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

The recent molecular cloning of the genes encoding three somatostatin (SRIF) receptor subtypes has allowed for the individual expression of these receptors in mammalian cells and characterization of their respective pharmacological profiles. In the present study, we have investigated the affinities of a battery of SRIF analogues to bind to SRIF receptor subtypes SSTR1 (cloned somatostatin complex), SSTR2, and SSTR3, as well as their abilities to inhibit the release of growth hormone from anterior pituitary cells in vitro. We labeled SSTR1 and SSTR3 receptors expressed in Chinese hamster ovary and COS-1 cells, respectively, with the metabolically stable SRIF analogue 125I-CGP 23996. SSTR2 receptors expressed in Chinese hamster ovary cells were labeled with the SSTR2-specific radioligand 125I-MK-678. Inhibition studies were performed using SRIF analogues of differing structures, including hexapeptide analogues similar to MK-678, octapeptide analogues similar to SMS 201-995, pentapeptide analogues similar to c[Ahep-Phe-D-Trp-Lys-Thr(Bzl)] (SA), and linear SRIF analogues. SSTR1 bound SRIF and SRIF-28 with high affinity and the peptide SA and its structural analogues with low affinity. The hexapeptides did not interact with SSTR1 at concentrations as high as 1 microM, and only a few of the octapeptides or linear peptides bound, with very low affinities. In contrast, 125I-MK-678 binding to SSTR2 was potently inhibited by the hexapeptides, octapeptides, and some of the linear compounds, whereas SA and its analogues did not bind to SSTR2. The potencies of the various SRIF agonists to inhibit growth hormone release in vitro was highly correlated with their potencies to inhibit radioligand binding to SSTR2, but not to SSTR1 or SSTR3. SSTR3 bound analogues of each class but with moderate to low affinities, with the exception of several linear peptides and one of the octapeptides. We report for the first time the binding affinities of linear analogues of SRIF, some of which display subnanomolar affinities and are highly selective for SRIF receptor subtypes. Most importantly, these studies identify several peptide analogues that are highly potent, specific, and selective for individual subtypes of SRIF receptors. Such information, coupled with the knowledge of the distribution of these receptor subtypes in normal and pathological tissues, will be critical for more specific experimental and therapeutic interventions.
 ...
PMID:Cloned somatostatin receptors: identification of subtype-selective peptides and demonstration of high affinity binding of linear peptides. 810 Mar 50

The recent molecular cloning of the genes and cDNAs encoding multiple somatostatin (SRIF) receptor subtypes has allowed for the individual expression of these receptors in mammalian cells and characterization of their respective pharmacological profiles. Previously, we fully described and compared the pharmacological properties of the first three SRIF receptor subtypes, SRIF receptor type (SSTR)1, SSTR2, and SSTR3. In the present study, we have investigated the properties of the newly cloned SRIF receptor subtypes SSTR4 and SSTR5 with regard to pharmacological profiles, the regulation of high affinity agonist binding to these receptors by stable GTP analogues, Na+, or prior exposure to agonists, and the inhibition of forskolin-stimulated cAMP accumulation mediated by these receptors. We labeled SSTR4 and SSTR5 expressed in Chinese hamster ovary (CHO-K1) and COS-1 cells, respectively, with the metabolically stable SRIF analogue 125I-CGP 23996. Radioligand binding competition studies were performed using SRIF analogues of differing structures, including hexapeptide analogues similar to MK-678, octapeptide analogues similar to SMS 201-995, pentapeptide analogues similar to c[Ahep-Phe-D-Trp-Lys-Thr(Bzl)], and linear SRIF analogues. SSTR4 bound compounds in all structural classes with high to moderate affinities, and several compounds were identified that are > 100-fold selective for SSTR4, compared with the other cloned SRIF receptors, including the linear SRIF analogue BIM-23052 and the CGP 23996-like SRIF analogue L-362,855. In contrast, SSTR5 bound very few SRIF analogues with high affinity. Both receptors could be regulated by prior exposure to agonist. In addition, agonist binding to SSTR4 was reduced by stable GTP analogues, Na+, and pertussis toxin, but agonist binding to SSTR5 was not affected by these treatments. SSTR4 is efficiently coupled to the inhibition of adenylyl cyclase activity, whereas SSTR5 appears not to couple to this cellular effector system. Such differences between the cloned SRIF receptors provide useful strategies for identifying regions of these receptor subtypes that may be involved in ligand-binding specificities and G protein and cellular effector system coupling. The identification of subtype-selective SRIF analogues may lead to more specific therapeutic interventions.
 ...
PMID:Characterization of cloned somatostatin receptors SSTR4 and SSTR5. 810 85

