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)

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

Panicogenic effects in humans of the selective cholecystokinin (CCK(B)) receptor agonist, cholecystokinin tetrapeptide (CCK4), have been reported to correlate with increases in heart rate (HR) and mean arterial pressure (MAP). Previous investigators have demonstrated that the nonselective CCK(A) and CCK(B) receptor agonist, sulfated cholecystokinin octapeptide, also produces increases in HR and mean arterial pressure. The purpose of our study is to determine if the cardiovascular changes induced by CCK4 are mediated by the CCK(A) or CCK(B) receptor subtype using selective CCK antagonists for both receptor subtypes. The rank order of potency of the CCK receptor antagonists affecting CCK4-induced HR and mean arterial pressure changes in the guinea pig corresponded to the rank order of potency for blockade of the CCK(B) receptor binding in rat cortex, phosphatidyl inositol turnover in AR 4-2J rat pancreatoma cells and inhibition of pentagastrin-induced acid secretion in the rat. The changes induced by CCK4 on HR, but not mean arterial pressure, appear to be species dependent as reflected by a decrease in the HR in the guinea pig and an increase in the dog. Nonetheless, the results from the antagonist studies indicate that the cardiovascular responses to CCK4 in both the guinea pig and dog are mediated by the CCK(B) receptor subtype.
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PMID:Cardiovascular effects of cholecystokinin-4 are mediated by the cholecystokinin-B receptor subtype in the conscious guinea pig and dog. 910 96

Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK4, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (microg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D1 (SCH23390, 25 microg/kg i.p.) or D2 (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects.
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PMID:The CCK-B agonist, BC264, increases dopamine in the nucleus accumbens and facilitates motivation and attention after intraperitoneal injection in rats. 938 3

1. The hypothesis of the existence of two CCK(B) receptor subsites, CCK(B1) and CCK(B2) corresponding probably to different coupling states of CCK(B) receptors, was studied by measuring grooming behaviour in rats. 2. The B1 receptor agonist, BC197 (300 microg kg(-1), i.p.) produced a 45-50% decrease in grooming activity, which was prevented by both the CCK(B) receptor antagonists CI-988 (20 microg kg(-1) i.p.) and L-365,260 (200 microg kg(-1), i.p.). 3. In contrast, 3, 10 and 30 microg kg(-1), i.p., of the potent B2 receptor agonist, BC264, enhanced grooming (150-190%). This effect was prevented by previous injection of 75 microg kg(-1) of L-365,260 while higher doses (200 microg kg(-1), i.p.) produced only a partial antagonism. Moreover, CI-988 (20 microg kg(-1), i.p.), showed an opposite effect in potentiating the responses induced by BC264. However, 200 microg kg(-1) of CI-988 tended to suppress the increase of grooming induced by BC264. 4. The effects of BC264 were prevented by the D1 receptor (SCH 23390) and D2 receptor (sulpiride) antagonists, while those of BC197 were only antagonized by sulpiride, emphasizing the existence of a link between peptidergic (CCK) and dopaminergic systems. 5. This study brings additional evidence for the existence of the two CCK(B) receptor subsites and suggests that particular attention should be focused on the selectivity of CCK(B) receptor agonists, notably to explain the fact that some compounds such as Boc-CCK4 induce anxiogenic-like effects while others, including BC264, are devoid of these effects.
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PMID:Opposite effects of CCK(B) agonists in grooming behaviour in rats: further evidence for two CCK(B) subsites. 972 Jul 78

