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)

The influence of two iontophoretically administered newly developed cholecystokinin (CCK) tetrapeptides with high selectivity and affinity to CCK-B receptors on the impulse activity of single hippocampal and thalamic neurons were tested in in-vivo experiments, in comparison to the effect of the sulfated octapeptide (CCK8S). A very similar responsiveness to the compared drugs was found. Most neurons responded with an increase of their discharge frequency. Only a few suppressive effects were elicited by each drug and in each of the structures. There was a good correspondence between the compared drugs concerning the direction and relative response amplitude, resulting in a highly significant correlation of the effects of both CCK4s with the CCK8S effects. On a subsample of neurons, the blocking effect of the selective CCK-B receptor blocker PD135 was tested and found to be effective in 16 out of 20 CCK4 responses, including also one inhibition. The results show that the new compounds act as effective CCK agonist binding to the B-type CCK receptor. The few inhibitory effects obtained could be explained by possible indirect effects mediated via inhibitory interneurons which are known to exist in both investigated structures.
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PMID:Effects of two newly synthetized cholecystokinin tetrapeptides on the activity of single hippocampal and thalamic neurons. 747 65

1. Ionic conductances controlled by type A and type B cholecystokinin (CCK) receptors were studied in neurons of the rat nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV), using intracellular and whole-cell patch clamp recordings in current or voltage clamp configuration during bath application of agonists (CCK8, CCK4, BC 264) and antagonists. 2. CCKA receptor-related inhibition was associated with a membrane hyperpolarization and a decrease in input resistance that developed 2-6 min after the arrival of drug into the extracellular medium. These effects were induced by 5 nM CCK8 but not BC 264 and they were blocked by the CCKA antagonist, L-364,718, but not by the CCKB antagonist, L-365,260. 3. CCKA receptor-related inhibition was generated by a potassium current that reversed at a reversal potential E(rev) of -73 +/- 1 (mean +/- SE) mV with bathing potassium concentration [K+]o = 6 mM and at -88 +/- 1 with [K+]o = 3 mM, in agreement with the Nernst equation for potassium ions. 4. CCKB receptor-related excitation was associated with a membrane depolarization and an increase of the input resistance induced by the following agonists at threshold concentrations: CCK8 (0.2 nM) > or = BC 264 (0.4 nM) > CCK4 (10.9 nM). The increase of input resistance was abolished by L-365,260 and was maintained after blockade of the CCKA current by L-364,718. 5. CCKB receptor-related excitation, in the neurons (30% of cases) in which clear response reversal was observed, appeared to be generated by a decrease of a potassium conductance. Responses showed a reversal potential E(rev) of -68 +/- 4 mV with [K+]o = 6 mM and -89 +/- 1 mV with [K+]o = 3 mM, verifying predictions from the Nernst equation applied to potassium ions. However, in 70% of cases, clear reversal was not observed at membrane potentials negative to the theoretical potassium equilibrium potential EK. 6. In voltage clamp studies, CCK8 induced a 181 +/- 17 pA inward current associated with a 26 +/- 4% decrease in the instantaneous current (I(ins)) generated by hyperpolarizing voltage steps. This effect on I(ins) was demonstrated in the absence of effects on the outward noninactivating potassium current (IM) and on the inward noninactivating cationic current (IQ). 7. CCKB receptor-mediated excitation was not suppressed by cobalt, a blocker of calcium currents, and was not associated with a change of the calcium-dependent potassium current (IK(Ca)).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cholecystokinin-gated currents in neurons of the rat solitary complex in vitro. 750 60

Cholecystokinin (CCK) is a gut hormone that regulates pancreatic endocrine functions via CCKA receptors. CCK4 (Trp-Met-Asp-Phe-NH2) has an insulinotropic effect, but is 1000-fold less potent than CCK8. The in vitro potencies and selectivity of newly synthesized CCK4 analogs were investigated. Exchanging various a amino acids, for example Met by Nle and modifying Phe and/or Trp, led to compounds that were much more effective than CCK4 itself and show insulinotropic effects comparable with those of CCK8. Compounds that possess electron withdrawing groups on the C-terminal phenylalanine were especially effective; compounds with electron-donating groups had no effect. In contrast to CCK8 the synthetic CCK4 compounds were selective for the endocrine pancreas: they had no agonistic or antagonistic effect on the contraction of the guinea pig ileum, amylase release from isolated acini, and no major effect on the feeding behavior of mice being supplied with either compound by an implantable AlzetR pump for 8 days. The data indicate that some of the synthetic tetrapeptides exhibit a high affinity for the CCK receptor of the endocrine pancreas and that they are highly selective for this (peripheral) CCKA receptor subtype. The beta-cell CCKA receptors are different from those in exocrine pancreas, smooth muscle, and those for regulating appetite; these peripheral receptor subtypes can be discriminated for the first time.
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PMID:Evidence for cholecystokinin receptor subtype in endocrine pancreas. 753 22

