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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of steroidogenesis in both the ovary and testis involves a complex interaction of a diversity of hormones and intracellular signaling pathways. The recent cloning of LH and FSH receptors has paved the way for an increased understanding of the mechanisms of receptor conformation, ligand-receptor interaction, and facilitation of post-receptor activity. The dominant role played by LH in the regulation of steroid production appears to be mediated by more than one intracellular signaling pathway. In addition to the stimulation of the adenylate cyclase-cAMP pathway, also known to be stimulated by FSH, the actions of LH may be additionally mediated by other intracellular messengers, such as those derived from the PLC pathway. Steroidogenesis in the gonads appears to be modulated by a variety of factors in addition to the gonadotropins. In this review, those factors of intracellular signaling mechanisms of which we have some understanding have been discussed. These include GnRH, PGF2 alpha, Ang II, VIP, GHRH, TNF alpha, CRF, EGF, and TGF alpha. Many of these factors have been shown to be locally synthesized, and specific receptors have been identified in the gonads. Many gonadal factors have the capacity to exert effects on steroidogenesis independent of the gonadotropins. Alternately, they have been demonstrated to alter the gonadal response to the gonadotropins via autocrine, paracrine, and intracrine mechanisms. As yet, our understanding of the intracellular signaling mechanisms used by novel gonadal regulators is limited. The involvement of the PLC, PLA2, and PLD pathways in this regard has been reviewed. It is becoming apparent that multiple signaling pathways may be stimulated by a single hormone, as in the case of GnRH, PGF2 alpha, and LH. The complexity of intracellular signal transduction in the gonads is enhanced by the potential cross-talk at numerous steps in the signaling cascades.
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PMID:Intracellular signaling in the gonads. 142 84

The Ca2+ ion exerts a profound influence on cellular processes and an understanding of control mechanisms of intracellular Ca2 homeostasis while complex is mandatory in this discussion. The identification and recognition of prolonged sustained increase in [Ca2+]i as a manifestation of neurotoxin-induced destabilization of [Ca2+]i homeostasis will be related to a variety of neurotoxicant-induced cell injuries. The sites of toxicant interaction with ATP-regulated Ca2+ pumps located in the neuronal/glial membrane and/or calciosomes; availability of Ca2+ proteins; disruption in mitochondrial mechanisms for Ca2+ storage; triggers of voltage-dependent Ca2+ channels and modulation of the Na+/Ca2+ exchanger will be identified and related to presumptive toxin action. Failure of one or more of these systems will result in continuous elevation of ionized [Ca2+]i--a reflection of Ca2+ destabilization. The targets resulting from Ca2+ destabilization will be identified, to include phospholipase C activation, PLA2 activation, protein kinase C (PKC) translocation, and activation of Ca(2+)-dependent calpain 1. The use of specific inhibitors of neurotoxicity, e.g., natural sphingolipids, sphingosine, down regulation of PKC, inhibitors and activators of adenylate cyclase, and antiprotease agents will allow for investigation of the role of these final common pathways in the evolution of neurotoxicity.
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PMID:Ca(2+)-dependent processes as mediators of neurotoxicity. 150 13

Angiotensin II (AngII) is a potent regulator of electrolyte transport with biphasic effects on salt and HCO3-resorption in proximal tubule epithelia (PCT). In cultured PCT cells, pM to nM AngII activates a GTP-binding protein to inhibit cAMP formation and thus releases inhibition of apical Na/H exchange. Phospholipase A2 is activated by nM to microM AngII releasing arachidonate which is metabolized by a novel P450 epoxygenase to form 5,6-epoxy-eicosatrienoic acid (5,6-EET). 5,6-EET and nM apical AngII cause dihydropyridine-sensitive Ca2+ influx from the extracellular space, inhibition of apical-to-basolateral Na flux, and decrease in epithelial monolayer short circuit current. 5,6-EET also inhibits Na/K-ATPase by 50%. This P450 epoxygenase is physiologically important in the AngII-signaling system because the P450 inhibitor ketoconazole blocks AngII effects while potentiating exogenous 5,6-EET effects. Finally, these AngII-mediated signaling systems are polarized in the PCT with pM basolateral AngII inhibiting adenylate cyclase and nM apical AngII activating PLA2 and subsequent generation of 5,6-EET.
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PMID:Angiotensin II actions in the rabbit proximal tubule. Angiotensin II mediated signaling mechanisms and electrolyte transport in the rabbit proximal tubule. 170 6

