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

Pulmonary neuroendocrine cells function as hypoxia-sensitive chemoreceptors, and they release peptides and biogenic amines that are important mediators of pulmonary neonatal adaptation. Some of these products additionally act as autocrine growth factors. Increased numbers of pulmonary neuroendocrine cells have been observed in several smoking-associated pediatric lung disorders such as bronchopulmonary dysplasia, cystic fibrosis, sudden infant death syndrome, and asthma. Disturbed pulmonary neuroendocrine function has been implicated in the etiology of this disease complex. One of the most common smoking-associated lung cancer types, small cell lung carcinoma, expresses phenotypic and functional features of pulmonary neuroendocrine cells. We, as well as others, have shown that the release of the autocrine growth factors 5-hydroxytryptamine (5-HT, serotonin) and mammalian bombesin/gastrin releasing peptide (MB/GRP) by cell lines derived from human small cell lung carcinoma or fetal hamster pulmonary neuroendocrine cells are regulated by a neuronal nicotinic acetylcholine receptor comprised of alpha(7) subunits. In radio-receptor assays, nicotine and the nicotine-derived carcinogenic nitrosamines NNNN. Binding of nicotine or NNK to the alpha(7) receptor resulted in calcium influx and overexpression and activation of the serine-threonine protein kinase Raf-1. In turn, this event lead to overexpression and activation of the mitogen activated (MAP) kinases extracellular signal regulated kinase 1 (ERK1) and extracellular signal regulated kinase 2 (ERK2) and stimulation of DNA synthesis accompanied by an increase in cell numbers in fetal pulmonary neuroendocrine cells and small cell carcinoma cells. Exposure of fetal pulmonary neuroendocrine cells for 6 days to NNK caused a prominant up-regulation of Raf-1. Our findings suggest that chronic exposure to nicotine and NNK in pregnant women who smoke may up-regulate the alpha(7) nicotinic receptor as well as components of its associated mitogenic signal transduction pathway, thus increasing the susceptibilities of the infants for the development of pediatric lung disorders. Similarly, up-regulation of one or several components of this nicotinic receptor pathway in smokers may be an important factor for the development of small cell lung carcinoma.
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PMID:Interaction of tobacco-specific toxicants with the neuronal alpha(7) nicotinic acetylcholine receptor and its associated mitogenic signal transduction pathway: potential role in lung carcinogenesis and pediatric lung disorders. 1077 Oct 23

The 5-hydroxytrptamine3 (5-HT3) receptor is a pentameric complex belonging to the family of ligand-gated ion channels. A variety of studies have suggested that phosphorylation regulates the rate of desensitisation and the size of amplitude of the receptor current. In this study we have examined the phosphorylation of the myc-tagged wild-type 5-HT3A receptor subunits from guinea-pig expressed in HEK293 cells (human embryonic kidney). Stably transfected cells were metabolically labelled with 32P-phosphoric acid. The results of immunoprecipitation and autoradiography demonstrate that both splicc variants of the 5-HT3A receptor subunit are phosphorylated in HEK293 cells. Site-specific mutagenesis revealed that phosphorylation occurs at serine 409, a potential target of protein kinase A. Thus the 5-HT3 receptor might be modulated by intracellular pathways, that allow variable 5-hydroxytryptamine action as responses to different extracellular stimuli.
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PMID:Phosphorylation of the 5-hydroxytryptamine3 (5-HT3) receptor expressed in HEK293 cells. 1080 Jul 72

We have identified a mechanism, mediated by the epsilon isozyme of protein kinase C (PKCepsilon) in peripheral neurons, which may have a role in chronic inflammatory pain. Acute inflammation, produced by carrageenan injection in the rat hindpaw, produced mechanical hyperalgesia that resolved by 72 hr. However, for up to 3 weeks after carrageenan, injection of the inflammatory mediators prostaglandin E(2) or 5-hydroxytryptamine or of an adenosine A(2) agonist into the same site induced a markedly prolonged hyperalgesia (>24 hr compared with 5 hr or less in control rats not pretreated with carrageenan). A nonselective inhibitor of several PKC isozymes and a selective PKCepsilon inhibitor antagonized this prolonged hyperalgesic response equally. Acute carrageenan hyperalgesia could be inhibited by PKA or PKG antagonists. However, these antagonists did not inhibit development of the hypersensitivity to inflammatory mediators. Our findings indicate that different second messenger pathways underlie acute and prolonged inflammatory pain.
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PMID:Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. 1084 37

