Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Sulphated cholecystokinin octapeptide (CCK8S, 0.03-1.00 microM), pentapeptide (CCK5) and tetrapeptide (CCK4) elicited concentration dependent depolarizations of neonate rat ventral roots in vitro. 2. CCK5 was equipotent with CCK8S although CCK4 was weaker (equipotent molar ratio 17.5). 3. CCK8S-induced depolarizations were depressed by tetrodotoxin (0.1 microM), Mg2+ ions (0.75 mM) and the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5, 10 microM). These results suggest that CCK8S-induced depolarizations were predominantly mediated through the release of an excitatory amino acid from interneuronal sites. 4. The selective CCKA and CCKB receptor antagonists, L-364,718 and L-365,260 both depressed CCK8S-induced depolarizations. CCK8S dose ratios in the presence of 1 microM L-364,718 or L-365,260 were 4.5 and 11.2 respectively, suggesting the response was mediated predominantly through stimulation of CCKB receptors. 5. These results suggest that the neonate rat hemicord preparation is a suitable tissue for functional CCK receptor assays.
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PMID:Cholecystokinin-induced ventral root depolarization of neonate rat hemicord in vitro. 809 38

Cholecystokinin (CCK) is a neurotransmitter found in high density in the brains of mammals. Microiontophoretic studies showing that benzodiazepines selectively antagonized CCK-induced excitation of rat hippocampal neurons have led to the hypothesis that CCK is an anxiogenic peptide. The hypothesis was supported by demonstrations that CCK-tetrapeptide (CCK4) induces panic attacks in humans. This paper reviews phases of investigations which studied the validity of CCK4 as a panicogenic agent and research strategies for the study of panic disorder using CCK4 as an investigative tool.
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PMID:Neurobiological investigations into the role of cholecystokinin in panic disorder. 810 32

The effects of cholecystokinin (CCK) fragments and Asp-Tyr-D-Phe-Gly-Trp-[N-Me]Nle-Asp-Phe-NH2 1(SNF 9007), a synthetic CCK analog which binds with high affinity to CCKB and opioid delta receptors, were evaluated in isolated sheets of mouse ileum mounted in Ussing flux chambers. Serosal, but not mucosal, administration of cholecystokinin octapeptide-sulfated [CCK8(s)] and cholecystokinin tetrapeptide (30-33) [CCK4(30-33)] produced a brief, concentration-related increase in short circuit current (Isc) without changing tissue conductance. Serosal, but not mucosal, SNF 9007 produced a similar concentration-related increase in Isc which was followed by an immediate concentration-related and sustained decrease in Isc; no decrease in Isc was observed for either CCK8 or CCK4(30-33). The increase and subsequent decrease in the SNF 9007 Isc response were respectively classified as phase I (i.e., CCK-like) and phase II (opioid-like) activity. CCK8(s) and SNF 9007 (phase I) were active at low nanomolar concentrations, whereas CCK4(30-33) was active only at high nanomolar concentrations: the rank order of potencies to increase Isc was CCK8(s) > SNF 9007 > CCK4(30-33). Devazepide (L364,718), a selective antagonist of CCKA receptors, effectively blocked the action of CCK8(s), but not that of CCK4(30-33) or SNF 9007 (phase I). In contrast, 3R[+]-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-benzodiazepin-3-yl ]-N'- [3-methyl-phenyl]urea (L365,260), a selective CCKB receptor antagonist, blocked the action of CCK4(30-33) and SNF 9007 (phase I), and also antagonized CCK8(s), though to a lesser degree.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of SNF 9007, a novel cholecystokinin/opoid ligand in mouse ileum in vitro: evidence for involvement of cholecystokininA and cholecystokininB receptors in regulation of ion transport. 811 56