A comprehensive model of cellular activation and proliferation is developed. The model has arachidonic acid (ARA) produced mainly from PLA2 on both sides of the membrane, and superoxide and other activated oxygen species (AOS) formed from O2 by electrons passing out through membrane NANPH and NADH oxidases, as the immediate stimulants of solute permeability. Both ARA and AOS interact with the various solute channel proteins especially their external thiols and disulfides, to increase influx of metabolic substrates, Na, Ca and O2. PLA2 and NADPH oxidase are turned on by growth factors at their receptors acting through tyrosine kinase phosphorylations of messenger proteins GP and ras p-21, stimulated proteases, and by Ca-calmodulin. The adenylate cyclase system has opposite, deactivating character as it increases efflux of Ca and desensitizes growth factor receptors by phosphorylation to shut down the increased solute permeability. Most cancer types are due to carcinogen binding to cell membrane channel and mitochondrial sites for increased solute influx with excessive AOS production inside the cell from mitochondria and other vesicles. High Ca, Na and AOS stimulate proliferation with extra high levels causing transformation to the autogenic, more embryonic-type cancer cell.
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PMID:Unitary model of cell activation, growth control, cancer and other diseases: 1. Activated oxygen species and arachidonic acid modulation of solute permeabilities, internal Ca, Na and AOS levels and DNA transcription and synthesis. 192 75

Purine release and prostaglandin (PG) outflow were simultaneously evaluated from untreated glial primary cultures of rat striatum, at rest and under field electrical stimulation. Purine release was also assayed from sister cultured cells in which a suitable pharmacological treatment with 1 x 10(-6) M dexamethasone or 1 x 10(-4) M indomethacin had produced a complete inhibition of the phospholipase A2-prostaglandin (PLA2-PG) system. Purine release from untreated cells seems to be regulated by specific receptor sites for released adenosine (Ado); A1 receptors exert an inhibitory control on purine release while A2 receptors facilitate it. PG release appears to be related to A1-mediated Ado activity, since culture treatment with 1 x 10(-10) M 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or 1 x 10(-4) M N-ethylmaleimide (NEM), A1 receptor inhibitory agents able to increase purine release, induced a significant reduction of the evoked PG outflow. Purine amount, released from glial cells with inhibited PLA2-PG system, was remarkably greater than that one assayed from control cultured cells. In so treated cultures, no additive effect, NEM-induced, was detected, while the addition of a mixture of PGs partially reduced the increased purine outflow. An electrically evoked cAMP accumulation, significantly greater than that found in controls, was even detected in cultured cells with inhibited PLA2-PG system. Since 10 micrograms/ml adenosine deaminase (ADA) reduced while DPCPX enhanced the evoked cAMP accumulation, it seems partially due to released Ado and accounts for a prevalent A2-stimulating rather than an A1-inhibitory control on adenylate cyclase activity. Thus, in cultured glial cells, the PLA2-PG system, likely linked to A1 receptor sites, concurs to control purine release and seems to affect less directly cAMP accumulation.
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PMID:Influence of PLA2-PG system on purine release and cAMP content in dissociated primary glial cultures from rat striatum. 254 40

Alpha-Adrenergic and GABAB receptor agonists regulate adenylate cyclase either negatively, by direct inhibition of the enzyme, or positively, by augmenting agonist-stimulated production of cyclic AMP. While the inhibition of adenylate cyclase is most likely to be mediated by a direct stimulation of Gi protein, the enhancement of production of cyclic nucleotide appears to involve protein kinase C and perhaps PLA2. alpha-Adrenergic and GABAB receptor augmentation of accumulation of cyclic AMP is also influenced by pituitary-adrenal hormones, suggesting a link between brain function and the endocrine system. The number of components associated with the modulation of neurotransmitter receptor-coupled second messenger production provides multiple targets for the pharmacological manipulation of this system. By influencing the modulatory response rather than receptor activity directly, it may be possible to produce subtle alterations in the function of the central nervous system yielding safer and perhaps more effective therapies for the treatment of mental illness.
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PMID:Modulation of receptor-mediated cyclic AMP production in brain. 282 37

Renal mesangial cells express group II phospholipase A2 in response to two principal classes of activating signals that may interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) and agents that elevate cellular levels of cAMP such as forskolin, an activator of adenylate cyclase. Using pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of nuclear factor NF kappa B, we determined its role in cytokine--and cAMP--triggered group II PLA2 expression. Micromolar amounts of PDTC suppress the IL-1 beta- and TNF alpha-dependent, but not the forskolin-stimulated group II PLA2 activity in mesangial cells. Furthermore, PDTC inhibited the increase of group II PLA2 mRNA steady state levels in response to IL-1 beta and TNF alpha, while only marginally affecting forskolin-induced PLA2 mRNA levels. Our data suggest that NF kappa B activation is an essential component of the cytokine signalling pathway responsible for group II PLA2 gene regulation and that cAMP triggers a separate signalling cascade not involving NF kappa B. These observations may provide a basis to study the underlying mechanisms involved in the regulation of group II PLA2 gene expression.
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PMID:Pyrrolidine dithiocarbamate differentially affects cytokine- and cAMP-induced expression of group II phospholipase A2 in rat renal mesangial cells. 775 May 75