Given the high resistance of the cholecystokinin octapeptide (CCK8) to in vivo peptidase degradation, the possible existence of a reuptake system for this peptide was investigated. Efficient accumulation of intact, tritiated propionyl CCK8 ([3H]pCCK8) was observed following its incubation with rat cortical synaptosomes but not with cerebellar synaptosomes, where no cholecystokinin immunoreactivity was found. This uptake process appeared to be dependent on temperature, duration of incubation, concentration of radioligand, the presence of glucose and the integrity of the synaptosomes. A Lineweaver-Burk analysis indicated that the putative uptake process is characterized by a single Km value of 10.7 nM and a Vmax of 8.5 fmol/min/mg of protein. Carbonyl cyanide-m-chlorophenyl hydrazone, an uncoupler of oxidative phosphorylation, blocked accumulation of [3H]pCCK8, whereas ouabain did not. The uptake was found to be highly specific since, among all the cholecystokinin analogues tested, only CCK8 and, to a lesser extent, CCK7, were able to inhibit [3H]pCCK8 uptake. The rate of [3H]pCCK8 uptake was not affected by CCK4, CCK5, D-Trp CCK8, BC 264, a potent and radioactivity was observed using [3H]pBC 264, a result which is not in favour of a cholecystokinin receptor-induced internalization mechanism. The potent and selective uptake mechanism characterized in this study could participate, in conjunction with extra and intracellular degradation of CCK8 by peptidases, in the interruption of cholecystokinin-conveyed messages in the brain.
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PMID:Evidence for a high-affinity uptake system for cholecystokinin octapeptide (CCK8) in rat cortical synaptosomes. 761 12

The effects of pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK4), were studied in 15 patients with panic disorder and 15 healthy controls. Three different intravenous dosages of pentagastrin (0.1, 0.3 and 0.6 microgram/kg) and saline were investigated. Subjects were randomly allocated to two of the four treatment groups and tested on two separate occasions, 1 week apart, using an unbalanced double-blind incomplete block design. The mean panic rate with pentagastrin was 55% (12/22) for patients and 5% (1/22) for controls. None of the subjects panicked with saline. The frequency of panic attacks between the three pentagastrin doses in patients was not different. One control subject had a panic-like attack at the highest dose of pentagastrin. These findings concur with previous studies on the panicogenic effect of CCK4 and pentagastrin and suggest a greater sensitivity for CCK receptor agonists in patients suffering from panic disorder than in healthy controls.
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PMID:Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients. 785 3

The aims of this work are to characterize the effects of cholecystokinin (CCK) on chicken ceca and to study in vitro the mechanisms through which such actions are mediated. Longitudinal and circular cecal strips kept in vitro in organ baths were responsive to CCK sulphated octapeptide (CCK-8s). On longitudinal strips the response consisted of a fast phasic contraction followed by a sustained increase in tone which was dose dependent and decreased markedly in the presence of tetrodotoxin (TTX). Ketanserin (10(-5) M) also caused a decrease in the CCK-8s response. CCK tetrapeptide (CCK-4) and CCK unsulphated octapeptide (CCK-8ns) induced slightly less contractile effects at concentrations of 2 x 10(-6) M only. L365,260 and L364,718 decreased the response of longitudinal strips to CCK-8s with similar efficacy. On circular strips CCK-8s caused rhythmic phasic contractions of dose dependent amplitude and frequency, and both effects were resistant to TTX. The EC50 for the amplitude was about 4 times higher than that for the frequency. CCK-8ns (2x 10(-6) M) also caused phasic contractions, whereas the same concentrations of CCK-4 did not elicit any motor effects. L365,260 and L364,718 showed different efficacy in decreasing amplitude or frequency of contraction. These results suggest that 1) Both muscularly and neurally located CCK receptors are present on the longitudinal layer of chicken ceca whereas only muscular receptors are present on the circular muscle. 2) 5HT2 receptors seem to be involved in the neurally mediated CCK-8s response observed in the longitudinal layer. 3) The different potency of CCK-8s, CCK-8ns and CCK4 to induce contractile effects and of the CCK-A and CCK-B antagonists to block such effects suggests the existence of two different CCK receptors on the circular layer.
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PMID:Effects of cholecystokinin on chicken cecal motility: mechanisms involved. 786 38

