Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Second Messenger Systems”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources
PubMed1988

The role of calcium in stimulus-secretion coupling in excitable and non-excitable cells.

Secretion of vesicular contents by exocytosis is a common feature of excitable (neurones, chromaffin cells, beta cells) and non-excitable cells (platelets, neutrophils, mast cells). The simplistic view that the universal mechanism controlling secretion is elevation of [Ca2+]i--whatever the source of this second messenger may be--is no longer tenable in view of recent reports demonstrating secretion at basal or even reduced [Ca2+]i. It is nevertheless clear that in excitable cells an increase in [Ca2+]i is the triggering event that induces secretion. In non-excitable cells, secretion is presumably triggered by other second messengers, although [Ca2+]i appears to act as an important modulator of the rate of secretion. Conversely, these second messenger systems may serve a regulatory function in excitable cells. Given the relative importance of [Ca2+]i in the regulation of cellular functions in excitable and non-excitable cells, it is not surprising that several mechanisms are expressed in these cells to regulate intracellular calcium concentration. The major pathway for Ca2+ in excitable cells is by voltage-activated Ca2+ channels, but release of Ca2+ from intracellular stores, via second messengers, predominates in non-excitable cells, and may also be important in excitable cells. In addition, receptor-operated channels and second messenger-gated conductances may prove to be important. All of these pathways are subject to regulation by a variety of interactive second messenger systems, which provide necessary tuning for an appropriate control of intracellular calcium level.

Animals↗
PubMed1989

Inhibition of Jv by ANF in rat proximal straight tubules requires angiotensin.

The effects of atrial natriuretic factor (ANF) on fluid absorption (Jv) by isolated perfused proximal straight tubules of rats were investigated. ANF alone (10(-8) M) added to the bath had no significant effect on absorption. In contrast, when tubules were first treated with 1.6 X 10(-10) M angiotensin II, this same concentration of ANF lowered fluid absorption from 0.99 +/- 0.03 to 0.69 +/- 0.02 nl.mm-1.min-1. A lower dose of ANF, 2 X 10(-10) M, reduced fluid absorption in the presence of angiotensin II from 1.13 +/- 0.06 to 0.65 +/- 0.05 nl.mm-1.min-1, an inhibition of 40%. Since guanosine 3',5'-cyclic monophosphate (cGMP) is reportedly part of the second messenger system of ANF, the effects of dibutyryl-cGMP (DBcGMP) on fluid absorption were studied. This membrane-permeant form of cGMP mimicked the effects of ANF, reducing fluid absorption from 1.15 +/- 0.18 to 0.54 +/- 0.08 nl.mm-1.min-1. These studies suggested the following: 1) ANF can regulate fluid absorption in the proximal nephron; 2) this inhibition occurs only in the presence of angiotensin; and 3) cGMP is part of the second messenger system of ANF in the rat proximal straight tubule, as it is in other tissues.

Absorption↗
PubMed1991

Reversal of multidrug resistance by calcium channel blocker SR33557 without photoaffinity labeling of P-glycoprotein.

The altered pharmacology of drugs in multidrug-resistant cells (decreased accumulation and retention) appears to be mediated by a high molecular weight integral membrane protein, called P-glycogprotein (P-gp). Agents known to reverse this pleiotropic drug resistance (chemosensitizers) have been shown to interact with P-gp; and as such, the inhibition of photoaffinity labeling by P-gp probes (such as [3H]azidopine) has been proposed as a basis for mass screening of chemosensitizers. In this study, we provide direct evidence that a novel calcium channel blocker (SR33557), which was 4.5 times more potent in sensitizing P388/ADR cells to doxorubicin as compared to verapamil (while inducing a similar increase in uptake and decrease in efflux of [14C]doxorubicin, did not compete for the [3H]azidopine-binding site on P-gp, whereas verapamil did. Moreover, SR33557, which is inherently photoactivable, did not photolabel P-gp, but a 65-kDa protein did appear to be an acceptor; and this binding was displaced by diltiazem and nifedipine, but not by verapamil. Finally, the implication for the participation of a sphingomyelin/sphingosine cycle (as a potential lipid second messenger system) in the chemosensitization of P388/ADR cells was investigated. 30 microM SR33557 induced a 72% inhibition in acid lysosomal sphingomyelinase activity, a 5-fold increase in sphingosine levels, and a 75% inhibition in intracellular protein kinase C activity. Although no direct link is established between these observations and P-gp activity, further studies on a possible sphingosine-mediated regulation of P-gp may yield information on the involvement of this second messenger system in the action of SR33557.

