Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine levels in brain regions receiving dense VTA input. Therefore, stress may activate the mesolimbic dopamine system in part through the actions of CRF in the VTA. Here, we explored the mechanism by which CRF affects VTA dopamine neuron firing. Using patch-clamp recordings from brain slices we first determined that the presence of I(h) is an excellent predictor of dopamine content in mice. We next showed that CRF dose-dependently increased VTA dopamine neuron firing, which was prevented by antagonism of the CRF receptor-1 (CRF-R1), and was mimicked by CRF-R1 agonists. Inhibition of the phospholipase C (PLC)-protein kinase C (PKC) signalling pathway, but not the cAMP-protein kinase A (PKA) signalling pathway, prevented the increase in dopamine neuron firing by CRF. Furthermore, the effect of CRF on VTA dopamine neurons was not attenuated by blockade of I(A), I(K(Ca)) or I(Kir), but was completely eliminated by inhibition of I(h). Although cAMP-dependent modulation of I(h) through changes in the voltage dependence of activation is well established, we surprisingly found that CRF, through a PKC-dependent mechanism, enhanced I(h) independent of changes in the voltage dependence of activation. Thus, our results demonstrated that CRF acted on the CRF-R1 to stimulate the PLC-PKC signalling pathway, which in turn enhanced I(h) to increase VTA dopamine neuron firing. These findings provide a cellular mechanism of the interaction between CRF and dopamine, which can be involved in promoting the avoidance of threatening stimuli, the pursuit of appetitive behaviours, as well as various psychiatric conditions.
 ...
PMID:Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. 1863 40

A major site of extrahypothalamic expression of corticotropin-releasing factor (CRF) and its G-protein-coupled CRF1 and CRF2 receptors is the amygdala, a key player in emotions and affective disorders. Pain-related plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) generates emotional-affective responses and anxiety-like behavior. CRF1 receptor antagonists have anxiolytic effects. Although both CRF1 and CRF2 receptors couple positively to adenylyl cyclase, they can have opposite effects, but the underlying mechanism is unknown. This study addressed CRF1 and CRF2 receptor functions and mechanisms in the amygdala in a model of arthritic pain. Using whole-cell patch-clamp recordings of CeLC neurons, we found that a selective CRF1 receptor antagonist (NBI27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)]) amino-pyridine inhibited synaptic facilitation in brain slices from arthritic rats through a postsynaptic mechanism. Inhibition of the NMDA receptor-mediated synaptic component was occluded by a protein kinase A (PKA) inhibitor, consistent with our previous demonstration of PKA-dependent increased NMDA receptor function in arthritis pain-related plasticity. NBI27914 also decreased neuronal excitability through inhibition of highly tetraethylammonium (TEA)-sensitive ion channels that contribute to action potential repolarization and firing rate. In contrast, a CRF2 receptor antagonist (astressin-2B [cyclo(31-34) [d-Phe11,His12,C alphaMeLeu13,39, Nle17, Glu31, Lys34] Ac-Sauvagine(8-40)]) facilitated synaptic transmission through presynaptic inhibition of GABAergic transmission (disinhibition). NBI27914 inhibited arthritis pain-related behaviors (audible and ultrasonic vocalizations and hindlimb withdrawal reflexes). Astressin-2B had no significant behavioral effect. The data suggest that endogenous CRF1 receptor activation in the amygdala contributes to pain-related synaptic facilitation, increased excitability, and pain behavior through a postsynaptic mechanism involving activation of PKA and highly TEA-sensitive K(+)-currents. Presynaptic CRF2 receptor-mediated inhibition does not reach behavioral significance.
 ...
PMID:Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. 1840 Aug 85

Corticotropin-releasing hormone (CRH) plays a major role in coordinating the organism's stress response, including the activity of the hypothalamic-pituitary-adrenocortical axis. The molecular underpinnings of CRH-dependent signal transduction mechanisms in the anterior pituitary have not yet been revealed in detail. In order to dissect the signal transduction cascades activated by CRH receptor type 1, a comparative proteome approach was performed in vitro utilizing murine corticotroph AtT-20 cells. Alterations in protein expression and posttranslational modification in response to CRH stimulation were studied by 2D gel electrophoresis. Selected candidates were analyzed by immunoblotting and quantitative real-time PCR. The differential analyses revealed proteins regulated or modified related to diverse cellular processes. Amongst others we identified alterations in PRKAR1A, the regulatory subunit of protein kinase A; in PGK1 and PGAM1, key regulators of glycolysis; and in proteins involved in proteasome-mediated proteolysis, PSMC2 and PSMA3. These results offer novel entry points to molecular mechanisms underlying stress responses elicited via the hypothalamic-pituitary-adrenocortical axis.
 ...
PMID:CRHR1-dependent effects on protein expression and posttranslational modification in AtT-20 cells. 1858 31