The effects of cholecystokinin (CCK) receptor agonists and antagonists on hypoxia/hypoglycemia (ischemia)-induced decrease in CA1 presynaptic fiber spikes elicited by the stimulation of Schaffer collaterals were investigated using rat hippocampal slices. Treatment with the CCKB receptor agonist CCK tetrapeptide (CCK4, 0.01-10 microM) exacerbated the ischemia-induced decrease in the CA1 presynaptic potential in a concentration-dependent manner. Whereas, treatment with the CCKB receptor antagonist [(3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-N1-(3-methylphenyl)-urea] (L365260), and not with CCKA receptor antagonist [(3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-1H-indole-2-carboxamide] (L364718), produced a concentration-dependent attenuation of the ischemia-induced decrease. The magnitude of recovery of the CA1 field potentials in L365260-treated groups at 10 and 100 nM was 34% and 45%, respectively. The neuroprotective effect of L365260 (0.01 and 0.1 microM) was completely blocked by co-treatment with CCK4 (0.1 microM), a concentration that did not affect the decreased presynaptic potential induced by ischemia. These results demonstrated that the stimulation of the CCKB receptor played a detrimental role in the development of ischemic damage, whereas the blockade of CCKB receptors played a neuroprotective role in ischemic damage, suggesting a facilitatory role of CCK receptor-operated function in ischemia-induced neuronal deficits.
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PMID:Neuroprotective effect of cholecystokininB receptor antagonist on ischemia-induced decrease in CA1 presynaptic fiber spikes in rat hippocampal slices. 817 34

Cholecystokinin (CCK) has not been isolated from chicken gut yet and there has been no study on the effects of chicken gastrin (CG), the only gastrin/CCK peptide isolated from avian gut, on gastrointestinal motility. The main objective was to study the effects of CCK and CG on gastroduodenal motility and coordination in chickens. Electrodes for electromyography were implanted in the stomach and proximal and distal duodenum of 4 wk old chickens. Sulphated CCK-octapeptide (CCK8) (10(-10) to 10(-8) moles/kg), CCK-tetrapeptide (CCK4) (2 x 10(-10) to 2 x 10(-8) moles/kg) and CG (3 x 10(-10) to 10(-8) moles/kg) were given in a 10 min i.v. infusion. All these peptides induced a dose-dependent inhibition of gastric motility. CCK8 induced a duodenal hyperactivity whereas CCK4 and CG induced a duodenal inhibition. Neither the CCK-A receptor antagonist L364,718 nor the CCK-B receptor antagonist L365,260 (10(-9)-10(-7) moles/kg) antagonized CCK8 actions. From these results we suggest that the receptors mediating CCK effects are different from those of mammals. The site of action for these peptides is the same in the stomach whereas in the duodenum there are two different ones, one mediating excitation and the other inhibition. These results suggest a physiological role for CCK regulating gastroduodenal motility in birds.
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PMID:Effects of cholecystokinin and gastrin on gastroduodenal motility and coordination in chickens. 835 59

Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK4-induced panic attacks in humans and to potentiate opioid effects in animals. The clinical use of these compounds is critically dependent on their ability to cross the blood-brain barrier. In order to improve this property, new, peptoid-derived CCK-B antagonists, endowed with high affinity, selectivity, and increased lipophilicity have been developed. The affinity and selectivity of these compounds have been characterized in vitro and in vivo using guinea pig, rat, and mouse. Most of these compounds proved to be selective for the CCK-B receptor, the most potent analog, N-[N-[(2-adamantyloxy)carbonyl]-D-alpha- methyltryptophanyl]-N-[2-(4-chlorophenyl)ethyl]glycine (26A), having a Ki value of 6.1 nM for guinea pig cortex membranes in vitro and a good selectivity ratio (Ki CCK-A/Ki CCK-B = 174). Furthermore, the in vivo affinity of 26A for mouse brain CCK-B receptors, following intracerebroventricular injection at different concentrations, was found to be 10 nmol. Using competition experiments with the specific CCK-B ligand [3H]pBC 264, compound 26A was shown to cross the blood-brain barrier (0.2%) after intraperitoneal administration in mice. This compound is therefore an interesting pharmacological tool to further elucidate the physiopathological role of endogenous CCK.
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PMID:Cholecystokinin peptidomimetics as selective CCK-B antagonists: design, synthesis, and in vitro and in vivo biochemical properties. 841 Oct 2