We have investigated the effect of 5-hydroxytryptamine (serotonin) (5-HT) on the membrane properties of bullfrog taste receptor cells (TRCs) using patch-clamp technique. External application of 5-HT reversibly suppressed the voltage-gated Na(+) current (I(Na)) in about half of the TRCs sampled. The magnitude of suppression of peak I(Na) was dependent on the holding potential of the cell. Forskolin and cyclic adenosine monophosphate (cAMP) mimicked the suppressive effect of 5-HT on I(Na), but an internal protein kinase A-inhibitor potentiated I(Na). These results suggest that 5-HT suppresses I(Na) of bullfrog TRCs via protein kinase A-dependent phosphorylation, resulting in suppression of the excitability of bullfrog TRCs.
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PMID:Serotonin inhibits voltage-gated sodium current by cyclic adenosine monophosphate-dependent mechanism in bullfrog taste receptor cells. 1107 37

It is well recognized that brainstem microinjections of 5-hydroxytryptamine (serotonin, 5-HT) and thyrotropin-releasing hormone (TRH) act synergistically to stimulate gastric function in vivo. Previous in vitro experiments have shown that this synergism does not occur at the level of the dorsal motor nucleus of the vagus (DMV) motoneurone. In order to determine the mechanism of this action, whole cell patch clamp recordings were made from identified gastric-projecting rat DMV neurones to investigate the effects of 5-HT and TRH on GABAergic inhibitory postsynaptic currents (IPSCs) evoked by stimulation of the nucleus of the tractus solitarius (NTS). 5-HT (30 microM) decreased IPSC amplitude by 26 +/- 2.5% in approximately 43% of DMV neurones. In the remaining neurones in which 5-HT had no effect on IPSC amplitude, exposure to TRH (1 microM) uncovered the ability of subsequent applications of 5-HT to decrease IPSC amplitude by 28 +/- 3%. Such TRH-induced 5-HT responses were prevented by the 5-HT1A antagonist NAN-190 (1 microM) and mimicked by the 5-HT1A agonist 8-OH-DPAT (1 microM). Increasing cAMP levels using the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 10 microM), the non-hydrolysable cAMP analogue 8-bromo-cAMP (1 mM), or the adenylate cyclase activator forskolin (10 microM), like TRH, uncovered the ability of 5-HT to decrease evoked IPSC amplitude (17 +/- 2.2 %, 28.5 +/- 5.3 % and 30 +/- 4.8%, respectively), in neurones previously unresponsive to 5-HT. Conversely, the adenylate cyclase inhibitor, dideoxyadenosine (10 microM) and the protein kinase A inhibitor, Rp-cAMP (10 microM), blocked the ability of TRH to uncover the presynaptic inhibitory actions of 5-HT. These results suggest that activation of presynaptic TRH receptors initiates an intracellular signalling cascade that raises the levels of cAMP sufficient to uncover previously silent 5-HT1A receptors on presynaptic nerve terminals within the dorsal vagal complex.
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PMID:The peptide TRH uncovers the presence of presynaptic 5-HT1A receptors via activation of a second messenger pathway in the rat dorsal vagal complex. 1123 May 15

Previous studies have shown that 5-hydroxytryptamine (5-HT) can modulate the hyperpolarization-activated nonselective cation current (I(h)) to elicit a membrane depolarization in neurons. However, the receptor subtype involved in this response remains controversial. In the accompanying study, we have identified a 5-HT7 receptor-mediated depolarization in the anterodorsal nucleus of the thalamus (ADn). In the present study, we have examined the possible role of I(h) in mediating this 5-HT7 receptor-mediated depolarization. We used the blind tight-seal patch clamp technique to examine the ability of 5-HT to modulate I(h) in the ADn. We found that 5-HT induced a shift in the voltage dependence of I(h) to more depolarized potentials. The pharmacology of the receptor mediating this effect was consistent with that of a 5-HT7 receptor. Since the 5-HT7 receptor is coupled positively to adenylate cyclase, we examined the cAMP dependence of the 5-HT-induced modulation of I(h). Intracellular addition of cAMP mimicked and occluded the 5-HT response. Conversely, in the presence of the protein kinase inhibitors H-8 and staurosporine, ADn neurons still expressed a 5-HT-induced shift in the voltage dependence of I(h). These results suggest that 5-HT regulates I(h) in the ADn through a cAMP-dependent but protein kinase A (PKA)-independent mechanism. To determine the contribution of I(h) to the 5-HT7 receptor-mediated depolarization, we used the selective I(h) blocker ZD7288. This compound greatly reduced the depolarizing response elicited by activation of 5-HT7 receptors. We conclude that 5-HT7 receptors depolarize ADn neurons primarily by increasing I(h) through a cAMP-dependent, PKA-independent mechanism.
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PMID:A 5-HT(7) receptor-mediated depolarization in the anterodorsal thalamus. II. Involvement of the hyperpolarization-activated current I(h). 1125 69

