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

---

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

Rat liver plasma membranes were incubated with phospholipase A2 (purified from snake venom) or with filipin, a polyene antibiotic, followed by analysis of the binding of glucagon to receptors, effects of GTP on the glucagon-receptor complex, and the activity and responses of adenylate cyclase to glucagon + GTP, GTP, Gpp(NH)p, and F-. Phospholipase A2 treatment resulted in concomitant lossess of glucagon binding and of activation of cyclase by glucagon + GTP. Greater than 85% of maximal hydrolysis of membrane phospholipids was required before significant effects of phospholipase A2 on receptor binding and activity response to glucagon were observed. The stimulatory effects of Gpp(NH)p or F- remained essentially unaffected even at maximal hydrolysis of phospholipids, whereas the stimulatory effect of GTP was reduced. Detailed analysis of receptor binding indicates that phospholipase A2 treatment affected the affinity but not the number of glucagon receptors. The receptors remain sensitive to the effects of GTP on hormone binding. Filipin also caused marked reduction in activation by glucagon + GTP. However, in contrast to phospholipase A2 treatment, the binding of glucagon to receptors was unaffected. The effect of GTP on the binding process was also not affected. The most sensitive parameter of activity altered by filipin was stimulation by GTP or Gpp(NH)p; basal and fluoride-stimulated activities were least affected. It is concluded from these findings that phospholipase A2 and filipin, as was previously shown with phospholipase C, are valuable tools for differentially affecting the components involved in hormone, guanyl nucleotide, and fluoride action on hepatic adenylate cyclase.
...
PMID:Effects of phospholipase A2 and filipin on the activation of adenylate cyclase. 42 Aug 40

Dopamine receptors of D2 type present on lactotroph cells are coupled to a large series of transduction mechanisms. Beside their negative coupling with adenylate cyclase, they are also coupled with potassium and calcium channels, leading to a decreased intracellular calcium concentration. In addition, D2 dopamine receptors also modulate phospholipase activities. Dopamine inhibits inositol phosphate production, through two distinct mechanisms. One of them could represent a direct negative coupling with phospholipase C. All these transduction mechanisms of the D2 dopamine receptors implicate G proteins sensitive to pertussis toxin. In contrast, these receptors are negatively coupled to phospholipase A2 through G proteins insensitive to this toxin. Both isoforms of the D2 dopamine receptor, generated by alternate splicing of a single gene, are present in lactotroph cells. After transfection in CH4C1 cells the two isoforms are coupled with adenylate cyclase while only the shortest isoform appears negatively coupled to phospholipase C. Functional D2 dopamine receptors are present in human prolactinomas. Resistance to bromocriptine therapy is associated with a decreased density of these receptors in the tumor. In addition, the ratio of the two receptor isoforms (measured by PCR) is different in responsive and resistant tumors. Furthermore, the activity of Gi/Go proteins coupled to adenylate cyclase appears also affected in resistant tumors. Resistance to bromocriptine therapy appears thus to involve multiple changes at the different levels of the multiple mechanisms of action of dopamine on lactotroph cells.
...
PMID:D2 dopaminergic receptors: normal and abnormal transduction mechanisms. 130 22

Goldfish preovulatory ovarian follicles (prior to germinal vesicle breakdown) were utilized for studies investigating the actions of activators of different signal transduction pathways on prostaglandin (PG) production. The protein kinase C (PKC) activators phorbol 12-myristate 13-acetate (PMA; 100-400 nM), 1-oleoyl-2-acetylglycerol (5 and 25 micrograms/ml), and 1,2-dioctanoylglycerol (10 and 50 micrograms/ml) stimulated PGE production; the inactive phorbol 4 alpha-phorbol didecanoate, which does not activate PKC, had no effect. Calcium ionophore A23187 (0.25-4.0 microM) stimulated PGE production and acted in a synergistic manner with activators of PKC. Although produced in lower amounts than PGE, PGF was stimulated by PMA and A23187. The direct activator of phospholipase A2, melittin (0.1-1.0 microM), stimulated a dose-related increase in PGE production, whereas chloroquine (100 microM), a putative inhibitor of phospholipase A2, blocked basal and PMA + A23187-stimulated PGE production. Several drugs known to elevate intracellular levels of cAMP including the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1-1.0 mM), forskolin (10 microM), and dibutyryl cAMP (dbcAMP; 5 mM) attenuate PMA + A23187-stimulated PGE production. Melittin-stimulated production of PGE was inhibited by dbcAMP, suggesting that the action of cAMP was distal to the activation of phospholipase A2. In summary, these studies demonstrate that activation of PKC and elevation of intracellular calcium levels stimulate PG production, in part, through activation of phospholipase A2. The adenylate cyclase/cAMP signalling pathway is inhibitory to PG production by goldfish ovarian follicles.
...
PMID:Multifactorial regulation of prostaglandin synthesis in preovulatory goldfish ovarian follicles. 131 82

