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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The term cholecystokinin (CCK) refers to a family of related peptides whose members play hormonal roles in the gastro-intestinal tract. The sulfated octapeptide CCK-8 [Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] is also abundant throughout the central nervous system where it satisfies the criteria for a neurotransmitter. CCK interacts with at least two types of receptor called CCK-A and CCK-B receptors. These binding sites can be distinguished on the basis of their affinities for different molecular forms of CCK. Moreover, selective nonpeptide antagonists have been developed for CCK-A and CCK-B receptors. CCK-A receptors occur predominantly at the peripheral level where they are responsible for the digestive effects of CCK: intestinal and biliary smooth muscle contraction, pancreatic enzyme secretion, trophic effects on gastric and intestinal mucosa and regulation of feeding. Some brain CCK-receptors belong to the A-type, but the majority of them are CCK-B receptors. High densities of brain CCK-B receptors are present in cortical and limbic areas such as the amygdala and the hippocampus. At the peripheral level, CCK-B receptor antagonists are active on gastrin receptors, and these two receptors are similar if not identical. Experimental evidence suggests involvement of brain CCK processes in 4 domains: modulation of dopaminergic function, control of pain sensation, anxiety and memory formation. Thus, CCK-B antagonists may be useful to treat certain neuropathological conditions associated with CCK dysfunction.
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PMID:[Cholecystokinins and their receptors. Functional aspects]. 130 46

The interaction of the novel CCK analogs JMV-180, JMV-320, and JMV-332 with CCK-B/gastrin receptors on small cell lung cancer (SCLC) cells was investigated. JMV-180, JMV-320, and JMV-332 potently inhibited specific binding of 125I-CCK-8 to CCK-B/gastrin receptors expressed on the SCLC cell line NCI-H345 (H345) with IC50 values of 4.9, 1.8, and 7.0 nM, respectively. JMV-320 and JMV-332 stimulated intracellular calcium ([Ca2+]i) release in a dose-dependent manner in cells preloaded with indo-1. JMV-180 did not stimulate [Ca2+]i but inhibited the [Ca2+]i release elicited by 10 nM CCK-8 in a dose-dependent manner. These data indicate that JMV-320 and JMV-332 function as CCK-B/gastrin receptor agonists while JMV-180 functions as a CCK-B/gastrin receptor antagonist in H345 cells.
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PMID:Characterization of the novel CCK analogs JMV-180, JMV-320, and JMV-332 in H345 cells. 133 81

To study the mechanism by which cholecystokinin octapeptide (CCK-8) and its potent analogue, ceruletide, prevent glutamate-induced neuronal cell death in rat neuron cultures, we examined the effect of both peptides on glutamate-induced increases in the intracellular free calcium concentrations ([Ca2+]i), which are known to be a crucial trigger of the neurodegeneration induced by glutamate. CCK-8 itself did not alter [Ca2+]i in rat neuron cultures. Glutamate increased [Ca2+]i in neuron cultures rapidly and markedly. CCK-8 and ceruletide significantly suppressed the increases in [Ca2+]i induced by glutamate. The maximum inhibitory effects of CCK-8 and ceruletide at 10(-6) M reached 43 and 46% of the response to glutamate, respectively. Gastrin-I and CCK-4 also significantly attenuated the increases in [Ca2+]i induced by glutamate. The inhibitory effect of CCK-8 was completely blocked by the selective antagonist for CCK-B receptors, (+)L-365,260, but not by (-)L-364,718, which is a selective antagonist for CCK-A receptors. CCK-8 significantly suppressed [Ca2+]i response to kainate and high concentrations of extracellular K+, but not to N-methyl-D-aspartate. With cultured astrocytes, CCK-8 did not inhibit the increment of [Ca2+]i induced by glutamate. These findings clearly demonstrated that CCK-8 and ceruletide inhibit glutamate-induced increases in [Ca2+]i in neuron cultures through CCK-B receptors, suggesting that CCK-8 may participate in the central actions of glutamate.
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PMID:Inhibitory effect of CCK-8 and ceruletide on glutamate-induced rises in intracellular free calcium concentrations in rat neuron cultures. 135 89

