Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The predominant brain cholecystokinin receptor (CCK-B/gastrin) has been implicated in mediating many of the central effects of cholecystokinin, including anxiety, panic attacks, satiety, and analgesia, suggesting it is an important pharmacologic target. We now report the cloning and characterization of the cDNA encoding the human brain CCK-B/gastrin receptor. The cDNA was isolated from a human brain library by low stringency screening using the canine "gastrin" receptor cDNA as a hybridization probe. Nucleotide sequence analysis revealed an open reading frame encoding a 447-amino-acid protein with seven putative hydrophobic transmembrane domains and significant homology with other known members of the gastrin/cholecystokinin receptor family. Agonist and antagonist affinities of the recombinant human brain receptor expressed in COS-7 cells are consistent with a classical "CCK-B" receptor as defined by the literature. In COS-7 cells expressing the cloned receptor, CCK-8-stimulated phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization suggesting second messenger signaling through phospholipase C. CCK-B/gastrin receptor transcripts were identified in human brain, stomach, and pancreas using high stringency Northern blot analysis. Southern blot hybridization analysis of human genomic DNA indicates that a single gene encodes both the brain and the stomach CCK-B/gastrin receptors. Our data suggest that the CCK-B and gastrin receptors are identical and that the long standing distinction between them may no longer apply.
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PMID:The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization. 768 36

The brain cholecystokinin-B/gastrin receptor (CCK-B/gastrin) has been implicated in mediating anxiety, panic attacks, satiety, and the perception of pain. The canine and human CCK-B/gastrin receptors share 90% amino-acid identity and have similar agonist affinities. These receptors can be selectively blocked by the non-peptide benzodiazepine-based antagonists L365260 (ref. 8) and L364718 (ref. 9); however, the binding of these antagonists to the human and canine receptors differs by up to 20-fold, resulting in a reversal of affinity rank order. Here we report the identification of a single amino acid in the sixth transmembrane domain of the CCK-B/gastrin receptor that corresponds to valine 319 in the human homologue and which is critical in determining the binding affinity for these non-peptide antagonists. We show that it is the variability in the aliphatic side chain of the amino acid in position 319 that confers antagonist specificity. Substitution of valine 319 with a leucine residue decreases the affinity for L365260 20-fold while concomitantly increasing the affinity for L364718. An isoleucine in the same position of the human receptor selectively increases affinity for L364718. Interspecies differences in the aliphatic amino acid occupying this single position selectively affect antagonist affinities without altering the agonist binding profile. We therefore conclude that the residues underlying non-peptide antagonist affinity must differ from those that confer agonist specificity. To our knowledge, these findings are the first example in which a critical antagonist binding determinant for a seven-transmembrane-domain peptide hormone receptor has been identified.
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PMID:A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists. 845 20

Animals or human subjects receiving brain stimulation in the dorsal periaqueductal gray matter (dPAG) show sudden fear-suggestive behavioral reactions and physical signs of autonomic activation which are reminiscent of the symptom profile characterizing a panic attack. An experimental situation in rats measuring dPAG stimulation self-interruption thresholds has been validated as realistically simulating several aspects of panic anxiety with objective signs of symptomatic and predictive validity using established antipanic and panicogenic agents; it was utilized here to evaluate the effects of various cholecystokinin B receptor ligands. A dose-dependent increase in self-interruption thresholds (antipanic-like effect) was recorded following injection of L-365,260 (3.2, 10 and 32 mg/kg i.p.), a CCKB receptor antagonist with good brain penetration, whereas no significant changes in thresholds were recorded following CI-988 (3.2, 10 and 32 mg/kg i.p.), a dipeptoid CCKB receptor antagonist with poor brain penetration. Latencies for self-interruption were not modified, suggesting that motor functions remained intact. No significant changes in self-interruption thresholds were recorded following peripheral administration of the CCKB receptor agonists CCK4 (0.03 to 0.32 mg/kg i.v.; 0.01 to 3.2 mg/kg i.p.) or the metabolically stabilized analog Boc-CCK4 (0.1 to 10 mg/kg i.p.). Systemic administration of the panicogenic compounds caffeine and yohimbine enhance acute anxiety in this model. These data indicate that, in the dPAG simulation of panic anxiety, central CCKB receptor blockade by L-365,260 induces antiaversive effects analogous to those observed following benzodiazepine receptor activation by clonazepam or alprazolam. Potency and efficacy of L-365,260 were lower than those of clonazepam or alprazolam, suggesting modest, but nonetheless authentic, antiaversive properties for this CCKB receptor antagonist. Lack of effects observed following peripheral administration of the agonists CCK4, and Boc-CCK4 or of the dipeptoid antagonist CI-988 is likely to reflect restricted brain penetration of those compounds in rats; it furthermore excludes a contribution of peripheral gastrin and CCKA receptors to the antipanic-like properties of selective CCKB receptor antagonists such as L-365,260.
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PMID:Behavioral effects of CCKB receptor ligands in a validated simulation of panic anxiety in rats. 898 12

Endogenous cholecystokinin tetrapeptide (CCK-4, Trp-Met-Asp-Phe-NH2) is a fragment derived from a larger peptide hormone, cholecystokinin (or gastrin). As a panicogenic agent, CCK-4 is commonly used in clinic settings to induce panic attacks for the study of new anxiolytic drugs. However, few studies on CCK-4 metabolism have been published to date. In the present study, we investigate the metabolism of CCK-4 in liver microsomes of human (HLM), Rhesus Monkey (RMLM), Sprague-Dawley rat (RLM) and CD1 mouse (MLM) using ultra-high performance liquid chromatography coupled to a high resolution mass spetrometer. Ten metabolites, inlcuding tryptophan (M1), tryptophan amide (M2), hydroxy metabolites (M3-M5), truncated peptides (M6-M9), and CCK-4 acid (M10), were identified and 8 of them were reported for the first time. The metabolic pattern of CCK-4 in HLM was distinctly different from these in RMLM, RLM, and MLM. M2 and M9 were the major metabolites in HLM and accounted for 19.8% and 13.4% of initial CCK-4, respectively. In contrast, M2 was the major metabolite in RMLM and accounted for 41.4%, whereas M6 was the major metabolite in RLM and account for 39.1%. Three major metabolites M2, M7 and M8 in MLM accounted for 22.6%, 17.9% and 17.8% of initial CCK-4, respectively. Chemical inhibition experiment showed that aminopeptidase and/or endopeptidase hydrolysis were the major metabolic pathways in human to generate these metabolites. We further showed that cytochrome P450 were also involved in the metabolism of CCK-4 via hydroxylation, but to a less extend. These findings provide valuable information for the metabolic processes of CCK-4 among various species and an important reference basis for its safety evaluation and rational clinical application.
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PMID:Identification of cholecystokinin tetrapeptide amide metabolites in liver microsomes of human, Rhesus Monkey, Sprague-Dawley rat and CD1 mouse using ultra-high performance liquid chromatography coupled to high resolution mass spectrometer. 3014 98