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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-hydroxytryptamine (5-HT) is a mitogen for fibroblasts, vascular smooth muscle cells, renal mesangial cells, and jejunal crypt cells. The human carcinoid cell line (termed BON) that we established in our laboratory from a pancreatic carcinoid tumor produces and secretes 5-HT. In this study, therefore, we examined the effect of 5-HT on growth of BON cells. Furthermore, by use of selective 5-HT receptor antagonists, we examined receptor and post-receptor mechanisms by which 5-HT-induced responses were produced. 5-HT stimulated growth of BON cells. 5-HT stimulated phosphatidylinositol (PI) hydrolysis in a dose-dependent fashion and inhibited cyclic AMP production in a dose-dependent fashion. The 5-HT1A/1B receptor antagonist, SDZ 21-009, prevented the reduction of cyclic AMP production evoked by 5-HT and inhibited the mitogenic action of 5-HT. The 5-HT1C/2 receptor antagonist, mesulergine, competitively inhibited PI hydrolysis, but did not affect the mitogenic action of 5-HT. The mitogenic action of 5-HT and the reduction of cyclic AMP production evoked by 5-HT were also inhibited by pertussis toxin. These results suggest that 5-HT is an autocrine growth factor for BON cells and that mitogenic mechanism of 5-HT involves receptor-mediated inhibition of the production of cyclic AMP which may be linked to pertussis toxin-sensitive GTP binding protein. 8-bromo-cyclic AMP inhibited growth of BON cells whereas 8-bromo-cyclic GMP had no effect on cell growth. Involvement of protein kinase A in BON cell growth regulation was confirmed by the observation that a cAMP-dependent protein kinase antagonist (Rp-cAMPS) could stimulate BON cell growth.
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PMID:Receptor-mediated autocrine growth-stimulatory effect of 5-hydroxytryptamine on cultured human pancreatic carcinoid cells. 130 21

In various species, including humans, 5-hydroxytryptamine (5-HT) has been shown to exert positive chronotropic and inotropic cardiac effects through different types of receptors. The goal of the present study was to investigate the regulation by 5-HT of voltage-gated Ca2+ channels in human atrial myocytes and to characterize the receptor involved. Cardiomyocytes isolated enzymatically and mechanically were voltage-clamped using the whole-cell configuration of the patch-clamp technique. Extracellular perfusion of 5-HT increased Ca2+ current (ICa) amplitude with a EC50 (0.1 microM) similar to that observed with isoprenaline. The effects of 5-HT were blocked by the addition of protein kinase A inhibitor in the pipette. In addition, the effects of 5-HT, isoprenaline, and intracellular cAMP on ICa were not additive. These results support the hypothesis that the inotropic effect of 5-HT in human atrial myocytes is related to an increase of ICa via an elevation of intracellular cAMP levels and stimulation of cAMP-dependent protein kinase. The effects of 5-HT were not blocked by antagonists of 5-HT1 (methiothepin), 5-HT2 (ketanserin), or 5-HT3 (ICS 205-930 at a low concentration) receptors. The benzamide derivatives renzapride and zacopride and the azabicyclobenzimidazolone derivative BIMU 8 increased ICa, but less efficiently than did 5-HT or 5-methoxytryptamine. Moreover, ICS 205-930 at high concentrations (greater than 1 microM) completely antagonized the effects of 5-HT. Thus, the pharmacology of the 5-HT receptor involved in an increase of ICa in human atrial myocytes resembles that recently described for the 5-HT4 receptor. In atrial myocytes dissociated from rat, rabbit, guinea pig, or frog, 5-HT at high concentrations had no effect on Ca2+ currents, suggesting that the distribution of 5-HT4 receptors in cardiac tissues is species dependent.
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PMID:Serotonin increases calcium current in human atrial myocytes via the newly described 5-hydroxytryptamine4 receptors. 131 10

