Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin, morphine, and opioids inhibit transmitter release at intact neuromuscular junctions between ciliary ganglion neurons and the choroidal smooth muscle of the chick eye. Somatostatin and morphine, however, have no effect on release from terminals on the striated muscle target of the ciliary ganglion, the iris. In neuronal terminals of both the choroid and the iris, a high-affinity Na+-dependent choline uptake-mediated ACh synthesis is present at hatching. Both tissues exhibit a basal release of 3H-ACh which is potentiated severalfold during a 5 minute incubation in 55 mM K+ Tyrodes. Fifty percent of the basal release and 100% of the stimulated release are Ca2+ dependent and probably mediated through N-like voltage-dependent Ca2+ channels. Co-incubation of the choroid with 10 microM morphine sulfate blocks approximately 90% of the stimulated release. The same effect is seen with 100 nM somatostatin, 10 microM dynorphin, and 100 microM met-enkephalin arginine phenylalanine. Preincubation of the excised choroid with pertussis toxin (200 ng/ml) reverses the inhibitory effects of both morphine and somatostatin. In contrast, 3H-ACh release from terminals in the striated iris is not affected by either morphine or somatostatin at micromolar levels. These results suggest that both opiate and somatostatin receptors are present in the choroid target and that they may act through a final common pathway to modulate ACh release via G proteins. Second messengers such as cyclic AMP or diacylglycerol do not appear to mediate these effects; neither increasing cAMP levels in terminals nor activation of protein kinase C affects evoked release or its inhibition by morphine or other neuromodulators. It is unclear whether endogenous neuromodulation occurs in this system, although somatostatin-like immunoreactivity can be demonstrated in terminals of choroid neurons.
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PMID:Opiate and peptide inhibition of transmitter release in parasympathetic nerve terminals. 256 61

A possible influence of botulinum A toxin on the modulation of evoked neurotransmitter release was investigated in hippocampus tissue. Rabbit hippocampal slices prelabelled with [3H]noradrenaline ([3H]NA), [3H]5-hydroxytryptamine ([3H]5-HT) or [3H]choline were superfused with physiological medium and were stimulated electrically during superfusion. The evoked release of [3H]NA, [3H]5-HT and [3H]acetylcholine [( 3H]ACh) was inhibited by botulinum A toxin in a concentration- and time-dependent manner. Neither the inhibition of release of [3H]NA and [3H]5-HT by the alpha 2-adrenoceptor agonist clonidine nor facilitation of release in the presence of alpha 2-antagonists were influenced by pretreatment of the tissue with botulinum toxin. The toxin caused no [32P]ADP ribosylation of synaptosomal proteins of hippocampus. The facilitation of the stimulation-induced [3H]NA and [3H]5-HT release by the specific protein kinase C (PKC) activator 4 beta-phorbol-12,13-dibutyrate (PDB) was significantly diminished by botulinum A toxin. These results show that the evoked transmitter release is inhibited by botulinum A toxin by a mechanism which does not involve ADP ribosylation or an interaction with the alpha 2-adrenoceptor mechanism.
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PMID:Effects of botulinum A toxin on presynaptic modulation of evoked transmitter release. 256 39