Cholecystokinin tetrapeptide (CCK4) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCKB) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCKB gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C-->A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G-->A, Val125-->Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder.
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PMID:Missense mutation of the cholecystokinin B receptor gene: lack of association with panic disorder. 883 9

We studied the effect of the cholecystokinin tetrapeptide (CCK4), a potent CCKB antagonist, in patients with panic disorder. Two different dosages (25 and 50 micrograms) of CCK4 and saline were tested in 12 patients who were randomly allocated to 2 of the 3 possible treatment groups. Patients were tested on 2 separate occasions, 1 week apart, using an unbalanced single-blind incomplete block design. A total of 24 intravenous injections were carried out. The panic rate with 25 micrograms CCK was 44% (4/9) and 71% (5/7) with 50 micrograms. None of the patients panicked with saline (0/8). Patients' symptom responses were very similar to their spontaneous panic attacks. Taking the Panic Symptom Scale (PSS) as outcome variable, we found that CCK4 provoked symptoms of panic in a dose-dependent fashion. The behavioral response to CCK4 was not accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis as measured by the prolactin and cortisol responses. Moreover, CCK4-induced panic symptoms were not correlated with plasma increases in the principal noradrenergic metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG), suggesting that activation of the locus coeruleus may not be critical for CCK4-induced panic.
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PMID:The panic-inducing properties of the cholecystokinin tetrapeptide CCK4 in patients with panic disorder. 888 78

Cholecystokinin (CCK) plays an important role in both the alimentary tract and the central nervous system (CNS). At present it seems to be the most abundant neuropeptide in the CNS. This paper reviews the CCK neuronal system and its interactions with gamma-aminobutyric acid (GABA) and serotonin (5-hydroxytryptamine; 5-HT). In addition, its putative role in anxiety will be discussed on the basis of animal data and studies in healthy volunteers and panic disorder patients. According to these investigations, the CCK4 challenge test fulfills most criteria for an ideal panicogenic agent and evidence has been found that CCKB receptor antagonists might possess anxiolytic properties in man.
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PMID:Cholecystokinin in anxiety. 898 9

New constrained cyclic pseudopeptide cholecystokinin-B (CCK-B) agonists have been designed on the basis of conformational characteristics of the potent and selective CCK-B agonist Boc-Trp-(NMe)Nle-Asp-Phe-NH2 (Ki = 0.8 nM, selectivity ratio CCK-A/CCK-B > 6000) (Goudreau et al. Biopolymers, 1994, 34, 155-169). These compounds are among the first successful examples of macrocyclic constrained CCK4 analogs endowed with agonist properties and as such may be of value for the development of nonpeptide CCK-B agonists. The affinities and selectivities of these compounds for CCK-B and CCK-A receptors have been determined in vitro by measuring the displacement of [3H]pCCK8 binding to guinea pig cortex and pancreas membranes, respectively. The most potent compound, 8b, N-(cycloamido)-alpha-Me(R)Trp-[(2S)-2-amino-9- ((cycloamido)carbonyl)nonanoyl]-Asp-Phe-NH2, has a Ki value of 15 +/- 1 nM for guinea pig cortex membranes with a good CCK-B selectivity ratio (CCK-A/CCK-B = 147). Furthermore, 8b behaved as a potent and full agonist in a functional assay which measures the stimulation of inositol phosphate accumulation in CHO cells transfected with the rat CCK-B receptor (EC50 = 7 nM). The in vivo affinity of 8b for mouse brain CCK-B receptors was determined following intracerebroventricular injection (ID50 approximately 29 nmol/kg). 8b was also shown to cross the blood-brain barrier (0.16%), after intravenous administration in mice. 8b also increased gastric acid secretion measured in anesthetized rats after intravenous injection. Therefore, 8b appears to be an interesting pharmacological tool and is currently under investigation as a lead for further development of nonpeptide CCK-B agonists.
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PMID:Structure-based design of new constrained cyclic agonists of the cholecystokinin CCK-B receptor. 905 51


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