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)

Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and has been implicated in the regulation of a diversity of emotions and motivations including negative affect and stress responses. In this experiment, we assayed levels of CCK (CCK4/5 and CCK8) from tissue homogenates in intruder animals 6 h after resident-intruder inter-male aggression. Intruder animals that demonstrated submissive behavior (freezing and 22-kHz ultrasonic vocalizations) had higher levels of CCK in the tegmentum and posterior cortex as compared to non-submissive (i.e., "Friendly") intruder animals. Ultrasonic vocalizations (22-kHz) were positively correlated with CCK levels in the tegmentum, posterior cortex and pituitary. These data suggest that CCK may play a role in the generation of negative affective states indexed by 22-kHz ultrasonic calls in certain regions of the brain.
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PMID:Regional brain cholecystokinin changes as a function of friendly and aggressive social interactions in rats. 1546 47

Somatostatin receptors are expressed in selected human cancers. They are particularly frequently expressed in gastroenteropancreatic neuroendocrine tumors (GEP NET), including both primaries and metastases. The density is often high, the distribution is usually homogeneous. While various somatostatin receptor subtypes can be expressed in these tumors, sst2 is clearly predominant. These receptors represent the molecular basis for a number of clinical applications, including symptomatic therapy with cold octreotide in hormone-secreting GEP NET, in vivo diagnostic with Octreoscan to evaluate the extend of the disease, and 90Y-DOTATOC radiotherapy. GEP NET can, however, express peptide receptors other than somatostatin receptors: insulinomas have more glucagon-like peptide 1 receptors than somatostatin receptors, gut NET (carcinoids) may also express cholecystokinin 2, bombesin or vasoactive intestinal peptide receptors. Often, several of these peptide receptors are expressed simultaneously in GEP NET, providing a molecular basis for in vivo multireceptor targeting of those tumors.
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PMID:Somatostatin and other Peptide receptors as tools for tumor diagnosis and treatment. 1547 18

Signals from the gut and hypothalamus converge in the caudal brainstem to control ingestive behavior. We have previously shown that phosphorylation of ERK1/2 in the solitary nucleus (NTS) is necessary for food intake suppression by exogenous cholecystokinin (CCK). Here we test whether this intracellular signaling cascade is also involved in the integration of melanocortin-receptor (MCR) mediated inputs to the caudal brainstem. Using fourth ventricular-cannulated rats and Western blotting of NTS tissue, we show that the MC4R agonist melanotan II (MTII) rapidly and dose-dependently increases phosphorylation of both ERK1/2 and cAMP response element-binding protein (CREB). Sequential administration of fourth ventricular MTII and peripheral CCK at doses that alone produced submaximal stimulation of pERK1/2 produced an additive increase. Prior fourth ventricular administration of the MC4R antagonist SHU9119 completely abolished the CCK-induced increases in pERK and pCREB and, in freely feeding rats, SHU9119 significantly increased meal size and satiety ratio. Prior administration of the MAPK kinase inhibitor U0126 abolished the capacity of MTII to suppress 2-h food intake and significantly decreased MTII-induced ERK phosphorylation in the NTS. Furthermore, pretreatment with the cAMP inhibitor, cAMP receptor protein-Rp isomer, significantly attenuated stimulation of pERK induced by either CCK or MTII. The results demonstrate that activation of the ERK pathway is necessary for peripheral CCK and central MTII to suppress food intake. The cAMP-->ERK-->CREB cascade may thus constitute a molecular integrator for converging satiety signals from the gut and adiposity signals from the hypothalamus in the control of meal size and food intake.
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PMID:Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus. 1596 54

Elucidation of mechanisms of acinar cell cytokine production is essential for a better understanding of acute pancreatitis pathogenesis. We hypothesize that the stress kinases ERK, p38, and JNK play an important role in acinar cell cytokine production. Rat pancreatic fragments were incubated with 100 nM concentration of the cholecystokinin analog caerulein or 100 nM caerulein and specific ERK inhibitor (100 microM PD98059), specific p38 inhibitor (10 microM SB203580), or specific JNK inhibitor (20 microM SP600125). After 3 hours of caerulein treatment, pancreatic fragments were homogenized and assayed for total and phosphorylated ERK, p38, and JNK, and for tumor necrosis factor-alpha or interleukin-1beta concentrations (ELISA). Pancreatic fragments stimulated with caerulein showed activation of ERK, p38, and JNK and increased cytokine concentrations (ANOVA, P<0.05). Specific stress kinase inhibitors significantly attenuated caerulein-induced activation of the corresponding stress kinase and cytokine production; however, the effect of the JNK inhibitor was comparatively less convincing. Increased activation of ERK, p38, and JNK in pancreatic fragments was not associated with significant increases in total ERK, total p38, or total JNK concentrations. The stress kinases ERK and p38 play an important role in caerulein-stimulated exocrine pancreatic overproduction of cytokines. The role of JNK needs further evaluation in this experimental model.
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PMID:In vitro evidence for role of ERK, p38, and JNK in exocrine pancreatic cytokine production. 1717 57