(1) The vasorelaxation produced by the phosphodiesterase 3 (PDE3) inhibitor, amrinone was investigated in isolated rat aorta denuded of endothelium. In the presence of extracellular Ca(2+), amrinone, milrinone and 3-isobutyl-1-methylxanthine (IBMX), relaxed endothelium-denuded rat aortic rings constricted with phenylephrine. While the actions of milrinone and IBMX were inhibited by the protein kinase G (PKG) inhibitor, Rp-8-Bromo guanosine-3',5' monophosphothioate (Rp-8-Br-cGMPS; 0.5 mM), that of amrinone was only slightly affected; whereas the protein kinase A (PKA) inhibitor, Rp-adenosine-3',5' cyclic monophosphothioate (Rp-cAMPS; 0.5 mM) had no effect on any agent. (2) Amrinone (100 microM) inhibited (45)Ca(2+) influx through receptor- or store-operated Ca(2+) channels following stimulation with phenylephrine (1 microM) or thapsigargin (1 microM). In contrast, amrinone had no effect on KCl (120 mM)-stimulated Ca(2+) influx. (3) In the absence of extracellular Ca(2+), amrinone (30 microM) inhibited the constriction produced by phenylephrine, 5-hydroxytryptamine (5HT) and U46619, and this effect was not affected by Rp-cAMPS or Rp-8-Br-cGMPS. (4) The intracellular mechanism of action of amrinone may involve the phospholipase C (PLC)-inositol 1,4,5 trisphosphate (IP(3))-intracellular Ca(2+) signal transduction pathway. However, amrinone (100 microM) had no effect on either basal- or noradrenaline (100 microM)-stimulated PLC activity. Similarly, IP(3) stimulated a concentration-dependent release of Ca(2+) from rat brain microsomes that was not affected by amrinone (30 and 100 microM). (5) In conclusion, the vasorelaxant action of amrinone does not involve adenosine 3',5' cyclic monophosphate (cAMP) or involve guanosine 3',5' cyclic monophosphate (cGMP) but may include an inhibition of Ca(2+) influx through receptor- or store-operated Ca(2+) channels, although it does not directly affect intracellular Ca(2+) release.
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PMID:The role of cyclic nucleotides and calcium in the relaxation produced by amrinone in rat aorta. 1128 18