Gastrin is an important stimulant of acid secretion by gastric parietal cells and is structurally related to the peptide hormone cholecystokinin (CCK). The pharmacologic properties of the parietal cell gastrin receptor are very similar to the predominant CCK receptor in the brain, CCK-B. Neither the gastrin nor the CCK-B receptor have been cloned thus far, making it difficult to resolve whether these two receptors are distinct. We have isolated a clone encoding the canine gastrin receptor by screening a parietal cell cDNA expression library using a radioligand-binding strategy. Nucleotide sequence analysis revealed an open reading frame encoding a 453-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the beta-adrenergic family of G protein-coupled receptors. The expressed recombinant receptor shows the same binding specificity for gastrin/CCK agonists and antagonists as the canine parietal cell receptor. Gastrin-stimulated phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization in COS-7 cells expressing the cloned receptor suggest second-messenger signaling through phospholipase C. Affinity labeling of the expressed receptor in COS-7 cells revealed a protein identical in size to the native parietal cell receptor. Gastrin receptor transcripts were identified by high-stringency RNA blot analysis in both parietal cells and cerebral cortex, suggesting that the gastrin and CCK-B receptors are either highly homologous or identical.
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PMID:Expression cloning and characterization of the canine parietal cell gastrin receptor. 137 4

Cholecystokinin (CCK) receptors on vagal afferents have been implicated in many of the actions of the brain-gut peptide CCK, including satiety. Autoradiographic studies in rats have demonstrated the presence of CCK-A-type receptors on vagus nerves. However, direct and detailed characterization of this important CCK receptor site has never been reported with membrane-binding techniques. Using 125I-Bolt-on-Hunter-CCK octapeptide (125I-BH-CCK-8) and the recently discovered selective agonists and antagonists of CCK receptors, we have delineated the properties of CCK receptors on rabbit vagus nerve. 125I-BH-CCK-8 binding sites appeared to be homogeneous by the Scatchard analysis, with a dissociation constant of 0.14 nM and a maximum binding of 72 fmol/mg protein. However, competition studies using selective CCK ligands showed that the vagal CCK receptors are heterogeneous. A71378, a selective CCK-A agonist, showed biphasic displacement curves, with the high-affinity portion (less than 10 nM) accounting for approximately 60% and the low-affinity portion for approximately 40%. Competitive binding studies using A63387, a selective CCK-B/gastrin receptor agonist, also showed biphasic displacement curves, with the high-affinity portion (less than 30 nM) at approximately 40% and the low-affinity portion at approximately 60%. Under conditions which selectively examined vagal CCK-A or CCK-B/gastrin receptors, we demonstrated that a number of CCK subtype selective agonists and antagonists possessed similar affinities for the vagal CCK-A and -B/gastrin receptors as those found on the guinea pig pancreas (CCK-A) and cerebral cortex (CCK-B), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Both CCK-A and CCK-B/gastrin receptors are present on rabbit vagus nerve. 141 46