Animals↗
PubMed1988

Drug receptors on single enteric neurons.

There are many substances contained within enteric nerves which excite or inhibit other nerves when these substances are applied to single neurons. The actions of these substances and of drugs which mimic these actions is to open or close membrane ion channels. The effects on membrane potential are dependent on the nature of the ions which pass through the channel and whether the channel is opened or closed. In the enteric nervous system, drugs can act at one of three broad classes of receptors: [1] those which are part of an ion channel complex and which open either cation channels or chloride channels, both of which result in membrane depolarization [2] those which open potassium channels resulting in hyperpolarization or [3] those which close potassium channels resulting in depolarization. Receptors which open potassium channels are coupled to the channel via a G-protein while receptors which close potassium channels are coupled to the channel, in some cases, via a cyclic AMP-dependent system while in other cases another second messenger system is involved.

Animals↗
PubMed1997

Characterization and partial purification of a keratinocyte-derived growth factor with wound-healing properties.

We have previously described the mitogenic and wound-healing properties of keratinocyte-conditioned medium (KCM). In this study we investigated the effect of KCM on the activation of second messenger systems and the expression of proto-oncogene in cultured human skin fibroblasts. We also present a partial purification of the factor responsible for the mitogenic and wound-healing effects of KCM. KCM was shown to increase the expression of the proto-oncogenes c-fos, c-myc and c-jun. The effect of KCM on three second messenger systems was investigated. The extracellular release of choline metabolites was increased by 40 per cent when cells were stimulated with KCM whereas the formation of cAMP and hydrolysis of phosphatidyl inositol (PI) was unaffected. KCM was purified by ion exchange chromatography and filtration. The biologically active fraction was eluted from an SP column and retained its activity after filtration through a 3-kDa filter. The fraction was inactivated by heat and acid, indicative of a peptide origin. Furthermore, the active fraction was shown to increase the extracellular release of choline metabolites and to stimulate re-epithelialization in wounds in human skin in vitro comparable to KCM. The study indicates that human keratinocytes produce a < 3 kDa peptide which may be partly responsible for the growth stimulatory and wound-healing properties of KCM.

3T3 Cells↗
PubMed1995

[Second messenger-mediated transcriptional regulation of neural genes and possible drug action sites].

Second messenger systems regulate transcription initiation of immediate-early genes (IEGs) through phosphorylation of transcriptional factors and repressors. Tissue-specific late response genes (LRGs) are induced dependently on protein synthesis slowly after IEGs, but the mechanisms of regulation of LRGs are still unknown. In this review, the mechanisms of transcriptional regulation of IEGs are summarized and possible drug action sites are discussed. As to the neuropeptide Y (NPY) gene, a typical neuronal LRG, the approach was introduced to elucidate the transcriptional regulations of the NPY gene induced by membrane depolarization and NGF-induced neuronal differentiation. The second messenger systems were Ca/calmodulin dependent protein kinases (CaM) and NGF-induced MAP kinases, respectively. The unique CaM- and NGF-responsive elements and DNA-binding factors were identified. The NDF1 protein bound to NGF-RE were cloned and characterized. NDF1 seems to a novel transcriptional factor that regulates neurotrophin-induced transcription of LRGs. Thus identification of novel regulatory factors is required to elucidate mechanisms of gene expression including transcriptional initiation, and pharmacological studies are also necessary to discover the novel drug action sites in the gene expression system.

Animals↗
PubMed1996

Effects of dynorphin A (1-17) on motor function and spinal intracellular messenger systems in rat.

