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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The mechanism by which acetylcholine (ACh), by stimulation of muscarinic receptors, acts to inhibit activation of the hyperpolarization-activated 'pacemaker' current, if was investigated in isolated rabbit sino-atrial (SA) node myocytes. 2. Intracellular loading with GTP gamma S, a non-hydrolysable analogue of GTP, did not impair the ACh action on if, but made it irreversible. On the other hand, the ACh action on if disappeared after a few minutes of cell loading with GDP beta S, a GDP analogue known to bind to G-proteins and prevent their receptor-stimulated action. Furthermore, incubation of cells in a solution containing pertussis toxin (PTX) led to abolition of the if response to ACh. These results indicate that the inhibitory effect of ACh on if is mediated by G-proteins activated by muscarinic receptors. 3. Intracellular loading with phosphodiesterase (PDE) increased the rate of if current run-down, but did not abolish the inhibitory action of ACh on if. 4. Extracellular perfusion with isobutylmethylxanthine (IBMX), a PDE inhibitor, increased if activation by shifting the current activation range to more positive voltages, as inferred by a three-pulse protocol analysis; in the presence of IBMX, the inhibition of if by ACh was not abolished. 5. The ACh-induced if depression persisted also in cells loaded with cyclic GMP. In these cells, as in those loaded with PDE, the if run-down was fast. 6. Oxotremorine, a muscarinic agonist coupled to adenylate cyclase but not to phosphoinositide turnover in cardiac cells, simulated ACh in its inhibitory action on if. The above results rule against the ACh action being mediated by PDE or by phosphoinositide turnover. 7. To investigate the possible involvement of cyclic AMP as a second messenger in the ACh action on if, we loaded cells with cyclic AMP and IBMX; under these conditions the action of ACh disappeared within a few minutes of whole-cell recording. 8. In cells where the slow inward Ca2+ current (isi) was measured together with if, ACh was seen to depress both currents. 9. In cells superfused with forskolin, the if amplitude on stepping to the half-activation voltage range was enhanced as a consequence of a depolarizing shift of the activation curve; ACh was not effective on if following stimulation by forskolin, but strongly depressed in the same cell the if current stimulated to a similar degree by isoprenaline.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Muscarinic control of the hyperpolarization-activated current (if) in rabbit sino-atrial node myocytes. 247 9

Neuropeptide Y (30-1000 nmol/l) significantly inhibited the fractional stimulation-induced outflow of radioactivity from mouse atria preincubated with [3H]-noradrenaline. The inhibitory effect of neuropeptide Y was observed at all frequencies tested (2, 5 and 10 Hz) as well as after alpha-adrenoceptor blockade with phentolamine (1 mumol/l). A combination of 8-bromo adenosine cyclic-3'-5'-monophosphate (90 or 270 mumol/l) with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (100 mumol/l) was used to saturate maximally the adenylate cyclase system and these drug combinations significantly enhanced the stimulation-induced outflow of radioactivity. However, neuropeptide Y inhibited the stimulation-induced outflow in the presence of these drugs, suggesting that the inhibitory effect of neuropeptide Y was not due to decreasing endogenous cyclic AMP formation. Finally, atria from mice treated with pertussis toxin were used. In this case, the inhibitory effect of neuropeptide Y on the stimulation-induced outflow of radioactivity was still observed suggesting that inhibitory prejunctional neuropeptide Y receptors are not coupled to a pertussis toxin-susceptible G protein.
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PMID:Inhibition of noradrenaline release by neuropeptide Y in mouse atria does not involve inhibition of adenylate cyclase or a pertussis toxin-susceptible G protein. 248 50