We have characterized the ANF-R2 receptor-mediated inhibition of adenylate cyclase with respect to its modulation by several regulators. ANF (99-126) inhibits adenylate cyclase activity only in the presence of guanine nucleotides. The maximal inhibition (approximately 45%) was observed in the presence of 10-30 microM GTP gamma S, and at higher concentrations, the inhibitory effect of ANF was completely abolished. ANF-mediated inhibition was not dependent on the presence of monovalent cations, however Na+ enhanced the degree of inhibition by about 60%, whereas K+ and Li+ suppressed the extent of inhibition by about 50%. On the other hand, divalent cation, such as Mn2+ decreased the degree of inhibition in a concentration dependent manner, with an apparent Ki of about 0.7 mM, and at 2 mM; the inhibition was completely abolished. In addition, proteolytic digestion of the membranes with trypsin (40 ng/ml) resulted in the attenuation of ANF-mediated inhibition of adenylate cyclase. Other membrane disrupting agents such as neuraminidase and phospholipase A2 treatments also inhibited completely, the ANF-mediated inhibition of enzyme activity. N-Ethylmaleimide (NEM), phorbol ester and Ca(2+)-phospholipid dependent protein kinase (C-kinase) which have been shown to interact with inhibitory guanine nucleotide regulating protein (Gi) also resulted in the attenuation of ANF-mediated inhibition of adenylate cyclase activity. These results indicate that in addition to the Gi, the phospholipids and glycoproteins may also play an important role in the expression of ANF-R2 receptor-mediated inhibition of adenylate cyclase.
...
PMID:Characterization of ANF-R2 receptor-mediated inhibition of adenylate cyclase. 132 94

We have previously reported that platelet-activating factor (PAF) elevates cytosolic free calcium concentration ([Ca2+]i) in fura-2-loaded glomerular mesangial cells. To confirm that this increase in [Ca2+]i is a result of receptor-mediated activation of phospholipase C, we investigated hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) in PAF-treated mesangial cells. PAF (10(-7) M) stimulated a rapid and transient formation of inositol trisphosphate. In concomitant experiments, PAF stimulated a biphasic accumulation of 3H-arachidonate-labeled 1,2-diacylglycerol (DAG). The secondary elevation in DAG was coincident with a rise in 3H-phosphorylcholine (PC) and 3H-phosphorylethanolamine (PE) suggesting that PAF stimulates delayed phospholipase activities which hydrolyze alternate phospholipids besides the polyphosphoinositides. This PAF-stimulated elevation in 3H-water soluble phosphorylbases was seen at 5 min but not at 15 sec suggesting that the initial rise in DAG as well as the initial elevation in [Ca2+]i are due primarily to PtdIns-4,5-P2 hydrolysis. PAF also stimulated PGE2 as well as 3H-arachidonic acid and 3H-lyso phosphatidylcholine (PtdCho) formation. We suggest that arachidonate released specifically from PtdCho via phospholipase A2 is a source of this PAF-elevated PGE2. It has been postulated that anti-inflammatory prostaglandins may antagonize the contractile and proinflammatory effects of PAF via activation of adenylate cyclase. Surprisingly, exogenous PAF reduced basal and receptor-mediated cAMP concentration indicating that PAF-stimulated transmembrane signaling pathways may oppose receptor-mediated activation of adenylyl cyclase. We have taken advantage of the different sensitivities of phospholipases A2 and C(s) to PMA, EGTA, and pertussis toxin to dissociate phospholipase A2 and C activities. Acute PMA-treatment enhanced PAF-stimulated PGE2 formation, reduced PAF-induced elevations in [Ca2+]i and had no effect upon PAF-stimulated 3H-PE. We have also demonstrated that phospholipase A2, but not PtdIns-specific phospholipase C, was sensitive to external calcium concentration. The role of a GTP-binding protein to couple PAF-receptors to the PtdIns-specific phospholipase C was confirmed as GTP gamma S synergistically elevated PAF-stimulated inositol phosphate formation. We also demonstrated that pertussis toxin ADP-ribosylates a single protein of an apparent 42 kD mass and that PAF pretreatment reduced subsequent ADP-ribosylation in a time-dependent manner. However, pertussis toxin had no effect upon phospholipase C-generated water soluble phosphorylbases or inositol phosphates. In contrast, PAF-stimulated phospholipase A2 and PAF-inhibited adenylyl cyclase activities were sensitive to pertussis toxin.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Platelet-activating factor stimulates multiple signaling pathways in cultured rat mesangial cells. 133 Nov 21

