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)

A dopamine-sensitive adenylate cyclase with characteristics similar to those measured in the striatum is present in the rat substantia nigra. Destruction of dopamine cell bodies by intranigral 6-hydroxydopamine application failed to abolish the response of nigral adenylate cyclase to dopamine. In contrast, brain hemitransection between the striatum and substantia nigra, or a more circumscribed lesion of striatonigral pathways, abolished the dopamine stimulation of adenylate cyclase in the substantia nigra. These results suggest that dopamine receptors within the substantia nigra are not located on dopamine cell bodies but are associated with a pathway, containing gamma-aminobutyric acid or substance P, which projects from forebrain structures to the substantia nigra.
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PMID:Dopamine-sensitive adenylate cyclase: location in substantia nigra. 1 99

Serotonin is a neuromodulator that mediates a wide range of effects by interacting with multiple receptors. Using a strategy based on nucleotide sequence homology between genes encoding receptors that interact with guanine nucleotide-binding proteins, we have isolated a mouse gene encoding an additional serotonin receptor. When expressed in cultured cells, it displayed the pharmacological profile and coupling with adenylate cyclase characteristic of the 5HT1B receptor subtype. In NIH 3T3 cells expressing this receptor, serotonin induced a decrease in forskolin-stimulated cAMP levels. This effect was blocked by pertussis toxin, indicating that the 5HT1B receptor interacts with a pertussis toxin-sensitive guanine nucleotide-binding protein. To obtain clues as to the possible function of the 5HT1B receptor, we have analyzed its pattern of expression in the adult mouse brain by in situ hybridization. Our results, together with previous autoradiographic studies, suggest that the 5HT1B receptors are localized presynaptically on the terminals of striatal neurons and Purkinje cells and that they might modulate the release of neurotransmitters such as gamma-aminobutyric acid. The predominant expression of the 5HT1B receptor in the striatum and cerebellum points to an involvement of this receptor in motor control.
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PMID:Mouse 5HT1B serotonin receptor: cloning, functional expression, and localization in motor control centers. 155 7

The regulation of cholecystokinin octapeptide (CCK-8) secretion was studied using a fetal cerebral cortical cell culture system. After 2-3 weeks in culture, the cells were utilized for short-term release experiments. CCK-8 was measured by RIA and its identity was confirmed by HPLC. Depolarization of the cells with K+ (6 x 10(-2) M) evoked CCK-8 release and this response was blocked by the Ca++ channel blocker verapamil (2 x 10(-5) M) and by Ca++ free medium. The Na+ channel opener veratridine (10(-4) M) stimulated CCK-8 release and was blocked by the Na+ channel blocker tetrodotoxin (10(-6) M) and by Ca++ free medium. The adenylate cyclase activator forskolin (10(-5) M) markedly increased CCK-8 secretion. No changes in CCK-8 release were induced by epinephrine, norepinephrine, dopamine, acetylcholine, or 5-hydroxytryptamine at 10(-5) and 10(-4) M, but gamma-aminobutyric acid (GABA) at 10(-4) M inhibited CCK-8 release. GABA inhibition was reversed by the GABA antagonist picrotoxin (10(-4) M). Both picrotoxin (10(-4) M) and bicuculline (10(-3) M), another GABA receptor antagonist, alone stimulated CCK-8 secretion. These data show that CCK-8 secretion by cerebral cortical cells 1) is stimulated by cell membrane depolarization in a calcium-dependent fashion, 2) is regulated by cAMP, 3) is unaffected by the neurotransmitters characteristic of corticopetal systems, 4) is tonically inhibited by GABA.
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PMID:Regulation of cholecystokinin octapeptide secretion by rat cerebral cortical cells in primary culture. 168 80