A role for endogenous histamine and histamine receptor subtypes in mediating the inhibition of eating induced by intragastric (i.g.) hypertonic NaCl was examined in adult male Sprague-Dawley rats surgically equipped with a chronic gastric catheter. The i.g. infusion of 2 mL 900 or 1,800 mOsm/kg of NaCl inhibited: 1) ingestion of pellets in rats eating after 24-h food deprivation; and 2) ingestion of cookies in rats eating without prior deprivation. The H1 receptor antagonists dexbrompheniramine (DXB; 1 mg/kg) and pyrilamine (PYR; 4 mg/kg) did not attenuate the inhibitory effects of i.g. 900 or 1,800 mOsm/kg of NaCl for rats eating pellets and for rats eating cookies. The H2 antagonists cimetidine (CIM; 16 mg/kg) and metiamide (MET; 16 mg/kg) attenuated the inhibitory effects of i.g. 1,800 mOsm/kg of NaCl upon ingestion of cookies, but intracerebroventricular (i.c.v.) infusion (through a chronic indwelling cannula) of 100 microg of CIM did not mimic this effect of intraperitoneal (i.p.) CIM. The i.p. CIM failed to attenuate the inhibition of eating cookies produced by i.p. octapeptide of cholecystokinin (CCK-8; 3 microg/kg). The H3 antagonist thioperamide (TH; 10 mg/kg i.p.) and the H3 agonist R-alpha-methylhistamine (RAM; 3 mg/kg i.p.) did not alter the inhibitory effect of i.g. 1,800 mOsm/kg of NaCl for rats eating cookies. Combined treatments of systemic DXB plus CIM, and DXB plus CIM plus thioperamide (TH) did not reverse the inhibitory effects of i.g. 1,800 mOsm/kg of NaCl upon ingestion of cookies. Finally, i.p. DXB, but not CIM, attenuated the ability of i.g. 900 mOsm/kg of NaCl to increase water intake; conversely, i.p. CIM, but not DXB, attenuated the ability of i.g. 900 mOsm/kg of NaCl to inhibit eating of cookies. These findings demonstrate a double dissociation of effects upon ingestive behavior: H1, but not H2, antagonism attenuates the effect of i.g. hypertonic NaCl on water intake, whereas H2, but not H1, antagonism attenuates the inhibition of eating produced by i.g. hypertonic NaCl. These results demonstrate that different subtypes of peripheral and/or central histamine receptors contribute to different behavioral consequences of postprandial gastrointestinal osmotic loads in rats.
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PMID:H2 histaminergic control of inhibition of eating induced by intragastric NaCl in rats. 981 72

Recently, the involvement of the MAP kinase ERK in mitogenic signaling of cholecystokininB (CCK(B)) receptors has been shown. However, the intracellular effector systems involved in this signaling pathway are poorly defined. In this study, we used COS-7 cells transiently transfected with the human CCK(B) receptor to investigate cholecystokinin-induced MAP kinase activation. CCK-8 induced activation of ERK2 which is associated with its phosphorylation and localization in the nucleus. The CCK-8-dependent ERK stimulation is sensitive to wortmannin an inhibitor of phosphoinositide 3-kinases (PI3Ks) indicating the involvement of PI3K activity. To identify the PI3K species involved in mitogenic signaling of the CCK(B) receptor several dominant-negative mutants of PI3K regulatory and catalytic subunits were transiently expressed. Surprisingly, different catalytically inactive mutants of the G protein-sensitive PI3Kgamma did not affect ERK stimulation induced by CCK, whereas a dominant-negative mutant of the regulatory p85 subunit induced significant inhibition of CCK-dependent ERK activity. These results indicate an involvement of PI3K class 1A species alpha, beta or/and delta in signal transduction via CCK(B) receptors. In addition, protein kinase C (PKC)-dependent signaling pathways contribute to CCK(B)-mediated MAP kinase signaling as shown by inhibition of CCK-8-induced ERK activation by the PKC inhibitor bisindolylmaleimide.
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PMID:Different signaling pathways are involved in CCK(B) receptor-mediated MAP kinase activation in COS-7 cells. 1103 Apr 34

Stereotyped behavior can be induced by the dopamine agonist apomorphine or by the releasing agent amphetamine. Cholecystokinin influence on dopamine-mediated behaviors has been extensively studied but a real controversy remains. Our purpose was to further characterize the dopamine-cholecystokinin interaction in apomorphine- and amphetamine-induced stereotyped behavior using sulphated cholecystokinin octapeptide (CCK8) and cholecystokinin tetrapeptide (CCK4) treatments. The results showed that CCK8 decreases apomorphine-induced stereotyped behavior and CCK4 has no effect. CCK4 and CCK8 increased the amphetamine-induced stereotyped behavior; CCK4 was more effective. The results confirm the opposite modulation of apomorphine or amphetamine-induced stereotyped behavior by CCK. These data suggest that this modulation is mediated by both CCK receptors on apomorphine-induced and only by CCK(2) receptors on amphetamine-induced stereotyped behavior.
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PMID:Cholecystokinin modulation of apomorphine- or amphetamine-induced stereotypy in rats: opposite effects. 1145 23