The cascade of transmembrane signaling events that follow the occupancy of the interleukin 1 receptor remain poorly defined. We examined potential postreceptor transduction systems involved in human recombinant interleukin 1-beta-stimulated prostacyclin synthesis in human umbilical vein endothelium. Challenge of human umbilical vein endothelium monolayers with recombinant interleukin 1-beta resulted in dose- and time-dependent tritiated arachidonate release and prostacyclin synthesis consistent with phospholipase A2 activation. Prostacyclin synthesis after interleukin 1-beta (10 ng/ml) was detected 4 hours after stimulation and peaked at 16 to 24 hours. To examine whether interleukin 1-beta produced early activation of a phosphoinositide-specific phospholipase C, human umbilical vein endothelium monolayers were labeled with tritiated-2-myoinositol and inositol polyphosphates recovered after interleukin 1-beta stimulation. In contrast to the potent agonist, alpha-thrombin, interleukin 1-beta failed to significantly increase inositol phosphate production when examined for up to 4 hours. The absence of a significant increase in the Cai++ secretagogue, IP3, was confirmed in human umbilical vein endothelium monolayers loaded with the Ca++ photoprotein probe aequorin. Basal aequorin luminescence was unaltered after interleukin 1-beta (0 to 2 hours), whereas both alpha-thrombin and Ca++ ionophore A23187 produced rapid rises in Cai++. The intracellular Ca++ antagonist BAPTA and the extracellular Ca++ chelator EGTA produced significant inhibition of interleukin 1-beta-stimulated prostacyclin generation at 4 to 8 hours, suggesting either an indirect inhibitory effect of these agents on phospholipase A2 activity or that an increase in Ca++ may be a late event in the transduction scheme after interleukin 1 stimulation. Interleukin 1-beta-stimulated protein kinase C, phospholipase D, and adenylyl cyclase activities (0 to 4 hours) were unchanged from controls. Despite the absence of increased plasma membrane protein kinase C activity up to 4 hours after interleukin 1, pretreatment of human umbilical vein endothelium monolayers with staurosporine or phorbol myristate acetate (18 hours) to reduce protein kinase C activities, significantly attenuated the interleukin 1-stimulated prostanoid responses at 16 hours but not at 4 hours. Furthermore, short (5 minute) pretreatment with phorbol myristate acetate dramatically augmented interleukin 1-mediated prostacyclin responses in synergistic fashion, suggesting that protein kinase C may modulate interleukin 1 signal transducing pathways. In summary, these studies suggest that interleukin 1-beta-mediated endothelial cell phospholipase A2 activity and prostacyclin synthesis occur via a novel transducing pathway that does not involve early activation of phospholipase C, phospholipase D, or adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Interleukin 1-stimulated prostacyclin synthesis in endothelium: lack of phospholipase C, phospholipase D, or protein kinase C involvement in early signal transduction. 133 14