The effects of 5-hydroxytryptamine (5-HT) on left atrial preparations obtained from 5 patients with terminal heart failure who were undergoing heart transplant surgery were investigated. The preparations were paced under isometric conditions. In the presence of (-)-pindolol 1 mumol/l (to block beta-adrenoceptors) and cocaine 6 mumol/l (to block tissue uptake of 5-HT) 5-HT increased contractile force with a pEC50 of 7.0. The maximum effect of 5-HT amounted to 24.5% of that caused by a maximally effective concentration of (-)-isoprenaline (200 mumol/l) and 25% of that caused by 6.75 mmol/l CaCl2. The effects of 5-HT were competitively antagonised by 3 alpha-tropanyl-1H-indole-3-carboxylate (ICS 205-930) with a pKB of 6.8. The effects of 5-HT on cyclic AMP levels and cyclic AMP-dependent protein kinase activity were also studied using left atrial tissues from one of the patients; 5-HT increased the cyclic AMP content and stimulated the kinase. The results are consistent with the existence of a human left atrial 5-HT receptor which is similar to the recently identified human right atrial 5-HT receptor that resembles the 5-HT4 receptor. The left atrial 5-HT4-like receptor is functional in tissues obtained from patients with terminal heart failure.
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PMID:A 5-HT4-like receptor in human left atrium. 132 Feb 6

1. The aim of the present study was to examine the effect of 5-hydroxytryptamine (5-HT) on K+ current in primary culture of mouse colliculi neurones and to identify the 5-HT receptor subtype that could be involved in this effect. 2. The voltage-activated K+ current of the neurones was partially blocked by 8-bromo adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP). This effect was mimicked by 5-HT and the action of 5-HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP-dependent protein kinase blocker. 3. A similar cyclic AMP-dependent blockade of the K+ current was found with renzapride (BRL 24,924) and other 5-HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT). ICS 205,930, the classical 5-HT4 receptor blocker, could not be used in this study because it inhibited the studied K+ current by itself. However, the novel 5-HT4 receptor antagonist, DAU 6285 blocked the effects of 5-HT and renzapride on the K+ current. 4. The current was insensitive to the 5-HT1 and 5-HT3 receptor agonists (8-hydroxy-2-(di-n-propylamino) tetralin, RU 24,969, carboxamidotryptamine, 2-CH3-5-HT) as well as to 5-HT1, 5-HT2 and 5-HT3 antagonists (methiothepin, ketanserin, ondansetron [GR 38,032]). Moreover, these antagonists did not affect the actions of the tested 5-HT4 receptor agonists. 5. The present results show that part of the voltage-activated K+ current in mouse colliculi neurones is cyclic AMP-sensitive and the blockade of the current by 5-HT involves the 5-HT4 receptor subtype.The putative implication of 5-HT4 receptors in neuronal plasticity, via a blockade of K+ channels, is discussed.
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PMID:The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase. 132 59

Exposure of mouse colliculi neurons to selective 5-hydroxytryptamine (5-HT)4 agonists was accompanied by a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Half-maximal desensitization occurred after 2 min. Only exposure of neurons to selective 5-HT4 agonists led to a potent desensitization of the 5-HT4-mediated response. Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors. Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization. No shift to lower potency of 5-HT4 agonists in the concentration-response curve was observed. These results suggest that 5-HT4 receptor agonists induced homologous but not cAMP-mediated heterologous desensitization. A good correlation was found between the affinities of nine 5-HT4 agonists and their abilities to desensitize the adenylyl cyclase response. This may indicate that homologous desensitization is a function of the mean occupancy time of the receptors by agonists. When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40%. Interestingly, Zn2+, an other inhibitor of beta ARK, totally prevented 5-HT4-induced desensitization. Pretreatment of neurons with concanavalin A, reported to inhibit sequestration of beta-adrenergic receptors from the cell surface, reduced the desensitization process by 70%. These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase.
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PMID:Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons. 133 63