The effect of intrathecal injection of dynorphin A (1-17) on second messenger systems of spinal cord relative to behavioral change in rats was studied. Dynorphin A (1-17) 5, 10 (20 nmol) caused dose-dependent flaccid paralysis of hindlimbs. Dynorphin A (1-17) 10, 20 nmol dose-dependently decreased spinal adenylate cyclase (AC) activity, cyclic AMP production, calmodulin (CaM) level and cyclic-nucleotide phosphodiesterase (PDE) activity 10 min after intrathecal injection. They recovered to a varying extent two hours later. Pretreatment with selective kappa-opioid receptor antagonist nor-BNI 30 nmol 10 min before dynorphin A (1-17) markedly antagonized the effects of dynorphin A (1-17) at 20 nmol on hindlimb paralysis and inhibition of intracellular second messengers. The L-type calcium channel blocker verapamil (100 nmol) also played a role in blocking dynorphin neurotoxicity. The NMDA receptor antagonist APV could partially or completely block dynorphin inhibition of CaM level and PDE activity without affecting paralysis and decrease of AC-cAMP level induced by dynorphin A (1-17) 10 min after intrathecal injection.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

The role of phosphoinositide-derived second messengers in oxytocin-stimulated prostaglandin F2 alpha release from endometrium of pigs.

The mechanism for prostaglandin (PG) F2 alpha release from pig endometrium after oxytocin (OT) treatment is unknown. OT may rapidly stimulate inositol (1,4,5)-trisphosphate (IP3) and diacylglycerol (DAG) formation, consistent with the concept of rapid activation of a second-messenger system. In support of this hypothesis, endometrial IP3 levels were increased (P < 0.05) within 0.5 min after treatment with 0.1 microM OT. In contrast, increased DAG formation was not detected after treatment with OT. However, similar to the stimulation of endometrial PGF2 alpha secretion observed after OT treatment (P < 0.001), PGF2 alpha release was increased (P < 0.01) after treatment with phorbol-12-myristate-13-acetate (PMA), which mimics DAG activation of protein kinase C. Further, stimulation of endometrial PGF2 alpha secretion did not result from cell death induced by PMA or OT because lactate dehydrogenase, a cytosolic marker of cellular integrity, did not leak into the medium after PMA or OT treatment. In contrast, 0.5% saponin (positive control for cell death and concomitant release of lactate dehydrogenase) increased PGF2 alpha secretion (P < 0.05) and lactate dehydrogenase release (P < 0.001). These results indicate that OT induces endometrial IP3 production in a rapid manner indicative of a second-messenger system. The finding that increased DAG was not also detected after OT treatment may reflect rapid metabolism or compartmentalized production of DAG involved in the second-messenger stimulation of phospholipase C. The high background of DAG used in the biosynthesis of cellular lipids would obscure the rather small spatially localized changes in DAG levels resulting from the activation of phospholipase C. The finding that DAG was present at approximately 10 to 20-fold higher levels than IP3 in resting cells was consistent with this conclusion.

Analysis of Variance↗
PubMed1989

Modulation of ionic currents in Aplysia motor neuron B15 by serotonin, neuropeptides, and second messengers.

Both 5-HT and the 9 amino acid neuropeptide SCPb modulate 3 ionic currents in B15, enhancing a voltage-dependent inward sodium current, decreasing an outward potassium current and increasing an inward rectifying potassium current. In contrast, FMRFamide decreases a voltage-dependent inward sodium current and increases an outward potassium current. We have also investigated the roles of several second-messenger systems that may be mediating the effects of these modulators. Bath application of membrane permeable analogs of cAMP enhance the voltage-dependent inward sodium current and both 5-HT and SCPb increase cAMP levels in B15, suggesting that cAMP may be mediating part of the observed effects of these transmitters on B15. Experiments with phorbol ester, a protein kinase inhibitor, and a phospholipase inhibitor suggest that the phospholipase C/protein kinase C cascade may decrease an outward potassium current. Thus, 5-HT and SCPb may activate multiple second-messenger systems to modulate 3 ionic currents in B15. Additional studies suggest that a cascade involving arachidonic acid may be involved in mediating part of the FMRFamide responses in B15. These studies are beginning to define molecular mechanisms whereby a neuron differentially modulates multiple ionic currents in response to distinct chemical messengers.