We have reported that dopamine (DA) inhibits Na-K-ATPase activity in the cortical collecting duct (CCD) by stimulating the DA1 receptor, and the present study was designed to evaluate the mechanism of this effect. Short-term exposure (15-30 min) of microdissected rat CCD to DA, a DA1 agonist (fenoldopam), vasopressin (AVP), forskolin, or dibutyryl cAMP (dBcAMP), which increase cAMP content by different mechanisms, strongly (approximately 60%) inhibited Na-K-ATPase activity. 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, completely blocked Na-K-ATPase inhibition by DA or fenoldopam, and IP20, an inhibitor peptide of cAMP-dependent protein kinase A (PKA), abolished the Na:K pump effect of all the cAMP agonists listed above. To verify whether the mechanism of pump inhibition by agents that increase cell cAMP involves phospholipase A2 (PLA2), we used mepacrine, a PLA2 inhibitor, which also abolished Na-K-ATPase inhibition by DA or fenoldopam, as well as by AVP, forskolin, or dBcAMP. Arachidonic acid (10(-7) - 10(-4) M) inhibited Na-K-ATPase activity in dose-dependent fashion. Corticosterone, which induces lipomodulin, a PLA2 inhibitor protein inactivated by PKA, equally abolished the pump effects of DA, fenoldopam, forskolin, and dBcAMP, suggesting that lipomodulin might act between PKA and PLA2 in cAMP-dependent pump regulation. We conclude that dopamine inhibits Na-K-ATPase activity in the CCD through a DA1 receptor-mediated cAMP-PKA pathway that involves the stimulation of PLA2 and arachidonic acid release, possibly mediated by inactivation of lipomodulin. This pathway is shared by other agonists that increase cell cAMP and thus stimulate PKA activity.
...
PMID:Intracellular signaling in the regulation of renal Na-K-ATPase. I. Role of cyclic AMP and phospholipase A2. 134 27

In the kidney, adenosine plays important regulatory roles, including renal blood flow, glomerular filtration rate, renin secretion, tubuloglomerular feedback, tubular reabsorption of sodium and water, sympathetic neurotransmitter release, and erythropoietin secretion. These functions are mediated through adenosine 1 (A1)-receptors and adenosine 2 (A2)-receptors. These receptors couple to the inhibition and stimulation of adenylate cyclase, through Gi and Gs proteins, respectively. A variety of other effecter systems have been reported to be coupled to A1 receptors, including phospholipase C, phospholipase A2 and potassium, as well as Ca++ channels. Recently, A1 receptors, A2 receptors and novel A2 receptor have been cloned, sequenced and expressed. In association with the development of selective adenosine analogues, we are now ready to take up problems at the biochemical and molecular biological levels.
...
PMID:[Adenosine and adenosine receptors in the kidney]. 149 49

1. Independent of its effects on renal haemodynamics and glomerular filtration, angiotensin II (AII) has direct actions on the proximal tubule involving transepithelial Na+, H+, HCO3-, and water reabsorption, ammoniagenesis, gluconeogenesis and renal growth. 2. The effects of AII on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12)-10(-9) mol/L) stimulate reabsorption whereas high concentrations (10(-7)-10(-6) mol/L) inhibit reabsorption. Similar dose-response relations have been obtained for luminal and peritubular addition of AII. 3. The cellular responses to AII are mediated via an AT-1 receptor coupled via G-regulatory proteins to several parallel signal transduction pathways. Low doses inhibit the basolateral adenylate cyclase, lower intracellular cAMP and withdraw the inhibitory effect of protein kinase A on the luminal Na/H exchanger. Stimulation of this exchanger may also occur due to AII-receptor activation of phospholipase C to release diacyl glycerol, or by local transduction in the brush-border membrane involving phospholipase A2. 4. Inhibition of proximal fluid reabsorption is associated with increased intracellular Ca2+ released from intracellular stores, or entering via voltage-sensitive channels in response to the release of inositol-1,4,5-trisphosphate, or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6-epoxy-eicosatrienoic acid. 5. The stimulatory actions of peritubular AII on proximal transport are inhibited by physiological concentrations of atrial natriuretic factor (ANF) and by parathyroid hormone (PTH). 6. It is concluded that intrarenal AII acts to maintain optimal matching of fluid reabsorption and filtered load in response to changes in sodium balance, as well as to promote acidification of the urine during acidosis and perhaps to potentiate tubular growth following renal injury.
...
PMID:Regulation of proximal tubule function by angiotensin. 151 68

Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+ epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fc gamma receptors. In contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1 and IgG2b must be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10 micrograms/ml. The responsible PG appears to be PGD2; in contrast to its known inhibitory effect on macrophages, PGE2 does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2 and cAMP in this process, triggering of the Fc gamma R by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1 or IgG2b, which bind to Fc gamma RII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to Fc gamma RI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same Fc gamma RI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fc gamma receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal Fc gamma RI, most likely on keratinocytes, results in the generation of cAMP via a Ca(++)-dependent protein kinase C pathway, whereas triggering of an epidermal Fc gamma RII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2 is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP. 165 69


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

---