The effects of 5-carboxamidotryptamine (5-CT) and the gastrokinetic benzamides renzapride and cisapride on contractile force were investigated using isolated paced right atrial appendages from patients treated with beta-adrenoceptor blocking agents who were undergoing open heart surgery. These effects were compared to those of 5-hydroxytryptamine (5-HT). The effects of the drugs on atrial cyclic AMP levels and cyclic AMP-dependent protein kinase ratios were also investigated. The drugs all increased contractile force of rank order of potency was 5-HT greater than renzapride greater than cisapride greater than 5-CT. The maximum responses, expressed as a fraction of the response to 200 mumol/l (-)-isoprenaline, were 5-HT 0.6, 5-CT 0.6, renzapride 0.4 and cisapride greater than or equal to 0.2, suggesting that the latter two are partial agonists. 5-HT, 5-CT and renzapride but not cisapride caused significant shortening of time to peak force. The effects of the four drugs were blocked by mumolar concentrations of ICS 205-930, suggesting an involvement of 5-HT4 receptors. As expected of partial agonists both renzapride and cisapride caused simple competitive antagonism of the positive inotropic effects of 5-HT. The estimated equilibrium dissociation constants pKP (-log mol/l KP) were 6.7 for renzapride and 6.2 for cisapride. 5-CT at concentrations up to 10 mumol/l did not antagonise the effects of 5-HT. In the presence of (+/-)-propranolol 0.4 mumol/l, 5-HT 10 mumol/l, 5-CT 100 mumol/l, renzapride 10 mumol/l and cisapride 40 mumol/l significantly increased cyclic AMP levels. 5-HT and renzapride also significantly increased cyclic AMP-dependent protein kinase activity, whereas 5-CT caused only marginal stimulation and cisapride was ineffective. The results confirm the existence of a human right atrial 5-HT receptor that is similar in nature to, but not necessarily identical with, the 5-HT4 receptor of mouse embryonic colliculi neurones. The main difference is that in human right atrium the benzamides are less potent and efficacious than 5-HT and that cisapride is less potent and less efficacious than renzapride while in mouse embryonic colliculi these two benzamides are equipotent with and more efficacious agonists than 5-HT. We designate the human right atrial 5-HT receptor 5-HT4-like. The human right atrial 5-HT4-like receptor greatly resembles porcine sinoatrial and left atrial 5-HT4-like receptors and also appears to be similar to 5-HT4-like receptors of guinea-pig ileum and rat oesophagus.
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PMID:A 5-HT4-like receptor in human right atrium. 165 64

Heterologous expression of the rat 5-HT1A receptor in stably transfected GH4C1 rat pituitary cells (clone GH4ZD10) and mouse Ltk- fibroblast cells (clone LZD-7) (Albert, P.R., Zhou, Q.-Y., VanTol, H.H.M., Bunzow, J.R., and Civelli, O. (1990) J. Biol. Chem. 265, 5825-5832) was used to characterize the cellular specificity of signal transduction by the 5-HT1A receptor. We demonstrate that the 5-HT1A receptor, acting via pertussis toxin-sensitive G proteins, can change its inhibitory signaling phenotype and become a stimulatory receptor, depending on the cell type, differentiation state, or intracellular milieu of the cell in which it is expressed. When expressed in pituitary GH4ZD10 cells, activation of 5-HT1A receptors decreased both basal and vasoactive intestinal peptide-enhanced cAMP accumulation and blocked (+/-)-Bay K8644-induced influx of calcium, inhibitory responses which are typical of neurons which endogenously express this receptor. Similarly, 5-hydroxytryptamine (5-HT) also inhibited adenylyl cyclase in fibroblast LZD-7 cells, reducing the forskolin-induced enhancement of cAMP levels by 50%, but did not alter basal cAMP levels. In contrast to GH4ZD10 cells, where 5-HT had no effect on basal or thyrotropin-releasing hormone-induced phosphatidylinositol turnover, 5-HT enhanced the accumulation of inositol phosphates and induced a biphasic increase in [Ca2+]i in LZD-7 cells. These dominant stimulatory actions of 5-HT, as well as the inhibitory effects, were absent in untransfected cells and displayed the potency and pharmacological specificity of the 5-HT1A receptor, indicating that the 5-HT1A subtype coupled to both inhibitory and stimulatory pathways in the fibroblast cell. The actions of 5-HT in GH and L cells were blocked by 24-h pretreatment with pertussis toxin, suggesting that inhibitory G proteins (Gi/G(o)) mediate both inhibitory and stimulatory signal transduction of the 5-HT1A receptor. However, the 5-HT-induced stimulatory pathway in fibroblasts was blocked selectively by acute (2-min) pretreatment with TPA, an activator of protein kinase C. This action of protein kinase C was potentiated by activation of protein kinase A, indicating that the expression of the stimulatory pathway of the 5-HT1A receptor in LZD-7 cells is modulated by second messengers.
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PMID:Cell-specific signaling of the 5-HT1A receptor. Modulation by protein kinases C and A. 166 Aug 81