The presence of somatostatin receptors has been demonstrated in various endocrine tumors as well as in normal tissues. We recently have cloned five human somatostatin receptor subtypes (SSTR1-SSTR5). These mRNAs are expressed in a tissue-specific manner. In this study, we have determined the somatostatin receptor subtypes expressed in various endocrine tumors using a reverse transcriptase polymerase chain reaction method. In two cases of glucagonoma and its metastatic lymph nodes in one case, all the SSTR subtype mRNAs except SSTR5 mRNA were expressed. In four cases of insulinoma, SSTR1 and SSTR4 mRNAs were detected, but SSTR2 mRNA was not detected in one case and SSTR3 mRNA was not detected in two cases, indicating a heterogeneous expression of SSTR subtypes in insulinomas. Interestingly, SSTR3 mRNA, which is highly expressed in rat pancreatic islets, is not expressed in normal human pancreatic islets, while SSTR1, SSTR2, and SSTR4 mRNAs are expressed. In three cases of pheochromocytoma, SSTR1 and SSTR2 mRNAs were detected, showing an expression pattern identical to that of normal adrenal gland. In a carcinoid, SSTR1 and SSTR4 mRNAs were detected. We have also found that human SSTR2 shows a high affinity for SMS 201-995, which has been used clinically for the treatment of endocrine tumors. Since SMS 201-995 was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, but had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, this study suggests that the efficacy of SMS 201-995 may depend, at least in part, on the expression of SSTR2 in tumors.
 ...
PMID:Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. 813 73

Using a polymerase chain reaction approach, we have studied the expression of somatostatin receptor (SSTR) subtypes in the GH3 rat pituitary cell line, a well established in vitro model for the cellular effects of somatostatin. We found that the previously identified SSTR1 and SSTR2 are the major subtypes expressed in this cell line. No other SSTR subtype was detected by our analysis. Northern blots confirmed that both subtypes, but not SSTR3, are expressed in GH3 cells. We studied the functional expression of both SSTR subtypes by transfection of their cDNAs into human embryonic kidney 293 cells. We found that somatostatin inhibited cAMP accumulation in human embryonic kidney 293 cells only when cells were transfected with either SSTR1 or SSTR2. This inhibition was blocked by treatment of the transfected cells with pertussis toxin, demonstrating that it is mediated by G proteins sensitive to this toxin. In addition, we provide pharmacological evidence that the endogenous SSTR2 subtype mediates inhibition of cAMP accumulation in intact GH3 cells. Our results contradict previous reports that concluded thsat neither SSTR1 nor SSTR2 is involved in inhibition of adenylyl cyclase. The reasons for this apparent contradiction are discussed. We conclude that both SSTR1 and SSTR2 are capable of coupling to pertussis toxin-sensitive G proteins to inhibit adenylyl cyclase.
 ...
PMID:Pituitary cell line GH3 expresses two somatostatin receptor subtypes that inhibit adenylyl cyclase: functional expression of rat somatostatin receptor subtypes 1 and 2 in human embryonic kidney 293 cells. 814 27