Many reports have emphasized the role of gastrin as a growth factor for normal gastrointestinal mucosa and gastrointestinal cancers. Recent studies have pointed out that this peptide acts also as a growth factor for the pancreatic cancer cell line AR42J. This effect is mediated by gastrin [cholecystokinin (CCK)-B] receptors. In the present study, we investigated gastrin (CCK-B) receptor expression in the azaserine-induced rat pancreatic carcinoma DSL-6, comparing it to normal rat pancreas, and we also characterized CCK receptor subtypes in this tumor. The results showed that there is extensive gastrin binding to the DSL-6 pancreatic carcinoma. No evidence of specific gastrin binding to normal pancreas was found. Analysis of the ability of gastrin-17-I to inhibit 125I-gastrin-I binding demonstrated that gastrin bound to a single class of receptors with a Kd of 0.21 +/- 0.04 nM and a binding capacity of 184 +/- 29 fmol/mg protein. 125I-Gastrin-I binding was inhibited by the specific CCK-B receptor antagonist L365,260 approximately 40 times more effectively than by the specific CCK-A receptor antagonist L364,718. Analysis of the ability of cholecystokinin octapeptide (CCK-8) to inhibit 125I-Bolton-Hunter-CCK-8 binding revealed two CCK binding sites, i.e., a high affinity site and a low affinity site. The observed binding affinities of CCK-8 were then introduced into the computer analysis of the dose-inhibition curve of the ability of gastrin-17-I to inhibit binding of 125I-Bolton-Hunter-CCK-8, which was significantly better fit by a three-site model than by a two-site model. The three sites meet the criteria for CCK-B, high affinity CCK-A, and low affinity CCK-A receptors. The binding capacity of CCK-B receptors constitutes 34% of the total high affinity CCK binding sites. This study demonstrated that DSL-6 pancreatic carcinoma expresses three subtypes of CCK receptors. Gastrin (CCK-B) receptors, which were not detected in normal rat pancreas, constitute about one third of the total high affinity CCK receptors. We suggest that novel expression of gastrin (CCK-B) receptors may be generated by gene mutation or amplification during carcinogenesis and may play an important role in promoting tumor growth.
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PMID:Novel expression of gastrin (cholecystokinin-B) receptors in azaserine-induced rat pancreatic carcinoma: receptor determination and characterization. 145 79

We evaluated the affinity of cholecystokinin octapeptide (CCK-8), gastrin, and subtype-selective CCK agonists for CCK/gastrin receptors and compared it with the ability of these peptides to stimulate phosphoinositide (PI) hydrolysis and pepsinogen release in guinea pig gastric glands. Competitive binding studies using 125I-labeled Bolton-Hunter-CCK-8 and 125I-gastrin showed the presence of CCK-B/gastrin receptors in gastric glands and dispersed chief cells. In contrast, the potency of peptides in stimulating PI hydrolysis in both gastric glands and dispersed chief cells displayed a profile similar to CCK-A receptors found in pancreatic acini, i.e., CCK-8 = A 71378 greater than A 71623 greater than A 70874 much greater than A 72962 = CCK-8 (desulfated) greater than gastrin II greater than gastrin I. In general, the rank order of potency of peptides for stimulation of PI hydrolysis correlated well with their ability to stimulate pepsinogen release. At concentrations greater than 10 microM, efficacies of gastrin I and II in stimulating pepsinogen release from gastric glands were near 90% of the maximal activity of CCK-8. The inhibitory potency of MK-329, a selective CCK-A receptor antagonist, was similar against either CCK-8 (10 nM) or gastrin I (10 microM), except that a minor portion (approximately 30-40%) of gastrin I-induced pepsinogen release was insensitive to MK-329. The MK-329-insensitive component was inhibited by CI-988, a potent and selective CCK-B/gastrin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Both CCK-A and CCK-B/gastrin receptors mediate pepsinogen release in guinea pig gastric glands. 161 41