Animals↗
PubMed1996

Sensitization of C-fibres by prostaglandin E2 in the rat is inhibited by guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor peptide.

Behavioral studies have shown that mechanical hyperalgesia induced by intradermal injection of prostaglandin E2 is blocked by inhibitors of the cAMP second messenger system. Similarly, injection of prostaglandin E2 also induces a decrease in mechanical threshold and an increase in the number of action potentials elicited by test stimuli in most C-fibre nociceptors. This change is called sensitization. To further evaluate the degree of correlation between primary afferent sensitization and mechanical hyperalgesia, we conducted a study to evaluate the effect of agents known to block the cAMP second messenger system and behavioral manifestations of mechanical hyperalgesia following injection of prostaglandin E2. The agents tested were guanosine 5'-O-(2-thiodiphosphate), an inhibitor of stimulatory guanine nucleotide-binding regulatory proteins; 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase; and Walsh Inhibitor Peptide, an inhibitor of cAMP-dependent protein kinase. Single fibre electrophysiologic studies of 138 C-fibres, innervating the dorsum of the hind paw, was done in male Sprague-Dawley rats. The number of spikes evoked by a 10 s application of a threshold von Frey hair were determined before and after intradermal injection of test agents administered alone and in combination with prostaglandin E2. Injection of prostaglandin E2 with the test agent vehicle (saline or distilled water) resulted in a significant decrease in von Frey hair threshold and an increase in the number of spikes generated in response to threshold von Frey hairs. In contrast, co-injection of prostaglandin E2 with guanosine-5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine or Walsh inhibitor peptide did not result in a significant decrease in von Frey hair mechanical threshold or increase in the number of spikes generated to the threshold stimuli, compared with vehicle/prostaglandin E2. It is suggested that guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor protein inhibited prostaglandin E2 sensitization of primary afferent C-fibres by inhibiting a stimulatory guanine nucleotide-binding regulatory protein, adenylyl cyclase, and protein kinase A, respectively. These results support the hypothesis that primary afferent sensitization by prostaglandin E2 underlies prostaglandin E2-induced hyperalgesia.

Animals↗
PubMed2002

Multifarious effects of estrogen on the pituitary gonadotrope with special emphasis on studies in the ovine species.

The gonadotrope is a complex cell that expresses receptors for gonadotropin releasing hormone (GnRH) and estrogen. It has synthetic machinery for the production of 3 gonadotropin subunits which are assembled into two gonadotropins, luteinising hormone (LH) and follicle stimulating hormone (FSH). The production and secretion of LH and FSH are differentially regulated by GnRH and estrogen. Patterns of secretion of LH are dictated by the pulsatile release of GnRH from the median eminence as well as the feedback effects of estrogen. The means by which estrogen plays such an important role in the regulation of LH and FSH is reviewed in this chapter, with emphasis on work that has been done in the sheep. Estrogen regulates the second messenger systems in the gonadotrope as well as the number of GnRH receptors and the function of ion channels in the plasma membrane. Estrogen also regulates gene expression in these cells. Additionally, GnRH appears to regulate the level of estrogen receptor in the ovine gonadotrope, so there is substantial cross-talk between the signalling pathways for GnRH and estrogen. No clear picture has emerged as to how estrogen exerts a positive feedback effect on the gonadotrope and it is suggested that this might be forthcoming from more definitive studies on the way that estrogen regulates the second messenger systems and the trafficking of secretory vesicles.

Animals↗
PubMed1988

Norepinephrine stimulation of adenylate cyclase potentiates protein kinase C action: electrophysiological studies in the dentate gyrus.

Protein kinase C and norepinephrine-stimulated adenylate cyclase have been linked to formation of long-term potentiation in the dentate gyrus. However, little is known about second messenger system interactions regulating synaptic transmission. In electrophysiological studies of the dentate gyrus, we observe synergistic interactions between norepinephrine and phorbol esters, activators of protein kinase C. Norepinephrine markedly potentiates the block of adenosine's inhibitory action by phorbol esters. Norepinephrine's action is mimicked by the beta-adrenoceptor agonist isoproterenol and blocked by the beta-adrenoceptor antagonists timolol and propranolol. Forskolin also mimicks norepinephrine's action. Accordingly, norepinephrine's potentiation of protein kinase C appears to be mediated by the cyclic AMP second messenger system. This mechanism may contribute to norepinephrine's facilitation of long-term potentiation in the dentate gyrus.