Specific labeling of tyrosine sulfate-containing peptides was achieved using a differential iodination approach. In a complex peptide mixture from human hemofiltrate, cold iodination to saturate free iodine binding sites was followed by mild acidic desulfation of tyrosine sulfate and subsequent radioiodination using iodine-125. Reaction steps were controlled by amino acid analysis using o-phthaldialdehyde precolumn derivatization and by spiking with a sulfated cholecystokinin fragment (CCK4-S). Separation of the peptide mixture with RP-HPLC on a C18 column coupled to a radioactivity monitor led to the sensitive (< or = 5 pM) and specific determination of tyrosine sulfate-containing peptides.
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PMID:High-performance liquid chromatographic determination of sulfated peptides in human hemofiltrate using a radioactivity monitor. 789 51

Both the sulphated and non-sulphated forms of cholecystokinin (CCK) octapeptide are susceptible to hydrolysis by the cell-surface peptidases endopeptidase-24.11 (NEP), angiotensin converting enzyme and aminopeptidase N (AP-N). Indirect studies have previously implicated an elastase-like serine endopeptidase in CCK metabolism in brain. We have therefore compared the hydrolysis of CCK, in both sulphated and non-sulphated forms by solubilized membrane preparations from the human astrocytoma clone D384 and the neuroblastoma line SH-SY5Y. Selective peptidase inhibitors were used to elucidate the principal activities involved in CCK metabolism. In the glial cell line the hydrolysis of cholecystokinin octapeptide (CCK-8), sulphated or non-sulphated, was inhibited predominantly by the NEP inhibitor, phosphoramidon (PR). In contrast, in the neuroblastoma line, angiotensin converting enzyme (ACE) was seen to play a major role in metabolism of CCK-8 with a lesser effect attributable to NEP but with some differences between sulphated and non-sulphated forms reflecting the preference of ACE for CCK-8ns. In neither cell line was a significant effect of the serine peptidase inhibitor Dip-F seen on CCK metabolism arguing against the presence of a putative CCK-degrading serine peptidase in these cell lines. Both NEP and ACE remain as candidates for inactivation of CCK at the cell surface.
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PMID:Comparison of cholecystokinin metabolism by membrane preparations from the human astrocytoma clone D384 and the neuroblastoma line SH-SY5Y. 791 87

Cholecystokinin (CCK) may mediate human anxiety and animal data suggest that cholecystokinin antagonists could provide an important advance in the treatment of anxiety disorders. The study of CCK receptor systems in psychiatric patients has, however, been severely limited by the lack of available probes. We utilized intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls. Pentagastrin produced substantial symptomatology, including anxiety, and increases in heart rate and blood pressure, in both patients and controls. Patients were more sensitive to the panicogenic effects of the pentagastrin. Panic attacks occurred in 70% of patients and 0% of controls. Patients' symptom responses were very similar to their "typical" panic attacks and to symptoms produced by CCK4. Pentagastrin provides a readily available alternative to CCK4 for studying the CCK receptor system and exploring its involvement in human anxiety.
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PMID:Pentagastrin infusions in patients with panic disorder. I. Symptoms and cardiovascular responses. 867 97

Extracellular K+ activities (aKe) and neuronal and glial membrane potentials were recorded in the nucleus tractus solitarius (NTS) and in the dorsal vagal motor nucleus (DVMN) of rat brainstem slices after orthodromic stimulation of the tractus solitarius (TS). In glial cells, repetitive stimulation of the TS induced depolarizations of up to 30 mV followed by repolarizations which were fitted by exponential curves with a time constant of 1.6-5 s. Similar stimulations induced elevations of aKe of up to 8 mM, the recovery of which was fitted by single exponential curves with a time constant ranging between 1.6 and 4 s. These elevations in aKe were reduced by 75% during blockage of synaptic transmission in low Ca2+, high Mg2+ solution, and by 24% with application of 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX, 50 microM). Perfusion with a low Mg2+ solution increased the aKe response to stimulation of the TS, an effect that was reduced by the addition of 2-amino-5-phosphono-valeric acid (AP7, 50 microM) to the bath. No significant change in aKe and glial potential was seen when superfusing high concentrations of the C-terminal octapeptide of cholecystokinin (CCK8, 1-5 microM) and C-terminal tetrapeptide (CCK4, 50-100 microM). The effect of TS stimulations on solitary complex neurons suggests that extracellular K+ concentration is increased during synaptic activation of non-NMDA or NMDA ionotropic receptors. Conversely, slow depolarizations elicited by repetitive afferent activity or excitation by CCK agonists develop in neurons in the absence of measurable extracellular K+ fluctuations or glial depolarization.
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PMID:Extracellular potassium, glial and neuronal potentials in the solitary complex of rat brainstem slices. 809 69


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