In this study we have used fluoride as a tool to investigate the involvement of G protein-coupled effector systems in the regulation of the depolarization-induced release of gamma-aminobutyric acid (GABA) from rat cerebral cortex. To distinguish among the activating effects of NaF on G proteins linked to different effectors, such as adenylate cyclase, polyphosphoinositide phospholipase C, and K+ channels, agents specific to these effectors have been used in parallel. NaF induced a marked dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, with an EC50 of 1.26 mM, increasing release by 103% at 5 mM NaF. No effect on basal release was seen up to 3 mM NaF, and no modulation of [3H]acetylcholine (ACh) release was seen up to 5 mM NaF. Phorbol 12,13-diacetate (PDA) produced a similar dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, potentiating the release of [14C]GABA by 50% at 10 microM PDA. The phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine (IBMX) and theophylline, inhibited the K(+)-evoked release of [14C]GABA, and IBMX reversed the NaF facilitation of GABA release in a dose-dependent manner (pA2 2.57). The K+ channel blocker (IA current) tetrahydroaminoacridine (THA), which markedly inhibits the K(+)-evoked release of [14C]GABA, also reversed the NaF facilitatory effect, but the release of [3H]ACh was less sensitive to the inhibitory effect of THA. On the other hand, the K+ channel blocker, tetraethylammonium, which has no effect on the release of [14C]GABA, caused a significant facilitation of K(+)-evoked release of [3H]ACh. From these studies, it is concluded that GABA release in cerebral cortex is subject to regulation by G protein-linked effector systems that are distinct from those affecting the release of [3H]ACh in cerebral cortex.
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PMID:Modulation of gamma-aminobutyric acid release in cerebral cortex by fluoride, phorbol ester, and phosphodiesterase inhibitors: differential sensitivity of acetylcholine release to fluoride and K+ channel blockers. 169 Feb 66

The most important central autonomic pathways in the control of arterial blood pressure are the baroreceptor reflex pathway and descending pathways from the hypothalamus. Central neurotransmitters in these pathways are L-glutamate, substance P, norepinephrine (NE), gamma-aminobutyric acid, epinephrine, neuropeptide Y, and acetylcholine. At peripheral autonomic neurovascular junctions, there are prejunctional alpha 2- and dopamine-2 receptors, which inhibit NE release, and beta- and serotonin receptors, which stimulate NE release. Postjunctional alpha 1-receptors open sodium channels, open calcium channels via phosphoinositol release, and release intracytoplasmic calcium. Postjunctional alpha 2-receptors, which are extrasynaptic, inhibit adenylate cyclase and also open calcium channels. In animal models of hypertension, changes in alpha-receptor density have been reported. In spontaneously hypertensive rats, increased renal beta- and alpha 2-receptors, respectively, may enhance renin release and cause sodium and water retention. In experimental (renovascular) hypertension, vascular postsynaptic (vasoconstrictor) alpha 1- and alpha 2-receptors are increased. In both models of hypertension, beta-receptors are down-regulated. Selective alpha 1-antagonists, such as indoramin and prazosin, decrease arterial blood pressure by postsynaptic alpha 1-blockade; alpha 2-receptor inhibition of NE release is unaffected so that there is no beta-receptor-mediated tachycardia.
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PMID:Alpha-adrenoreceptors in hypertension. 242 93

The effects of the cyclic nucleotide cAMP on gamma-aminobutyric acid-gated chloride channel function were investigated. The membrane-permeant cAMP analog N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate inhibited muscimol-induced 36Cl- uptake into rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (IC50 = 1.3 mM). The inhibition was due to a decrease in the maximal effect of muscimol, with no change in potency. Similar effects were observed with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, 8-bromoadenosine 3',5'-cyclic monophosphate, and the phosphodiesterase inhibitor isobutylmethylxanthine. The effect of endogenous cAMP accumulation on the gamma-aminobutyric acid-gated Cl- channel was studied with forskolin, an activator of adenylate cyclase. Under identical conditions, in the intact synaptoneurosomes, forskolin inhibited muscimol-induced 36Cl- uptake and generated cAMP with similar potencies (IC50 = 14.3 microM; EC50 = 6.2 microM, respectively). Surprisingly, 1,9-dideoxyforskolin, which does not activate adenylate cyclase, also inhibited the muscimol response, suggesting that forskolin and its lipophilic derivatives may interact with the Cl- channel directly. Indeed, forskolin inhibition of muscimol-induced 36Cl- uptake was extremely rapid (within 5 sec), preceding the accumulation of sufficient levels of cAMP. After 5 min, a slower phase of inhibition was seen, similar to the time course for cAMP accumulation. The data suggest that gamma-aminobutyric acid (GABAA) receptor function in brain can be regulated by cAMP-dependent phosphorylation.
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PMID:cAMP and forskolin decrease gamma-aminobutyric acid-gated chloride flux in rat brain synaptoneurosomes. 246 63

