brain Abeta levels with somatostatin receptor agonists.
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PMID:Metabolism of amyloid-beta peptide and Alzheimer's disease. 1611 36

The sst1 receptor was the first of the 5 somatostatin receptors to be cloned by homology with the glucagon receptor 13 years ago. It is a 7-transmembrane domain G-protein-coupled receptor that is negatively coupled to adenylyl cyclase, but can also trigger other transduction pathways. The distribution of sst1 mRNA, immunolabeling, and radioligand binding are not entirely overlapping, but the recent availability of knockout (KO) mice and a (still limited) number of selective agonists/antagonists has increased our knowledge about this receptor. These new tools have helped to reveal a role for the sst1 receptor in hippocampal, hypothalamic, basal ganglia, and retinal functions. In at least the latter 3 structures, the sst1 receptor appears to act as an inhibitory autoreceptor located on somatostatin neurons, whereas in the hippocampus such a role is still based on circumstantial evidence.
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PMID:The somatostatin sst1 receptor: an autoreceptor for somatostatin in brain and retina? 1627 47

Cortistatin (CST) is a recently described neuropeptide. Although the expression of CST was initially reported to be restricted to the rat cerebral cortex and hippocampus, it is currently known to have wide distribution in many human organs. CST shares high homology with somatostatin and binds with high affinity to all somatostatin receptor (SSTR) subtypes. Indeed, many of its endocrine and biological activities overlap with somatostatin. However, CST and somatostatin are expressed in only partially overlapping cortical neuron populations. They are regulated by different stimuli, their cortical actions are diverse and CST, at variance with somatostatin, was shown to have a possible role in the human immune system. The activities specific to cortistatin may be attributable to its unique binding to the GH secretagogue (GHS) receptor (GHS-R) and the orphan G-protein-coupled receptor, MrgX2, which is not shared by somatostatin. The potential biological roles and therapeutic use of CST and the receptors involved in its action require further investigation.
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PMID:Cortistatin - a new neuroendocrine hormone? 1734 27

Somatostatin is abundantly expressed in mammalian brain. The peptide binds with high affinity to six somatostatin receptors, sst1, sst2A and B, sst3 to 5, all belonging to the G-protein-coupled receptor family. Recent advances in the neuroanatomy of somatostatin neurons and cellular distribution of sst receptors shed light on their functional roles in the neuronal network. Beside their initially described neuroendocrine role, somatostatin systems subserve neuromodulatory roles in the brain, influencing motor activity, sleep, sensory processes and cognitive functions, and are altered in brain diseases like affective disorders, epilepsia and Alzheimer's disease.
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PMID:Somatostatinergic systems in brain: networks and functions. 1799 29


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