High doses of phthalate esters in vivo cause testicular lesions. One initial target for these effects is the sustentacular Sertoli cell. Sertoli cells are unique in that they have surface membrane receptors for follicle-stimulating hormone (FSH), which couple to adenylate cyclase. As a means of investigating why phthalates appear specific for Sertoli cells, we evaluated possible effects of an active monoester [mono(2-ethylhexyl) phthalate, MEHP] on the ability of FSH to elevate intracellular levels of cAMP. MEHP reduced FSH-induced elevation of cAMP levels by approximately 40%. This inhibition by MEHP required a lag period of 6 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that MEHP does not compete with FSH for binding to its receptor. The MEHP inhibition was not affected by incubation in the presence of methylisobutylxanthine, a phosphodiesterase inhibitor, suggesting that MEHP does not stimulate the breakdown of cAMP. The MEHP-induced inhibition is specific for FSH; it does not affect the ability of forskolin, cholera toxin, isoproterenol, or prostaglandin E1 to stimulate Sertoli cell cAMP. Furthermore, inhibition occurs in the presence of pertussis toxin suggesting that MEHP action is independent of the inhibitory adenylate cyclase pathway. Further experiments will be necessary to define the specific mechanism of action of phthalates on Sertoli cells; however, these experiments do describe a specific site of action of MEHP in vitro which may be related to the in vivo testicular toxicity of phthalate esters.
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PMID:Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures. 253 9

In curarized rat skeletal muscle, rat calcitonin gene-related peptide (CGRP), a peptide coexisted with acetylcholine in the motor nerve terminal, increased the isometric twitch force, accompanied by an increase in the active state intensity of shortening, prolonged duration of the active state and additive effect of a phosphodiesterase inhibitor; the results reflect a potentiation in the sarcoplasmic calcium transport system. This CGRP effect was enhanced by cholera toxin, suggesting the activation of guanine nucleotide binding regulatory protein (G protein) that stimulates adenylate cyclase (Gs). The pertussis toxin (IAP), a factor to prevent the cyclic AMP decrease by inactivating the G protein that inhibits adenylate cyclase (Gi), provided no effect on the action of CGRP. The existence of CGRP binding site in the sarcolemmal membrane was confirmed by Scatchard analysis of binding data; affinity of the binding site for CGRP was decreased in the presence of guanosine-5'-[gamma-thio]triphosphate (GTP gamma S). The Gs protein is thus implicated in the CGRP binding site and intracellular processes of signal transduction. CGRP did not modify the neuromuscular transmission and cable properties of the muscle membrane.
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PMID:Effect of calcitonin gene-related peptide on skeletal muscle via specific binding site and G protein. 254 67

We quantified the TSH-induced morphological change in FRTL-5 thyroid cells according to a morphological index corresponding to the mean cell area measured from microscopic photographs. Within 15 min, TSH induced, at 10 pM and higher concentrations, a decrease in morphological index together with a rise in cAMP levels in a TSH dose-dependent manner. Forskolin, 3-isobutyl-1-methylxanthine, and RO 20-1724, the latter two being phosphodiesterase inhibitors, mimicked these TSH effects, indicating that the rise in cAMP levels is responsible for the TSH effect. Extracellular ATP and its derivatives, known as purinergic receptor agonists, decreased cAMP levels and caused a complete reversal of the TSH morphological effect. Prior exposure of the cells to islet-activating protein (pertussis toxin), the depletion of extracellular Ca2+, or the addition of low doses of protein kinase-C inhibitors completely abolished the inhibitory action of ATP on the TSH effect, whereas phorbol 12-myristate 13-acetate, which activates protein kinase-C, mimicked the ATP action to some extent. Thus, although the TSH-induced change in cell morphology seems to be dependent on cAMP levels, the inhibition of TSH action by ATP seems to be mediated by at least two signal transduction pathways involving islet-activating protein substrate G-proteins: one inhibiting adenylate cyclase and the other involving Ca2+ and protein kinase-C.
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PMID:Extracellular adenosine triphosphate completely reverses the thyrotropin-induced morphological change in FRTL-5 cells. 254 96