Previous in vivo studies from our laboratory have consistently shown that iontophoretically applied norepinephrine (NE) can potentiate gamma-aminobutyric acid (GABA)-induced depressant responses of cerebrocortical, cerebellar and hypothalamic neurons. Additional experiments have further suggested that this noradrenergic facilitating action is specific for GABA and results from the activation of a beta-type adrenoceptor. The goal of the present studies was to determine if the cAMP second messenger system might also be a component of the mechanism responsible for this NE modulatory action on GABA-mediated inhibition. In one set of in vitro experiments, we examined cerebellar neuronal responses to GABA before, during and after iontophoretic application of NE, 8-bromo-3',5'-cyclic AMP (BcAMP) or 3-isobutyl-1-methyl xanthine (IBMX) or bath application of forskolin (10-30 microM). In a second group of in vivo studies, extracellularly recorded responses of individual cerebellar Purkinje (P) cells to iontophoretic pulses of GABA or beta-alanine were examined before, during and after NE or BcAMP microiontophoresis. In 20 of 25 cerebellar cells recorded from tissue slices, iontophoretically applied NE markedly enhanced responses to GABA in a manner similar to that observed previously in vivo. In these in vitro preparations, bath application of forskolin was also capable of potentiating GABA-induced inhibition in each of 4 cases tested whereas dideoxy-forskolin was not. Iontophoretic application of IBMX further enhanced the facilitating effects of NE on GABA-induced inhibition in 10 of 11 cases tested. Furthermore, under in vitro conditions, BcAMP augmented inhibitory responses to GABA in all cerebellar neurons tested. In the intact rat brain, iontophoretic administration of BcAMP caused a marked NE-like augmentation of P-cell responses to GABA in 73% of the cells tested. As with NE, BcAMP was ineffective in enhancing P-cell inhibitory responses to beta-alanine, an agent which like GABA causes hyperpolarization, by increasing Cl conductance. In summary, these results indicate that a membrane permeant analog of cAMP, a phosphodiesterase inhibitor and an agent which directly activates adenyl cyclase can mimic the previously observed GABA-potentiating actions of NE. Thus, these findings provide further support for the contention that noradrenergic enhancement of GABA inhibition results from a cascade of transmembrane events which includes beta-receptor activation, adenyl cyclase stimulation and increased intracellular production of cAMP.
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PMID:Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: evidence for mediation through the beta-adrenoceptor-coupled cyclic AMP system. 247 58

The regulation of GRF secretion was studied using a fetal rat hypothalamic cell culture system. The cells were subjected to short term release experiments on days 10-18 after plating, and GRF secretion was assessed by RIA. The identity of GRF immunoreactivity in the incubation medium was confirmed by reverse phase liquid chromatographic analysis. Depolarization of the cells with 56 mM K+ evoked a 4-fold increase in basal GRF release. When cultures were pretreated for 6 days with the adenylate cyclase activator forskolin, basal GRF release was augmented in subsequent release experiments to levels 2-fold greater than those in the control cultures. In nonpretreated cultures, forskolin (1-100 microM) and the protein kinase C activator phorbol 12-myristate 13-acetate (10 nM-1 microM), stimulated basal GRF release in a dose-dependent fashion. The Ca2+ channel blocker verapamil (100 microM) significantly inhibited the GRF response to both forskolin and phorbol 12-myristate 13-acetate. The gamma-aminobutyric acid (GABA) agonist muscimol (0.1-10 microM) inhibited forskolin-stimulated, but not K+ stimulated, GRF release in a dose-dependent manner. This inhibition was reversed by the GABA antagonists bicuculline and picrotoxinin. Muscimol (10 microM) slightly suppressed basal GRF release. The present findings suggest that GRF secretion can be evoked by agents known to increase intracellular cAMP levels or activate protein kinase-C. They also support a role for GABA in the inhibitory control of GRF secretion.
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PMID:Growth hormone-releasing factor secretion from fetal hypothalamic cell cultures is modulated by forskolin, phorbol esters, and muscimol. 253