The discovery of orally active nonpeptide angiotensin II (A II)-receptor antagonists has initiated a growing understanding of the physiologic and pathophysiologic roles of A II. Losartan is the first of the new class of antagonists that block all the well-known effects of A II, including vasoconstriction, aldosterone release, renin release (negative feedback), and the stimulation of thirst. A II-receptor subtypes have been described, with losartan antagonism defining the AT1 subtype and with PD123319 antagonism defining the AT2 subtype. The AT1 receptor is G-protein-coupled, involving PLC, PLA2, PLD, or adenylate cyclase and the release of intracellular calcium. The receptor-response coupling of the AT2 site remains elusive but may involve protein tyrosine phosphatase and subserve an antiproliferative role. Losartan as the prototype of an AT1-selective antagonist: i) inhibits A II binding, ii) antagonizes effects of A II in vivo and in vitro, and iii) lowers blood pressure in models of A II-dependent hypertension A II stimulates growth in vitro (DNA and protein synthesis) and in vivo (cardiac and vascular hypertrophy), and these effects are blocked by losartan. Losartan, like angiotensin-converting enzyme inhibitors, has significant renal, cardiac, and cerebral protective effects in models of renal failure, cardiac failure, and stroke, confirming the pathologic role of A II in these models. The pioneering studies in experimental animals are being confirmed by a growing number of other AT1-selective blockers and provide the basis of use of losartan for hypertension and its clinical trial in other disease states.
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PMID:The diversified pharmacology of angiotensin II-receptor blockade. 891 41

Expression of group II phospholipase A2 (PLA2; EC 3.1.1.4) in rat renal mesangial cells is triggered in response to two principal classes of activating signals. These two groups of activators comprise inflammatory cytokines such as interleukin 1beta (IL-1beta) or tumor necrosis factor alpha and agents that elevate cellular levels of cyclic AMP (cAMP) such as forskolin, an activator of adenylate cyclase. Treatment of mesangial cells with IL-1beta or forskolin for 24 h induces group II PLA2 activity secreted into cell culture supernatants by about 15-fold and 11-fold, respectively. Platelet-derived growth factor (PDGF)-BB potently inhibits secretion of IL-1beta- and forskolin-induced group II PLA2 activity. By Western and Northern blot analyses, we demonstrate that this is due to a reduction of PLA2 protein levels and the corresponding PLA2 mRNA steady-state levels. Basic fibroblast growth factor (bFGF) virtually does not inhibit IL-1beta-stimulated group II PLA2 activity, but markedly inhibits forskolin-induced expression of group II PLA2 activity. These effects are caused by changes in the corresponding PLA2 protein and PLA2 mRNA steady-state levels. Inhibition of protein kinase C (PKC) by the potent and selective PKC inhibitor calphostin C converted the inhibitory action of PDGF into a bFGF-type of response thus suggesting that PKC is a major effector in PDGF-induced inhibition of IL-1beta-stimulated group II sPLA2 expression. In summary, our data suggest that PDGF and bFGF differentially modulate in a stimulus-specific manner the expression of group II PLA2 in mesangial cells.
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PMID:Platelet-derived growth factor and fibroblast growth factor differentially regulate interleukin 1beta- and cAMP-induced group II phospholipase A2 expression in rat renal mesangial cells. 955 20

The stimulatory effect of noradrenaline (NA) as well as oxytocin (OT) on bovine endometrial prostaglandin (PG) F2alpha production, and the intracellular mechanisms of their actions, were investigated in cultured bovine endometrial cells (a mixture of epithelial, stromal, and glandular cells). The cells were cultured in Dulbecco's Modified Eagle's medium and Ham's F-12 medium (1:1 [v:v]) with 10% calf serum. When the cells reached confluence, the culture medium was replaced with fresh medium with 0.1% BSA and various doses of NA (10(-8)-10(-4) M). NA stimulated PGF2alpha production in a dose-dependent manner (p < 0.05). To evaluate the intracellular mechanisms of NA and OT actions, the cells were treated with forskolin (an activator of adenylate cyclase), phorbol 12-myristate 13-acetate (PMA, an activator of protein kinase [PK] C), Rp-cAMP (a competitive cAMP antagonist and an inhibitor of PKA), U-73122 (an inhibitor of phospholipase [PL] C), or anthranilic acid (ACA, an inhibitor of PLA2). Forskolin and PMA stimulated PGF2alpha production in a dose-dependent manner (p < 0.05). Rp-cAMP completely inhibited (p < 0.001) the NA-induced, but not the OT-induced, PGF2alpha production. Although U-73122 inhibited only OT-induced PGF2alpha production (p < 0.001), ACA completely stopped the actions of NA and OT. The overall results indicate that NA as well as OT is involved in the regulation of the endometrial PGF2alpha production in cattle and that the stimulatory effects of NA and OT on PGF2alpha production are mediated via the PKA and PKC pathways, respectively.
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PMID:Noradrenaline stimulates the production of prostaglandin f2alpha in cultured bovine endometrial cells. 991 91


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