Antilipolysis induced by insulin by adenylate cyclase inhibitors was compared in isolated human fat cells when lipolysis was activated at well-defined steps in the cyclic AMP system. The latter was achieved with isoprenaline (beta-adrenoreceptor agonist), cholera toxin and pertussis toxin (acting on the GTP-sensitive coupling proteins), forskolin (stimulating the catalytic component of adenylate cyclase), enprofylline (selective phosphodiesterase inhibitor) and N6-monobutyryl-cyclic-AMP or 8-bromo cyclic-AMP (cyclic AMP analogues which are resistant or sensitive to phosphodiesterase, respectively). Clonidine (alpha 2-adrenoreceptor agonist), prostaglandin E2 and N6-(phenylisopropyl) adenosine (adenosine analogue) failed to inhibit lipolysis stimulated by cholera toxin or pertussis toxin, but were effective under all other conditions. Insulin failed to inhibit lipolysis stimulated by enprofylline or N6-monobutyryl cyclic AMP, but was effective under all other circumstances. In conclusion, insulin and adenylate cyclase inhibitors are antilipolytic in human fat cells through different mechanisms. Adenylate cyclase inhibitors act predominantly on the GTP-sensitive coupling proteins and, to a minor extent, at some yet unidentified distal step in the lipolytic machinery. As regards insulin, the major site of the antilipolytic action is phosphodiesterase.
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PMID:Antilipolytic effects of insulin and adenylate cyclase inhibitors on isolated human fat cells. 254 39

Serotonin has no obvious effect on basal cyclic AMP levels but reduces the forskolin-, isoproterenol-, and vasoactive intestinal peptide-induced stimulation of cyclic AMP levels in a dose-dependent manner. Serotonergic, cholinergic, muscarinic, alpha-adrenergic, and dopaminergic antagonists have no effect on the serotonin response. Topical application of a serotonin/pargyline solution to the living eye causes desensitisation of the serotonin response in the iris-ciliary body, an observation confirming the presence of specific serotonergic receptors linked to adenylate cyclase. The 5-HT1A [5-hydroxytryptamine (serotonin) type 1A] receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone mimic the serotonin response in reducing the forskolin-stimulated cyclic AMP levels, as do the indole derivatives 5-methoxytryptamine, 5-hydroxtryptophan, and tryptamine. However, the ineffectiveness of the 5-HT1A agonist ipsapirone and the inability of spiroxatrine to block the serotonin response show that classical 5-HT1A receptors are not involved. The serotonin response is blocked by pertussis toxin and is insensitive to the phosphodiesterase inhibitor theophylline, which indicates the involvement of an inhibitory guanine regulatory protein in the coupling of the serotonin receptor to the adenylate cyclase catalytic unit.
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PMID:Evidence for the presence of serotonin receptors negatively coupled to adenylate cyclase in the rabbit iris-ciliary body. 254 97

Several neurotransmitters activate polyphosphoinositide (PPI) hydrolysis in CNS neurons as the first step of a transmembrane signalling cascade that may lead to neuronal circuit modulation. Muscarinic and quisqualate receptor-triggered PPI hydrolysis was investigated in neuronal primary cultures. A clear increase in inositol phosphates (Ins-Ps) was detected as early as 15 s after the agonist addition; at this time, the increases of inositol 1,4,5-trisphosphate (measured by HPLC) were relatively larger with respect to the other Ins-Ps. Ins-P accumulation was maintained in part in a Ca2+-free medium, excluding that Ca2+ entry is the fundamental step of the receptor-induced PPI hydrolysis. Acute cell pretreatment with phorbol dibutyrate, an activator of protein kinase C, was able to inhibit 50% of the response to carbachol, and almost completely the quisqualate effect, suggesting a negative feedback modulation by the enzyme. Finally, pertussis toxin failed to inhibit muscarinic responses, whereas it blocked greater than 70% of the quisqualate stimulation. The two receptors therefore appear coupled to phosphodiesterase by two different G proteins. The comparison of the results obtained by stimulating the two receptor systems suggests that the generation of the same intracellular signal at two distinct receptor types may occur by different coupling mechanisms, and be differently regulated even in the same neuronal preparations.
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PMID:Muscarinic and quisqualate receptor-induced phosphoinositide hydrolysis in primary cultures of striatal and hippocampal neurons. Evidence for differential mechanisms of activation. 254 3