A major cellular action of the neuropeptide somatostatin (SRIF) is the inhibition of adenylyl cyclase activity. SRIF induces this effect after its interaction with membrane-bound receptors. Five SRIF receptors (SSTRs), which differ in their functional coupling to adenylyl cyclase, have recently been cloned. The third SSTR cloned, SSTR3, effectively mediates the inhibition of adenylyl cyclase by SRIF. The molecular mechanism by which SRIF modulates intracellular cAMP synthesis via SSTR3 was investigated by initially identifying which G alpha subunits are involved in coupling SSTR3 to adenylyl cyclase. SRIF did not inhibit cAMP formation in Chinese hamster ovary cells stably expressing SSTR3 and Gi alpha 2 or Gi alpha 3 but lacking Gi alpha 1. However, SRIF did inhibit forskolin-stimulated cAMP formation in Chinese hamster ovary cells stably expressing SSTR3 and Gi alpha 1, indicating that Gi alpha 1 selectively couples SSTR3 to adenylyl cyclase. To investigate the functional domains of Gi alpha 1 necessary for interaction with SSTR3, a chimeric alpha subunit (Gi alpha 2/Gi alpha 1) was constructed, consisting of the amino-terminal two thirds of Gi alpha 2 ligated to the carboxyl-terminal third of Gi alpha 1. SRIF inhibited cAMP formation in cells expressing SSTR3 and the Gi alpha 2/Gi alpha 1 chimera. These findings indicate that the carboxy-terminal third of Gi alpha 1 interacts with SSTR3 and is important in transmitting the signal of SSTR3 activation to adenylyl cyclase. In contrast, a similar Gi alpha 2/Gi alpha 3 chimera did not couple SSTR3 to adenylyl cyclase, further indicating that Gi alpha 3 does not contribute to SRIF inhibition of adenylyl cyclase activity. These findings demonstrate that Gi alpha 1 selectively couples SSTR3 to adenylyl cyclase, and they indicate that the carboxyl-terminal region of this alpha subunit is involved in mediating SRIF inhibition of adenylyl cyclase activity.
 ...
PMID:Gi alpha 1 selectively couples somatostatin receptor subtype 3 to adenylyl cyclase: identification of the functional domains of this alpha subunit necessary for mediating the inhibition by somatostatin of cAMP formation. 818 36

The tissue distribution of mRNA encoding five somatostatin receptor subtypes, SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, was determined in adult rat tissues by solution hybridization/nuclease protection analysis using sequence-specific cRNA probes. In the central nervous system, SSTR1 and SSTR2 mRNA were expressed widely, with highest levels in hippocampus, hypothalamus, cortex, and amygdala and expression of both isoforms in cerebellum and spinal cord. Expression of SSTR3 was also widespread, occurring in all brain regions examined, with the highest level of expression in the cerebellum. SSTR4 mRNA was detected in most brain regions, with highest levels occurring in the hippocampus, cortex, and olfactory bulb. No detectable levels were found in cerebellum. SSTR5 showed a unique pattern of expression in the central nervous system, being found primarily in the hypothalamus and preoptic area. In peripheral tissues, high levels of SSTR1 and SSTR2 mRNA were found in pituitary and spleen. SSTR1 mRNA was also found in the heart and intestine, SSTR2 was detected in pancreas, and both isoforms were expressed in stomach. Expression of SSTR3 was noted in heart, liver, stomach, intestine, kidney, spleen, and pituitary. The patterns of expression were similar for SSTR4 and SSTR3 mRNA; however, SSTR4 was not expressed in liver. SSTR5 was expressed predominantly in the pituitary, but detectible levels were observed in spleen and intestine. Thus, the SSTR subtype mRNA showed both a tissue-specific and overlapping pattern of expression. Taken together with SSTR-specific signal transduction systems, this probably explains the diverse physiological actions of somatostatin.
 ...
PMID:Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. 824 78

The mRNA distribution in the brain and the coupling to cellular effector systems of four somatostatin receptors (SSTR1-4) was studied. All four SRIF receptor subtypes were expressed in cortex and hippocampus. In addition, SSTR1 mRNA was relatively abundant in the spinal cord whereas SSTR2 mRNA was also present in the striatum. The SSTR3 gene was predominantly expressed in the olfactory bulb and in the cerebellum. Conflicting results about the effector coupling of SSTR1-3 have been published previously. We have stably expressed human SSTR1-4 in HEK 293 human embryonal kidney cells. Agonist binding to the receptor subtypes, including the recently cloned SSTR4, inhibited the formation of forskolin-induced cAMP. Is is concluded that, in an appropriate cellular environment, all four receptor subtypes can functionally couple to the inhibition of adenylyl cyclase.
 ...
PMID:Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain. 840 11

Somatostatin (SRIF) analogues display anti-tumor properties believed to be mediated by specific cell surface somatostatin receptors (SSTR). SSTR subtypes have unique pharmacological properties, including specific GTP-binding protein coupling, ion channel regulation, and cAMP inhibition; therefore, identification of isotypes expressed in tumor cells facilitates current efforts to design potent anti-tumor SRIF analogues. Human and rodent solid, transplantable tumors and tumor cell lines were examined for gene expression of SSTR1, SSTR2 and SSTR3 by reverse transcription of tumor mRNA and subsequent amplification of cDNA by the polymerase chain reaction, using SSTR subtype-specific oligonucleotide primers. SSTR2 mRNA transcripts were observed in all of the tumor cell lines examined. SSTR1 gene expression was seen in several human and rat tumor types, and SSTR3 gene expression observed in two rodent tumor types. SSTR mRNA-positive tumors are expected to possess membrane-bound receptors which could potentially interact with anti-tumor SRIF analogues.
 ...
PMID:Somatostatin receptor subtype gene expression in human and rodent tumors. 851 84