Adenylyl Cyclases↗
PubMed1993

Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity.

Peptide hormones, neurotransmitters, and autacoids activate a family of seven-transmembrane-domain receptors. Each of these receptors specifically couples to one of several G proteins, Gs, Gi, G(o) and Gp, to activate a specific second messenger system. Cell surface receptors for prostanoids have been characterized pharmacologically and the complementary DNAs for thromboxane A2 receptor and the EP3 subtype of the prostaglandin (PG)E receptor reveal that they belong to the seven-transmembrane-domain receptor family. The EP3 receptor mediates the diverse physiological actions of PGE2 (ref. 3). Although most of them occur through coupling of the EP3 receptor to Gi and inhibition of adenylyl cyclase, the EP3-mediated contraction of uterine muscle can only occur by activation of another second messenger pathway. In chromaffin cells, two different second messenger pathways are activated by PGE2 binding to an apparently single EP3 receptor class. Here we show that at least four isoforms of the EP3 receptor, which differ only at their C-terminal tails and are produced by alternative splicing, couple to different G proteins to activate different second messenger systems.

Adrenal Medulla↗
PubMed1996

Structural requirements of CCK analogues to differentiate second messengers and pancreatic secretion.

We previously demonstrated that, in rat pancreatic acinar cells, the high-affinity cholecystokinin (CCK) receptor agonist JMV-180 utilizes the phospholipase A2 (PLA2) cascade to mediate Ca2+ oscillations and amylase secretion. In contrast, the low-affinity CCK receptor utilizes the phospholipase C beta 1 (PLC beta 1) pathway. We have investigated structural requirements of CCK analogues to activate different intracellular pathways. CCK analogues such as CCK-8 [Met28,31; half-maximal effective concentration (EC50) = 0.4 pM], CCK-7 (Met28,31; EC50 = 0.7 pM), and NONA (Thr28/Nle31; EC50 = 5 pM) caused a biphasic amylase secretion. Reduction of secretion occurred with high doses of these peptides (> 100 pM). In contrast, CCK-5 (Met31; EC50 = 20,000pM), JMV-180 (Nle28,31; 1,500 pM), and OPE (Nle28,31; 200 pM) caused a monophasic secretion. CCK-8, but not JMV-180, increased protein kinase C (PKC) activities. The PKC activator phorbol ester inhibited an increase in myo-inositol 1,4,5-trisphosphate levels induced by CCK-8 and abolished monophasic amylase secretion induced by OPE. CCK-8, CCK-7, and NONA caused Ca2+ oscillations (< 100 pM) or large Ca2+ transients (> 100 pM). In contrast, JMV-180 and OPE evoked Ca2+ oscillations, even in high doses. Ca(2+)-signaling modes induced by CCK-5 were intermediate types between CCK-8 and JMV-180. CCK-8- and CCK-7-stimulated Ca2+ spikes were inhibited by the PLC inhibitor U-73122, but not by the PLA2 inhibitor ONO-RS-082. The action of CCK-5 was only partially sensitive to the PLC inhibitor. In contrast, JMV-180- and OPE-stimulated Ca2+ oscillations were inhibited by the PLA2, but not by the PLC, inhibitor. NONA was sensitive to PLC and PLA2 inhibitors. Although JMV-180 differs from CCK-8 by having an Asp-2 phenylethylester, rather than an Asp-phenylalanine amide, it is unlikely that these differences in the carboxyl terminus are important in determining which second-messenger systems will be activated. This is because CCK-5 (Phe33-CONH2) causes monophasic amylase secretion and Ca2+ oscillation in a manner similar to those induced by JMV-180 (2-phenylethylester). Meanwhile NONA (Phe33-CONH2) appeared to activate PLC and PLA2 pathways. The actions of all CCK analogues were abolished by L-364,718, indicating mediation by CCK-A receptors. Therefore, depending on the agonists used, CCK-A receptor activation in pancreatic acini may result in differential involvement of second-messenger systems, Ca2+ signal transduction, and amylase secretion. On the basis of the amino acid sequence of the carboxy terminus of CCK analogues, it appears that key amino acids for this differentiation are Met28 (or Thr28) for PLC pathways and Nle28 for PLA2 pathways.