Atrial myocardium of man and pig possess receptors that mediate positive inotropic effects and/or positive chronotropic effects of 5-hydroxytryptamine (5-HT). These 5-HT receptors are blocked with moderate affinity (pKB = 6.7-6.9) by 3 alpha-trophanyl-1H-indole-3-carboxylate (ICS 205930) but not by antagonists of alpha- and beta-adrenoceptors, or 5-HT1 subtypes, 5-HT2 and 5-HT3 receptors. In human and porcine atrium the receptors also mediate 5-HT-induced increases of both cyclic AMP levels and cyclic AMP-dependent protein kinase activity. Human and porcine atrial 5-HT receptors are also partially activated by the benzamides renzapride and cisapride albeit with lower potency and efficacy than 5-HT. The properties of these atrial 5-HT receptors resemble those of "so called" 5-HT4 receptors, positively coupled to the adenylyl cyclase of mouse embyonic colliculi neurons. However, for colliculi 5-HT4 receptors the benzamides have greater efficacy and ICS 205930 lower affinity than for atrial 5-HT receptors. The atrial 5-HT receptors of man and pig are, therefore, designated 5-HT4-like receptors. Guinea-pig night atria appear to have a mixture of 5-HT3- and 5-HT4-like receptors involved in the mediation of positive chronotropic effects of 5-HT.
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PMID:5-HT4-like receptors in mammalian atria. 166 72

Application of 5-hydroxytryptamine (5HT) induces a slowly depolarizing response in the neurons of Aplysia abdominal ganglion. In voltage-clamped cells, 5HT induced a slow inward current that increased steeply with membrane depolarization from -85 mV showing a negative slope conductance, but never reversed into outward when hyperpolarized beyond the equilibrium potential for K+. The 5HT-induced response was markedly augmented in Ca(2+)-free media, but depressed in Na(+)-free media, and unaffected by a change in external potassium. Intracellular injection of guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) significantly depressed the 5HT response in a dose-dependent way. Injection of cholera toxin (CTX) selectively blocked the 5HT-induced response, the effect being irreversible. Neither 3'-deoxyadenosine, an inhibitor of adenylate cyclase, nor H-8, an inhibitor of protein kinase A, depressed the 5HT response. 3-Isobutyl-1-methylxanthine (IBMX) did not augment the 5HT response appreciably. The 5HT responses were not depressed at all during a saturated response to Br-cyclic AMP injected intracellularly. It was concluded that the 5HT response is produced by opening of the voltage-dependent Na(+)-channels with activation of CTX-sensitive G-protein but not necessarily with an increase in intracellular cyclic AMP.
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PMID:A slow voltage-dependent Na(+)-current induced by 5-hydroxytryptamine and the G-protein-coupled activation mechanism in the ganglion cells of Aplysia. 171 63

1. The effects of 5-hydroxytryptamine (5-HT) were investigated on right atrial appendages obtained from patients treated with beta-adrenoceptor blocking agents who were undergoing open heart surgery. Atrial strips were paced under isometric conditions. 2. 5-HT increased contractile force to approximately one half of the force produced by a saturating concentration of (-)-isoprenaline. Both 5-HT and (-)-isoprenaline accelerated the onset of relaxation, as indicated by an abbreviation of time to peak force. 3. The effects of 5-HT were resistant to blockade by 0.4 microM (+/-)-propranolol, 1 microM (-)-pindolol, 0.4 microM methiothepin, 4 microM yohimbine, 0.4 microM ketanserin, 10 microM phenoxybenzamine, 1 microM methysergide, 2 microM MDL 72222 and 20 microM granisetron. 4. Cocaine 6 microM potentiated the effects of 5-HT, increasing the pEC50 from 6.6 to 7.4. The inotropic potency of 5-HT is five times greater than that of (-)-noradrenaline. 5. ICS 205930 antagonized competitively the effects of 5-HT with a pKB of 6.7. 6. In the presence of 0.4 microM (+/-)-propranolol, 10 microM 5-HT increased both adenosine 3':5' cyclic-monophosphate (cyclic AMP) levels and cyclic AMP-dependent protein kinase activity by approximately one half and two thirds respectively, of the corresponding effects of 200 microM (-)-isoprenaline. 7. Both the increase in cyclic AMP levels and the stimulation of protein kinase activity are consistent with the inotropic effects of 5-HT being mediated by cyclic AMP-dependent phosphorylation of Ca2+ channels and of proteins involved in contraction and relaxation. 8. The human atrial 5-HT receptor resembles the neuronal 'so called' 5-HT4 receptor of rodents both in increasing cyclic AMP levels and in its affinity for ICS 205930.
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PMID:A 5-hydroxytryptamine receptor in human atrium. 216 44


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