Numerous peptide receptors have recently been reported to be expressed or overexpressed in various human cancers. For instance, somatostatin receptors are particularly frequently expressed in gastroenteropancreatic neuroendocrine tumors (GEP-NET), including both primaries and metastases. The density is often high, and the distribution is usually homogenous. While various somatostatin receptor subtypes can be expressed in these tumors, the sst(2) is clearly predominant. These receptors represent the molecular basis for a number of clinical applications, including symptomatic therapy with octreotide in hormone-secreting GEP-NET, in vivo diagnostic with radiolabeled diethylene triamine pentaacetic acid octreotide (Octreoscan) to evaluate the extend of the disease, and (90)Y- or (177)Lu-[(90)Y-DOTA]-D: -Phe(1)-Tyr(3) octreotide radiotherapy. GEP-NET can, however, express peptide receptors other than somatostatin receptor: Insulinomas have more glucagon-like peptide 1 receptors than somatostatin receptors; gastrinomas express very high levels of secretin receptors. GEP-NET may also express cholecystokinin 2, bombesin, neuropeptide Y, or vasoactive intestinal peptide receptors. Often, several of these peptide receptors are expressed simultaneously in GEP-NET, providing a molecular basis for in vivo multireceptor targeting of those tumors.
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PMID:Peptide receptor expression in GEP-NET. 1768 67

The neuropeptide cholecystokinin (CCK) is anxiogenic in studies of human and animal behavior. As the amygdala formation has been implicated in generation of emotional states such as anxiety, we tested the effect of CCK on spontaneous synaptic events in the basolateral amygdala (BLA) using whole cell patch recordings in rat brain slice preparation. We found that CCK increased the frequency of spontaneous inhibitory postsynaptic potentials (sIPSPs) and currents (sIPSCs). This effect was blocked by the fast sodium channel blocker tetrodotoxin (TTX), indicating that the CCK effect is likely mediated by direct excitation of GABAergic interneurons. The CCK(B) receptor subtype antagonist, CR2945, blocked the CCK effect, while CCK4, a specific CCK(B) agonist, increased sIPSC frequency. We hypothesize that these actions may underlie the anxiogenic effects of CCK observed in behavioral studies.
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PMID:Cholecystokinin enhances GABAergic inhibitory transmission in basolateral amygdala. 1790 18

The transmission of extracellular proliferation and differentiation signals into their intracellular targets is mediated by a signaling cascade culminating in mitogen-activated protein kinase (MAPK) also known as ERK. In pancreatic acinar cells both cholecystokinin (CCK) and epidermal growth factor (EGF) are known to stimulate ERK. Regulatory interactions among individual receptor-coupled signaling cascades are critically important for establishing cellular responses in the face of multiple stimuli. The aim of our study was to evaluate the effect of concomitant stimulation of G protein-coupled receptors (GPCR) and EGF receptors on ERK activity in isolated pancreatic acinar cells. ERK activity was determined by means of Western-blotting, with the use of the antibody which recognizes active, tyrosine-phosphorylated kinase (pY-ERK). pY-ERK level was strongly elevated by 10 nM CCK-8, 100 microM carbachol (CAR), or 100 nM EGF. The addition of EGF to 60 min-lasting incubations of acini with CCK-8 or CAR caused abrupt decrease of pY-ERK level to 56 and 59% of control, respectively. Similar phenomenon was observed when short stimulation with CCK-8 or CAR was superimposed on the effect of EGF. After the addition of EGF to acini incubated previously with phorbol ester TPA, strong decrease in pY-ERK level was also observed. In conclusion, in pancreatic acinar cells, concomitant stimulation with CCK or CAR and EGF has strong inhibitory effect on ERK cascade. This inhibitory cross-talk may be mediated, at least partially, by protein kinase C (PKC). These mutual inhibitory interactions demonstrate novel mechanism for integration of multiple signals generated by activation of G-protein-coupled and growth factor receptors in pancreatic acinar cells.
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PMID:The effect of concomitant stimulation with cholecystokinin and epidermal growth factor on extracellular signal-regulated kinase (ERK) activity in pancreatic acinar cells. 1792 41