Properties of the 5-hydroxytryptamine (5-HT)-induced current (I(5-HT)) were examined in neurons of rat dorsolateral septal nucleus (DLSN) by using whole cell patch-clamp techniques. I(5-HT) was associated with an increase in the membrane conductance of DLSN neurons. The reversal potential of I(5-HT) was -93 +/- 6 (SE) mV (n = 7) in the artificial cerebrospinal fluid (ACSF) and was changed by 54 mV per decade change in the external K(+) concentration, indicating that I(5-HT) is carried exclusively by K(+). Voltage dependency of the K(+) conductance underlying I(5-HT) was investigated by using current-voltage relationship. I(5-HT) showed a linear I-V relation in 63%, inward rectification in 21%, and outward rectification in 16% of DLSN neurons. (+/-)-8-Hydroxy-dipropylaminotetralin hydrobromide (30 microM), a selective 5-HT(1A) receptor agonist, also produced outward currents with three types of voltage dependency. Ba(2+) (100 microM) blocked the inward rectifier I(5-HT) but not the outward rectifier I(5-HT). In I(5-HT) with linear I-V relation, blockade of the inward rectifier K(+) current by Ba(2+) (100 microM) unmasked the outward rectifier current in DLSN neurons. These results suggest that I(5-HT) with linear I-V relation is the sum of inward rectifier and outward rectifier K(+) currents in DLSN neurons. Intracellular application of guanosine-5'-O-(3-thiotriphosphate) (300 microM) and guanosine-5'-O-(2-thiodiphosphate) (5 mM), blockers of G protein, irreversibly depressed I(5-HT). Protein kinase C (PKC) 19-36 (20 microM), a specific PKC inhibitor, depressed the outward rectifier I(5-HT) but not the inward rectifier I(5-HT). I(5-HT) was depressed by N-ethylmaleimide, which uncouples the G-protein-coupled receptor from pertussis-toxin-sensitive G proteins. H-89 (10 microM) and adenosine 3',5'-cyclic monophosphothioate Rp-isomer (300 microM), protein kinase A inhibitors, did not depress I(5-HT). Phorbol 12-myristate 13-acetate (10 microM), an activator of PKC, produced an outward rectifying K(+) current. These results suggest that both 5-HT-induced inward and outward rectifying currents are mediated by a G protein and that PKC is probably involved in the transduction pathway of the outward rectifying I(5-HT) in DLSN neurons.
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PMID:Characterization of outward currents induced by 5-HT in neurons of rat dorsolateral septal nucleus. 1128 69

Calcitonin gene-related peptide (CGRP), a potent vasodilator, has been implicated in the pathogenesis of migraine. Its release from adult rat trigeminal neurons in culture was shown to be markedly increased by the activation of adenylate cyclase with forskolin. Modulation of this secretion was investigated by a number of agents with known inhibitory effects on cAMP generation mediated via receptor coupling to G(i/o) proteins. Significantly, forskolin-stimulated CGRP release could be closely correlated with the phosphorylation of the protein kinase A (PKA) substrate cyclic AMP response element-binding protein (CREB). Forskolin-stimulated CGRP release could be potently and effectively inhibited by the adenosine A(1) receptor-selective agonist GR79236X (pIC(50) = 7.7 +/- 0.1, maximal inhibition 65 +/- 2.5% at 300 nM), whereas the A(2A) (CGS21680) and the A(3) (2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide) receptor-selective agonists were without effect. GR79236X-mediated inhibition was abolished by the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Immunocytochemical studies and Western analysis revealed the presence of adenosine A(1) receptors on trigeminal neurons. However, despite the additional detection of 5-hydroxytryptamine (5-HT)(1B) receptors on these cells, the clinically effective antimigraine 5-HT(1B/1D) agonist sumatriptan did not inhibit forskolin-stimulated CGRP release nor did it show any effect on the concomitant CREB phosphorylation. In contrast, the mu-opioid agonist fentanyl elicited a 74 +/- 4% reduction in CGRP levels. Forskolin-stimulated CGRP release and CREB phosphorylation could be mimicked by incubation of the cells with chlorophenylthio-cAMP and blocked by pretreatment with the PKA inhibitor myrPKI(14-22). Taken together, the present data confirm the PKA-dependence of forskolin-stimulated CGRP release and suggest that A(1) adenosine agonists may warrant further investigation in models of migraine and neurogenic inflammation.
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PMID:Adenosine A(1) receptor-mediated inhibition of protein kinase A-induced calcitonin gene-related peptide release from rat trigeminal neurons. 1135 15

The daily rhythm in melatonin levels is controlled by cAMP through actions on the penultimate enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT; serotonin N-acetyltransferase, EC ). Results presented here describe a regulatory/binding sequence in AANAT that encodes a cAMP-operated binding switch through which cAMP-regulated protein kinase-catalyzed phosphorylation [RRHTLPAN --> RRHpTLPAN] promotes formation of a complex with 14-3-3 proteins. Formation of this AANAT/14-3-3 complex enhances melatonin production by shielding AANAT from dephosphorylation and/or proteolysis and by decreasing the K(m) for 5-hydroxytryptamine (serotonin). Similar switches could play a role in cAMP signal transduction in other biological systems.
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PMID:Role of a pineal cAMP-operated arylalkylamine N-acetyltransferase/14-3-3-binding switch in melatonin synthesis. 1142 21


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