Intestinal metabolism and poor permeability were known to be major barriers for oral absorption of large peptide drugs. Dimensionless wall permeability values of C-terminal octa- and tetra-peptides cholecystokinin analogs (CCK8 and CCK4) were estimated and found out to be greater than 1, suggesting no permeability-limited absorption for CCK analogs. Thus, a strategy employing enzyme inhibitors and a specific delivery site to improve the absorption was developed and tested with CCK8, followed by identification of metabolites of the analogs and their participating enzymes in rabbit brush-border membrane vesicles. Thiorphan and amastatin, a specific enzyme inhibitor for enkephalinase and aminopeptidase, respectively, in pH 4 buffer solution were coadministered with CCK8 to the ileum in fistulated rats. The absolute bioavailability (F) of CCK8 was 5.4% and increased to 19% in the presence of the enzyme inhibitors, while the F values following oral administration were close to zero. These results indicate that peptide oral delivery is possible.
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PMID:Intestinal metabolism and absorption of cholecystokinin analogs in rats. 1192 13

In the present study, we investigated whether activation of protease-activated receptor type 2 (PAR-2) with SLIGRL (SL)NH2, a short mimetic agonistic peptide, directly stimulates pepsinogen secretion from gastric-isolated, pepsinogen-secreting (chief) cells. Immunostaining of gastric-dispersed chief cells with a specific anti-PAR-2 antibody demonstrated expression of PAR-2 receptors on membrane and cytoplasm. SL-NH2 and trypsin potently stimulated pepsinogen secretion (EC50 = 0.3 nM) and caused Ca2+ mobilization (EC50 = 0.6 nM). In contrast to SL-NH2, the scramble peptide LSIGRL-NH2 failed to stimulate pepsinogen release. Exposure to SL-NH2 also resulted in ERK1/2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, a selective MEK inhibitor, significantly reduced secretion induced by SL-NH2. Pepsinogen secretion induced by SL-NH2 was desensitized by pretreating the cells with the mimetic peptide and trypsin, and exposure to SL-NH2 abrogates pepsinogen secretion induced by carbachol and CCK-8, but not secretion induced by secretin and vasointestinal peptide. Exposure to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) but not to calcitonin gene-related peptide increased pepsinogen release. The neurokinin-1 receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester, inhibited substance P-stimulated pepsinogen secretion, whereas it did not affect secretion induced by SL-NH2. Collectively, these data indicate that PAR-2 is expressed on gastric chief cells and that its activation causes a Ca2+-ERK-dependent stimulation of pepsinogen secretion.
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PMID:PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells. 1274 62

At present there is an increasing literature demonstrating heterogeneity of the CCK-B receptor. Recent reports by our laboratory have demonstrated that the Fawn-Hooded rat demonstrates atypical neurochemical responses to CCK4, in vitro. Since the ability of CCK-B receptor ligands to modulate affective state is dependent on the putative receptor subtype activated, the aim of the present study was to examine the behavioural effects of the CCK-B receptor agonist, t-boc-CCK4, and the CCK-B receptor antagonist, Ci-988 in Fawn-Hooded and Wistar Kyoto rats. Interestingly, both t-boc-CCK4 and Ci-988 produced an anxiolytic profile in FH rats as determined by an increased time spent on the open arms of an elevated plus maze, while both drugs were devoid of any behavioural effect in WKY rats, lending further support to the theory that the FH rat strain has an atypical relative proportion of these putative subtypes apparently resulting in a predominantly CCK-B2 receptor effect.
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PMID:Atypical behavioural responses to CCK-B receptor ligands in Fawn-Hooded rats. 1457 8


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