We previously showed that betaxolol, a selective beta(1)-adrenergic receptor antagonist, administered during early phases of cocaine abstinence, ameliorated withdrawal-induced anxiety and blocked increases in amygdalar beta(1)-adrenergic receptor expression in rats. Here, we report the efficacy of betaxolol in reducing increases in gene expression of amygdalar corticotropin-releasing factor (CRF), a peptide known to be involved in mediating 'anxiety-like' behaviors during initial phases of cocaine abstinence. We also demonstrate attenuation of an amygdalar beta(1)-adrenergic receptor-mediated cell-signaling pathway following this treatment. Male rats were administered betaxolol at 24 and 44 h following chronic cocaine administration. Animals were euthanized at the 48-h time point and the amygdala was microdissected and processed for quantitative reverse transcriptase-polymerase chain reaction and/or western blot analysis. Results showed that betaxolol treatment during early cocaine withdrawal attenuated increases in amygdalar CRF gene expression and cyclic adenosine monophosphate-dependent protein kinase regulatory and catalytic subunit (nuclear fraction) protein expression. Our data also reveal that beta(1)-adrenergic receptors are on amygdalar neurons, which are immunoreactive for CRF. The present findings suggest that the efficacy of betaxolol treatment on cocaine withdrawal-induced anxiety may be related, in part, to its effect on amygdalar beta(1)-adrenergic receptor, modulation of its downstream cell-signaling elements and CRF gene expression.
 ...
PMID:Evidence for beta1-adrenergic receptor involvement in amygdalar corticotropin-releasing factor gene expression: implications for cocaine withdrawal. 1859 87

Corticotropin-releasing hormone (CRH) has been shown to exhibit various functions in hippocampus. In the present study, we examined the effect of CRH on the expression of serum/glucocorticoid-inducible protein kinase-1 (SGK-1), a novel protein kinase, in primary cultured hippocampal neurons. A dose-dependent increase in mRNA and protein levels of SGK-1 as well as frequency of SGK-1-positive neurons occurred upon exposure to CRH (1 pmol/l to 10 nmol/l). These effects can be reversed by the specific CRH-R1 antagonist antalarmin but not by the CRH-R2 antagonist astressin 2B. Blocking adenylate cyclase (AC) activity with SQ22536 and PKA with H89 completely prevented CRH-induced mRNA and protein expression of SGK-1. Blockage of PLC or PKC did not block CRH-induced SGK-1 expression. Our results suggest that CRH act on CRH-R1 to stimulate SGK-1 mRNA and protein expression in cultured hippocampal neurons via a mechanism that is involved in AC/PKA signaling pathways.
 ...
PMID:Corticotropin-releasing hormone stimulates SGK-1 kinase expression in cultured hippocampal neurons via CRH-R1. 1871 60

Relaxin 3 is expressed in neurons of the brain stem that inneravate wide areas of the forebrain. Relaxin 3 mRNA levels in these neurons are increased in response to restraint stress, and by central administration of corticotropin-releasing factor (CRF). In the present study, we observed that relaxin 3 was expressed in a mouse neuroblastoma cell line, Neuro2a, and investigated the intracellular signaling that activated relaxin 3 gene transcription in vitro. By means of a clone stably transfected with a relaxin 3 promoter-EGFP gene, we observed that dibutyryl cyclic AMP and forskolin increased the relaxin 3 promoter activity. These increases were inhibited by pretreatment with PKA inhibitors, H89 and KT5720. Moreover, the promoter activity was enhanced by CRF treatment after expression of CRF-R1 receptor on the cells. Taken together, these results indicate that relaxin 3 transcription is activated via the cAMP-PKA pathway in the downstream of CRF-R1.
 ...
PMID:Regulation of relaxin 3 gene expression via cAMP-PKA in a neuroblastoma cell line. 1883 Oct 67

Corticotropin-releasing factor (CRF), produced in the hypothalamic paraventricular nucleus (PVN) in response to stress, stimulates the synthesis and secretion of adrenocorticotropin (ACTH) via CRF receptor type 1 (CRF(1) receptor) in the anterior pituitary (AP) of mammals. CRF is critical for the circadian rhythmicity of the hypothalamic-pituitary-adrenal axis and the augmented release of ACTH from the pituitary in response to the stress. A higher molecular weight form of immunoreactive beta-endorphin, putative proopiomelanocortin (POMC), is increased in CRF-knockout mice (CRF KO), suggesting the important role of CRF in the processing of POMC. In fact, CRF is able to modulate the processing of POMC through changes in prohormone convertase (PC)-1 expression levels. Multiple forms of ACTH-related peptides containing unprocessed ones are present in some cases of ACTH-producing tumors, presumably without action of PC-1 under the control of CRF. Following CRF-activated stimulation of the receptor signaling, CRF(1) receptor is down-regulated and desensitized. In fact, CRF facilitates the degradation of CRF(1) receptor mRNA via the protein kinase A pathway. Prolonged agonist activation of CRF(1) receptor leads to a loss of responsiveness, or desensitization of the receptor. G protein-coupled receptor kinase 2 is involved in desensitization of CRF(1) receptor by CRF in the corticotroph.
 ...
PMID:Role and action in the pituitary corticotroph of corticotropin-releasing factor (CRF) in the hypothalamus. 1912 55

Corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. In the hypothalamic paraventricular nucleus (PVN), CRF, produced in response to stress, stimulates the release of ACTH from the anterior pituitary. ACTH then stimulates the release of glucocorticoids from the adrenal glands; circulating glucocorticoids are critical for recovery from stress conditions. Cytokines are also implicated in the regulation of CRF expression. Among them, interleukin (IL)-6 plays a role in the regulation of CRF. Factors other than glucocorticoids are likely to be involved in limiting the stimulation of CRF during stress. Suppressor of cytokine signaling (SOCS)-3 acts as a potent negative regulator of cytokine signaling. Little is known about the ability of the inhibitory signaling pathways to limit activation of the CRF gene in parvocellular PVN neurons. Hypothalamic 4B cells are useful for exploring the mechanisms, because these cells show characteristics of the parvocellular neurons of the PVN. In the present study, we examined whether SOCS-3 is regulated by IL-6 and cAMP in hypothalamic 4B cells. We also explored the involvement of SOCS-3 in the regulation of CRF gene expression. SOCS-3 was found to be regulated by IL-6 and via the cAMP/protein kinase A pathway in the hypothalamic cells. SOCS-3 knockdown increased IL-6- or forskolin-induced CRF gene transcription and mRNA levels. Therefore, SOCS-3, induced by a cAMP stimulant and IL-6, would be involved in the negative regulation of CRF gene expression in hypothalamic cells.
 ...
PMID:Regulation and role of suppressor of cytokine signaling-3 in hypothalamic 4B cells. 1929 94

The hypothalamic-pituitary-adrenal (HPA) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (ACTH) production via CRF receptor type 1 (CRF(1) receptor) from the corticotrophs of the anterior pituitary (AP). Cyclic AMP (cAMP)-protein kinase A (PKA) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclase-activating polypeptide (PACAP) stimulate adenylate cyclase, intracellular cAMP production, and then CRF and arginine vasopressin (AVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and AVP gene expression. Estradiol may enhance the activation of CRF gene expression in response to stress. The HPA axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and ACTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. Glucocorticoids-dependent repression of cAMP-stimulated CRF promoter activity is mainly localized to promoter sequences between -278 and -233 bp. Both negative glucocorticoid regulatory element (nGRE) and serum response element (SRE) are involved in the repression of the CRF gene in the hypothalamic cells.
 ...
PMID:Regulatory mechanisms underlying corticotropin-releasing factor gene expression in the hypothalamus. 1935 56

We have previously reported that repeated central administration of sub-anxiogenic doses of the corticotropin releasing factor 1 (CRF(1)) agonist Cortagine, termed "priming," elicits a phenotype of increased anxiety-like behaviors in the elevated plus maze (EPM) and open-field test, and enhanced retention of contextual conditioned fear in C57BL/6J mice. Observed behavioral changes were functionally coupled to CRF(1)-mediated elevated central cholecystokinin (CCK) tone in discrete brain regions. However, the changes in gene expression that mediated "priming"-induced behavioral and concurrent molecular changes in specific brain regions remained unknown. In the present study, a complementary DNA microarray analysis was used to investigate gene expression profiles in the hippocampus and prefrontal cortex (PFC) of C57BL/6J mice following the "priming" procedure. Here, we report that chronic stimulation of CRF(1), by i.c.v. administration of 10 ng Cortagine for five days, brought about alterations in the expression of a wide range of hippocampal (31 genes) and PFC (18 genes) genes, implicated in anxiety and aversive memory formation. These expression changes involved genes associated with signal transduction, neurotransmitter secretion, synaptic transmission, myelination, and others involved in the transport, biosynthesis, and binding of proteins. In particular, several genes of the protein kinase A (PKA) and protein kinase C (PKC) signaling cascades, known to be involved in synaptic plasticity, such as neurogranin, calmodulin 3, and the PKA regulatory subunit 1 b were found to be upregulated in the PFC and hippocampus of CRF(1) agonist "primed" mice. Moreover, we show pharmacologically that one of the newly implicated memory regulatory elements, diazepam-binding inhibitor (DBI) is functionally involved in hippocampus-dependent enhancement of contextual fear, a cardinal phenotypic feature of the "primed" mice. Finally, an interaction network mapping of the altered genes and their known interacting partners identified additional molecular candidates responsible for CRF(1)-mediated hypersensitive fear circuitry.
 ...
PMID:Region specific gene expression profile in mouse brain after chronic corticotropin releasing factor receptor 1 activation: the novel role for diazepam binding inhibitor in contextual fear conditioning. 1936 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>