Amino Acid Sequence↗
PubMed1991

[What is next in the development of antidepressives?].

After some findings concerning the mode of action of antidepressants, it was possible to hypothesize the molecular basis of depressive disorders (monoamine hypothesis, receptor hypothesis). These informations made the preparation of drugs acting by a completely new mechanism. Possible an antidepressant effect was observed after the administration of GABA-ergic agonists, or agents influencing dopaminergic transmission, S-adenosylmethionine, and drugs influencing second messenger systems. As a consequence of these findings, the GABA-ergic hypothesis, hypothesis of endogenous ligand (barinine hypothesis is discussed in more detail), and second messenger hypothesis of affective disorders were formulated. Agents influencing second messenger systems and S-adenosylmethionine seem to be a promising field of future investigation.

Antidepressive Agents↗
PubMed1993

cAMP and arachidonic acid simulate long-term structural and functional changes produced by neurotransmitters in Aplysia sensory neurons.

The efficacy of the synapses between the sensory and motor cells of Aplysia, as well as the number of presynaptic sensory cell varicosities in vitro, can undergo long-term increases and decreases, respectively, following application of the facilitatory modulator serotonin or the inhibitory modulator FMRFamide. We here report that cAMP and arachidonic acid, two second messenger systems mediating some of the short-term actions of serotonin and FMRFamide on sensory cells, reproduce some of the long-term changes in the structure of the sensory cells, and these structural changes in turn parallel the long-term changes in the functional effectiveness of the synapses. cAMP enhances the strength of the connections between the sensory and motor cells and increases the number of sensory varicosities. Conversely, arachidonic acid decreases the strength of the connections and decreases the number of sensory varicosities. Thus, each of the modulatory neurotransmitters may activate the same intracellular second messenger system to establish both short and long lasting functional changes in synaptic efficacy, as well as to produce enduring structural changes in neuron connectivity.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Modulation of cellular excitability in neocortex: muscarinic receptor and second messenger-mediated actions of acetylcholine.

Muscarinic-type acetylcholine (ACh) receptor are involved in a variety of cortical functions. ACh "activates" neocortex; simultaneously modifying spontaneous subthreshold activity, intrinsic neuronal oscillations and spike discharge modes, and responsiveness to fast (putative glutamatergic) synaptic inputs. However, beyond the general involvement of muscarinic receptors, a mechanistic understanding of integrated cholinergic actions, and interactions with non-cholinergic transmission, is lacking. We have addressed this problem using intracellular recordings from the in vitro auditory neocortex. First, we investigated cholinergic modification of responses to the excitatory amino acid glutamate. ACh, or the muscarinic agonist methacholine, produced a lasting enhancement of glutamate-mediated membrane depolarizations. Muscarinic receptors of the M1 and/or M3 subtype, rather than M2 or nicotinic receptors, mediated this enhancement. Subsequently, we investigated whether second messenger systems contribute to observed muscarinic actions. Activation of protein kinase C with phorbol 12,13-dibutyrate (4 beta-PDBu), enhanced neuronal responses to glutamate. The effect of 4 beta-PDBu was attenuated by the kinase antagonist H7. Finally, we attempted to identify postsynaptic actions of endogenous ACh. Tetanic stimulation of cholinergic afferents elicited voltage-dependent effects, including reduced spike frequency adaptation and reduced slow afterhyperpolarization (sAHP) elicited by transmembrane depolarizing stimuli. These effects were mimicked by methacholine, enhanced by eserine, and antagonized by muscarinic receptor antagonists. These data suggest that cholinergic modulation in neocortex likely involves the integrated actions of diverse mechanisms, primarily gated by muscarinic receptors, and at least partly involving second messenger systems.

Acetylcholine↗