The gamma-aminobutyric acid (GABA) receptor has been classified into two receptor subtypes (GABAA and GABAB receptors) based on their pharmacological properties. The GABAA receptor in the central nervous system (CNS) has been found to be coupled structurally as well as functionally with the benzodiazepine receptor and Cl- channel. Purified GABAA receptor from bovine brain consisted of both alpha and beta subunits. The complementary DNAs encoding the GABAA receptor alpha and beta subunits have been cloned; and from their elucidated nucleotide sequences, the amino acid sequences of the subunits were deduced. The structure of both subunits, having four putative membrane domains, has been found to be similar to other ligand-gated receptors such as the nicotinic acetylcholine receptor alpha subunit and glycine receptor 48K subunit. Therefore, it has been suggested that these ligand-gated receptors comprise a superfamily. In addition, the presence of similarities in the nucleotide and deduced amino acid sequences of human brain GABAA receptor with those of bovine brain has been noted. On the other hand, the GABAB receptor, which is insensitive to bicuculline but sensitive to baclofen, has been found to be pharmacologically distinct from the GABAA receptor. The GABAB receptor in the brain has been found to be coupled with GTP-binding protein and generates the inhibitory transmission coupled with various intracellular effector systems such as adenylate cyclase and phosphoinositides turnover. The exact structure and function of the GABAB receptor in the CNS, however, remain to be clarified in future studies.
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PMID:[Structure and function of gamma-aminobutyric acid (GABA) receptor: current state and prospectives]. 255 2

An investigation of the effects of gamma-aminobutyric acid (GABA) and the selective GABAB receptor agonist, baclofen, on basal and stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in slices of rat cerebral cortex has been carried out. Neither GABA nor baclofen produced any significant change in basal cyclic AMP levels. By contrast noradrenaline and forskolin both produced dose-dependent increases in cellular cyclic AMP accumulation. GABA (in the presence of nipecotic acid) and baclofen both potentiated the maximal response to noradrenaline with baclofen (100 microM) increasing the level of cyclic AMP produced by noradrenaline (100 microM) by 133%. GABA (0.3-100 microM) was rather less effective than baclofen, increasing the response to noradrenaline by 70% at 100 microM. (-)-Baclofen was the active isomer with (+)-baclofen failing to potentiate noradrenaline responses. Bicuculline-methobromide (100 microM) failed to block the action of either GABA or baclofen. The enhancement of adrenoceptor-stimulated cyclic AMP accumulation persisted in the presence of a phosphodiesterase inhibitor (1 mM 3-isobutyl-1-methylxanthine) and also in Ca2+-free solution. When forskolin was used to stimulate adenylate cyclase, the effect of baclofen was to inhibit the rise in cyclic AMP levels. Thus (-)-baclofen (100 microM) shifted the dose-response curve to forskolin to the right 5 fold in an apparently parallel fashion. The effect was again stereospecific for the (-)-isomer of baclofen. When GABA uptake was reduced using low sodium (40 mM) incubation medium, GABA also attenuated the rise in cyclic AMP induced by 10 microM forskolin. GABA produced little effect in normal Krebs solution.
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PMID:GABAB receptor modulation of adenylate cyclase activity in rat brain slices. 257


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