The aim of the present study is to provide a review of the expression and action of trophic factors in the carotid body. In glomic type I cells, the following factors have been identified: brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, artemin, ciliary neurotrophic factor, insulin-like growth factors-I and -II, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha and -beta1, interleukin-1beta and -6, tumour necrosis factor-alpha, vascular endothelial growth factor, and endothelin-1 (ET-1). Growth factor receptors in the above cells include p75LNGFR, TrkA, TrkB, RET, GDNF family receptors alpha1-3, gp130, IL-6Ralpha, EGFR, FGFR1, IL1-RI, TNF-RI, VEGFR-1 and -2, ETA and ETB receptors, and PDGFR-alpha. Differential local expression of growth factors and corresponding receptors plays a role in pre- and postnatal development of the carotid body. Their local actions contribute toward producing the morphologic and molecular changes associated with chronic hypoxia and/or hypertension, such as cellular hyperplasia, extracellular matrix expansion, changes in channel densities, and neurotransmitter patterns. Neurotrophic factor production is also considered to play a key role in the therapeutic effects of intracerebral carotid body grafts in Parkinson's disease. Future research should also focus on trophic actions on carotid body type I cells by peptide neuromodulators, which are known to be present in the carotid body and to show trophic effects on other cell populations, that is, angiotensin II, adrenomedullin, bombesin, calcitonin, calcitonin gene-related peptide, cholecystokinin, erythropoietin, galanin, opioids, pituitary adenylate cyclase-activating polypeptide, atrial natriuretic peptide, somatostatin, tachykinins, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.
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PMID:Trophic factors in the carotid body. 1877 56

The protein kinase D (PKD) family of serine/threonine kinases, which can be activated by gastrointestinal hormones, consists of three distinct isoforms that modulate a variety of cellular processes including intracellular protein transport as well as constitutive and regulated secretion. Although isoform-specific functions have been identified in a variety of cell lines, the expression and function of PKD isoforms in normal, differentiated secretory tissues is unknown. Here, we demonstrate that PKD isoforms are differentially expressed in the exocrine and endocrine cells of the pancreas. Specifically, PKD3 is the predominant isoform expressed in exocrine cells of the mouse and human pancreas, whereas PKD1 and PKD2 are more abundantly expressed in the pancreatic islets. Within isolated mouse pancreatic acinar cells, PKD3 undergoes rapid membrane translocation, trans-activating phosphorylation, and kinase activation after gastrointestinal hormone or cholinergic stimulation. PKD phosphorylation in pancreatic acinar cells occurs viaaCa2+-independent, diacylglycerol- and protein kinase C-dependent mechanism. PKD phosphorylation can also be induced by physiologic concentrations of secretagogues and by in vivo stimulation of the pancreas. Furthermore, activation of PKD3 potentiates MEK/ERK/RSK (RSK, ribosomal S6 kinase) signaling and significantly enhances cholecystokinin-mediated pancreatic amylase secretion. These findings reveal a novel distinction between the exocrine and endocrine cells of the pancreas and further identify PKD3 as a signaling molecule that promotes hormone-stimulated amylase secretion.
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PMID:PKD3 is the predominant protein kinase D isoform in mouse exocrine pancreas and promotes hormone-induced amylase secretion. 1902 87

Layer 6b in neocortex is a distinct sublamina at the ventral portion of layer 6. Corticothalamic projections arise from 6b neurons, but few studies have examined the functional properties of these cells. In the present study we examined the actions of cholecystokinin (CCK) on layer 6b neocortical neurons using whole-cell patch clamp recording techniques. We found that the general CCK receptor agonist CCK8S (sulfated CCK octapeptide) strongly depolarized the neurons, and this action persisted in the presence of tetrodotoxin, suggesting a postsynaptic site of action. The excitatory actions of CCK8S were mimicked by the selective CCK(B) receptor agonist CCK4, and attenuated by the selective CCK(B) receptor antagonist L365260, indicating a role for CCK(B) receptors. Voltage-clamp recordings revealed that CCK8S produced a slow inward current associated with a decreased conductance with a reversal potential near the K(+) equilibrium potential. In addition, intracellular cesium also blocked the inward current, suggesting the involvement of a K(+) conductance, likely K(leak). Our data indicate that CCK, acting via CCK(B) receptors, produces a long-lasting excitation of layer 6b neocortical neurons, and this action may play a critical role in modulation of corticothalamic circuit activity.
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PMID:Cholecystokinin action on layer 6b neurons in somatosensory cortex. 1949 13


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