Somatostatin (SST) is one of the major peptide transmitters in the mammalian central nervous system and also seems to exert specific functions during brain development. In contrast to ligand binding experiments, by which two pharmacologically different binding sites were characterized, molecular cloning techniques have led to the identification of at least five different receptor subtypes (SSTR1-5), which according to RNA blot analyses seem to be differentially distributed and regulated in the developing brain. In order to provide more precise data on the distribution of SSTR1 during ontogenesis, we have performed an in situ hybridization analysis, using a 35S-labelled RNA probe, in the developing rat cortex between embryonic day (E)12 and adulthood. Within the cortical plate, expression of SSTR1 gene was first detected in parallel with the establishment of the deep laminae V/VI at E16, thereby following the characteristic morphogenetic gradients of cortical plate construction. Thus, with the subsequent addition of cells along the radial dimension, e.g. the deposition of the supragranular neurons beyond E18, the hybridization signal spreads as an uniform homogenous band through the entire cortical plate, whereby silver grains reach their peak density around birth. Similar developmental gradients were observed along the lateromedial and frontooccipital dimension, whereby SSTR1 transcripts were detected near the frontal pole and the lateral cortical areas roughly 2 days before they appeared in the occipital and medial cortical anlage, respectively. From the initially homogenous distribution, two distinct SSTR1 mRNA-positive bands coextensive with laminae V/VI and II/III, respectively, and sparing lamina IV evolved during the first postnatal week, the grain density of which decreased during further postnatal development. Within the hippocampal formation, SSTR1 transcripts were initially observed at E18 in the subicular complex, and after birth also extending into the neighboring CA1 region. During the 1st and 2nd postnatal week, silver grains were observed over the pyramidal cell layer of CA2 and CA3 and as a faint supragranular band in the dentate gyrus. Similar to the isocortex, grain density decreased thereafter. Hypothetically, the pronounced temporospatial regulation of SSTR1 gene expression during brain development can be correlated with (1) the establishment and eventual reduction of transient cortical SSTergic neuron populations described for late pregnancy and early postnatal development and (2) a receptor subtype exchange during maturation as evidenced by the late (from postnatal day 7 onward) appearance of e.g. SSTR3.
 ...
PMID:Distribution of somatostatin receptor subtype 1 mRNA in the developing cerebral hemispheres of the rat. 857 44

A variety of human neuroendocrine tumours express SSTR. The five recently cloned human SSTR subtypes have a distinct chromosomal localization and pharmacological profile, and a tissue-specific expression pattern which suggests a differential function of SSTR subtypes in different organ systems. Most tumours carrying SSTR may express multiple SSTR subtypes, while the SSTR2 subtype is most predominantly expressed. The somatostatin analogue, octreotide, binds with high affinity to the SSTR2 and SSTR5 subtype and with a low affinity to the SSTR3 subtype. This analogue does not bind to the SSTR1 and SSTR4 subtypes. No major differences in the binding characteristics have been found between octreotide and two other clinically used octapeptide SST-analogues, BIM-23014 and RC-160. Our preliminary data indicate that an absent hormonal response to octreotide in vitro also implies an absent response to BIM-23014 and RC-160. The expression of the SSTR2 subtype in human tumours is proposed to be related to a clinical beneficial effect of octreotide treatment, while the functional significance of the other SSTR subtypes is not clear at present. In addition it is unclear which subtype(s) is involved in the antimitotic actions of SST(-analogues). Further developments with regard to the oncological application of SST analogues await the identification of the SSTR subtype(s) mediating anti-proliferative effects, as well as the development of analogues which selectively activate this subtype(s). A good correlation has been found between the presence of SSTR2 subtype mRNA and binding of [125I-Tyr3]octreotide in human primary tumours. Therefore, SSTR scintigraphy of human primary tumours and their metastases presumably visualizes SSTR2-expressing tumours, although it is reasonable to assume that SSTR5, and to a lesser extent SSTR3, when expressed simultaneously with SSTR2, also contribute to the visualization of tumours.
 ...
PMID:Somatostatin receptors and disease: role of receptor subtypes. 873 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>