The intracellular messengers that seem to be involved in renin secretion (RS) from juxtaglomerular cells (JG) are calcium (Ca), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Unlike the majority of secretory systems, an increase in intracellular Ca concentration and calmodulin and protein kinase C activation inhibit RS. The intracellular Ca concentration in JG cells can be modified if: 1) the normal mechanisms of Ca extrusion of these cells is altered; 2) the calcium output is blocked by lanthanum; 3) the function of the voltage-sensitive Ca-channels is modified; 4) uptake or liberation of Ca from endoplasmic reticulum is modified; 5) plasmatic membrane is bypassed with calcium ionophores such as A 23187. 6) JG cells are stimulated by hormones that increase Ca and activate protein kinase C such as angiotensin II, vasopressin or alpha-1 adrenergic agonists; 7) extracellular Ca concentration increases or decreases. RS is stimulated by dibutyryl cAMP, cAMP phosphodiesterase inhibitors and by hormones and agents that activate adenylate cyclase (beta adrenergic agonists, bradykinin, histamine, forskolin and ethylcarboxamide adenosine). On the contrary, RS is inhibited by hormones and agents that inhibit adenylate cyclase such as: alpha-2 adrenergic agonists, neuropeptide Y, angiotensin II and cyclohexyladenosine. Pertussis toxin increases basal RS, blocks the inhibition by agents and hormones which inhibit adenylate cyclase and potentiate the stimulation produced by beta-adrenergic agonists. In JG cells, atrial natriuretic peptide inhibits RS, increases cGMP and decreases cAMP. The increase in cGMP correlates well with the inhibition of RS.
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PMID:[Intracellular messengers in the regulation of renin secretion]. 255 Oct 26

The exact nature of the interaction(s) between cAMP and calcium-sensitive phospholipid-dependent protein kinase-C effector pathways is not well understood in many tissues, including the ovary. In the present work we have evaluated the ability of protein kinase-C to modulate receptor-and nonreceptor-mediated cAMP generation in acute suspension cultures of swine luteal cells. Cells were exposed to LH (1 micrograms/ml), forskolin (100 microM), cholera toxin (1 microgram/ml), pertussis toxin (100 ng/ml), and/or phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] for 0-90 min. TPA had no effect on basal cAMP accumulation, but increased (P less than 0.05) LH-, forskolin-, and cholera toxin-activated cAMP formation, with maximal facilitation at 30, 45, and 60 min, respectively. This facilitative effect was robust, as it could be demonstrated in both the presence and absence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.5 mM). TPA increased dose-dependent LH (0.1-1 microgram/ml)-, forskolin (3-300 microM-, and cholera toxin (0.3-10 microgram/ml)-stimulated cAMP accumulation. TPA induced a dose-dependent (0.3-30 ng/ml) increase in cAMP accumulation when incubated with the half-maximally effective (ED50) and maximally effective doses of LH (0.8 and 1 microgram/ml, respectively), forskolin (10 and 300 microM), and cholera toxin (0.2 and 3 micrograms/ml). TPA had an ED50 for this functional activation of 6.1 (67% confidence interval, 4.4-9.7) nM. The stimulatory effect of TPA could be mimicked by two synthetic diacylglycerols, 1,2-Dioctanoylglycerol and 1-oleoyl-2-acetylglycerol, but not by inactive phorbol esters. In addition, TPA augmented the stimulatory effect of pertussis toxin when combined with maximally effective doses of LH, forskolin, and cholera toxin. The stimulatory action of TPA on cAMP production was limited to endogenous cellular adenylyl cyclase. Bacterially derived adenylyl cyclase toxin isolated from Bordetella pertussis resulted in a dose-dependent increase in cAMP formation over 60 min, which was not facilitated by phorbol ester. We conclude that stimulatory coupling exists between the calcium-dependent protein kinase-C and cAMP-generating systems in swine luteal cells. This stimulatory coupling is enacted in part at the levels of both the guanine binding and the catalytic subunits of adenylyl cyclase.
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PMID:Facilitative actions of the protein kinase-C effector system on hormonally stimulated adenosine 3',5'-monophosphate production by swine luteal cells. 255 49


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