The control of cell proliferation by gastrin has been investigated in a rat pancreatic tumour cell line, AR4-2J. Exogenous gastrin, 10(-12) to 10(-8) M, stimulated cell growth of thymidine-synchronised AR4-2J cells cultured over 48 h in serum-free medium. Cell lysates of AR4-2J cells contained an average of 4.5 and 3.5 pg gastrin per 10(6) cells, when grown in serum-supplemented or serum-free media, respectively, as revealed by radioimmunoassay. In serum-free medium, AR4-2J secrete 34 ng 1(-1) 10(-6) cells of gastrin over 48 h. Addition of an anti-gastrin immunoglobulin preparation, but not control immunoglobulins, caused a maximum 52% reduction in cell growth. These data are consistent with an autocrine role for gastrin in the control of AR4-2J cell growth. These results were supported by studies with gastrin/CCK receptor antagonists. Six non-peptide gastrin/CCK receptor antagonists inhibited AR4-2J cell growth in a concentration-related manner. The concentration required for 50% inhibition (IC50) of cell growth by the amino acid-derived antagonists proglumide (3.5 x 10(-3) M), benzotript (1.8 x 10(-3) M), loxiglumide (1.1 x 10(-4) M) and lorglumide (6.7 x 10(-5) M) were of the same order and significantly correlated with their IC50 for inhibition of 125I-gastrin binding to AR4-2J cells. Inhibition of cell growth by these antagonists was partially reversed by the addition of exogenous gastrin. In contrast, the IC50 for inhibition of cell growth with two benzodiazepine-derived antagonists, the CCK-B receptor antagonist L-365,260 (4.6 x 10(-5) M) and the CCK-A receptor antagonist devazepide (1.7 x 10(-5) M) were two-three orders of magnitude greater than those required to inhibit gastrin binding (10(-8)-10(-7) M). The growth inhibitory effects of L-365,260 and devazepide were not reversed by exogenous gastrin suggesting these benzodiazepine-derived antagonists do not inhibit cell growth by interaction with gastrin receptors. The results are consistent with gastrin being an autocrine growth factor in AR4-2J cells, and that stimulation of cell growth is due to stimulation of the gastrin, rather than CCK-B, receptor sub-type. This study highlights that gastrin receptor antagonists warrant further investigation as agents to control growth of tumours, such as those from the gastrointestinal tract, which express gastrin receptors.
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PMID:Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin. 163 73

Cholecystokinin octapeptide (CCK-8), ceruletide (CLT) and gastrin-I, which were added simultaneously with glutamate to rat neuron cultures, significantly suppressed the neuronal cell death induced by glutamate which can be observed from the efflux of lactate dehydroxylase into the culture medium. However, gastrin-I (1-13) had no effect on the response to glutamate. The inhibitory effect of CLT on glutamate-induced neuronal cell death could be completely blocked by a selective antagonist for CCK-B receptors, (+)L-365,260. These findings clearly indicate that CCK-8, CLT and gastrin-I exhibit a protective effect against glutamate-induced neurotoxicity via the CCK-B receptor.
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PMID:Protective effect of CCK-8 and ceruletide on glutamate-induced neuronal cell death in rat neuron cultures: possible involvement of CCK-B receptors. 168 72

Cholecystokinin (CCK) is a peptide found high density in the cerebral cortex, the amygdala and the hippocampus of the mammalian brain. Molecular forms of varying amino acid lengths of CCK have been isolated. The sulphated octapeptide (CCK-8S) is the most abundant form and shorter molecular forms are also present in the brain. CCK-8S has been shown to coexist with neurotensin and dopamine in neurons projecting from the ventral tegmental area to the nucleus accumbens, and to a lesser extent in neurons of the substantia nigra projecting to periventricular regions of the caudate. Evidence suggests that CCK acts as a neurotransmitter in the NCS it is synthesized and stored in nerve terminals and cell bodies; it is released by depolarization; it has specific binding sites; it can affect the firing rate of CNS neurons; and its effects can be interfered with by analogues. Studies have found microiontophoretic application of CCK-8S and CCK-4 on cortical and hippocampal neurons to elicit a strong excitatory action. CCK receptors are widely distributed throughout the central nervous system with high densities in the striatum and nucleus accumbens. Considerable effort has been devoted to characterizing the specificity of brain CCK receptors. So far, two types of CCK receptors have been described: CCK-A receptors which have a higher affinity for sulphated CCK-8 than for de-sulphated CCK-8 (CCK-8US), CCK 4 or gastrin, and CCK-B receptors have a high affinity for all of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Is cholecystokinin a biological support in panic attacks?]. 168 50


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