1. In single, enzymatically dissociated, rat pancreatic acinar cells both ACh stimulation and IP3 (inositol 1,4,5-trisphosphate) injection can evoke Ca(+)-dependent transient current responses. However, exogenously applied IP3 (10 microM) gradually loses its ability to induce the Ca2(+)-dependent response (an increase in [Ca2+]i) during cell incubation with a saline solution. 2. Administration of IP4 (inositol 1,3,4,5-tetrakisphosphate, 10 microM) together with the IP3 (the injection of IP3-IP4 mixture) allows partial recovery of the response, but not full replication of the response induced by ACh (0.2 microM). Injection of IP4 alone never induces the current response. 3. The sensitivity of IP3 recovers after short-term administration of ACh (0.2 microM), and in turn, the ACh-induced response is augmented by the presence of internal IP3. These results suggest that a synergism between IP3 and another ACh-induced substance plays an important role in muscarinic Ca2+ signalling. 4. ACh-induced responses are inhibited by pre-incubation (10 min) with an activator of protein kinase C, TPA (12-O-tetradecanoylphorbol-13-acetate, 16 nM), or augmented by pre-incubation (10 min) with an inhibitor, H-7 (1-(5-isoquinoline-sulphonyl)-2-methylpiperazine, 10 microM), whilst IP3-induced responses are unaffected by that with both agents. These results indicate that protein kinase C acts negatively on the signalling elements prior to the formation of IP3. 5. The oscillatory responses, induced by cell dialysis with a nominally Ca2(+)-free (ca 1-10 microM) solution containing GTP gamma S (100 microM), are unaffected by the pre-treatment with TPA or H-7. In addition, these responses and/or those triggered by short-term stimulation with ACh and internal GTP gamma S are not influenced by external ACh. On the other hand, the oscillatory responses recorded in acinar cells pre-treated with H-7 are tightly controlled by external ACh. 6. Taken together these results suggest that activation of protein kinase C does not affect the activity of GTP-binding protein, but disconnects the link between the muscarinic ACh receptor and GTP-binding protein, or inhibits ACh binding to the receptor, in rat pancreatic acinar cells.
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PMID:Activation and desensitization mechanisms of muscarinic current response in single pancreatic acinar cells of rats. 262 98

(1) The effect of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a specific activator of the protein kinase C (PrkC), on the function of junctional nicotinic acetylcholine receptors (nAChR) was examined on muscle fibres isolated from the M. flexor digitorum brevis of the rat. (2) In the presence of TPA the sensitivity of the whole endplates to iontophoretically applied ACh exhibited multiphasic oscillations: an early decrease followed by a delayed increase and, at the end again, a decrease to below pretreatment levels. This effect was more pronounced as the TPA concentration was increased in the range of 0.1-1 microM and was blocked by the PrkC-inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7). (3) TPA (0.1-0.5 microM) shortly applied to patch-clamped fibres caused a slight decrease in nAChR-channel slope conductance without affecting the mean lifetime. In a patch the opening frequency increased over time, after an initial decrease. (4) It is concluded that specific activation of the PrkC may be of regulatory significance on nAChR function.
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PMID:Regulation of acetylcholine receptor function by the phorbol ester TPA in rat skeletal muscle. 279 18

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) might have a presynaptic modulatory effect at cholinergic terminals in the rat hippocampal formation. The exposure of rat hippocampal slices to VIP increased [3H]acetylcholine ([3H]ACh) synthesis from the precursor [3H]choline when tissue was incubated in normal or in high K+ medium; the maximal effect was apparent at 10(-8) M VIP and 10(-7) M VIP, respectively. Also, 10(-7) M VIP increased the activity of choline acetyltransferase (ChAT) in a hippocampal homogenate system. The increased synthesis by hippocampal slices was not the result of a VIP-induced alteration in either the basal release of ACh or the uptake of choline via the high-affinity uptake system. The increase in ACh synthesis induced by VIP in hippocampal slices was not associated with either adenylate cyclase or protein kinase C second messenger systems. There was no correlation between the effect of VIP on cyclic AMP production with that on ACh synthesis; also, forskolin, an activator of adenylate cyclase that increased cyclic AMP production 3.5-fold, did not mimic the effect of VIP on ACh synthesis. Similarly, there was no effect of the protein kinase C activator, phorbol myristate acetate, on ACh synthesis in hippocampal slices. However, the effect of VIP to increase ACh synthesis was not evident in the absence of extracellular calcium, suggesting that the effect of VIP is mediated by a calcium-requiring mechanism. The results suggest that, in the rat hippocampus, VIP has a presynaptic action at cholinergic terminals that results in enhanced synthesis of ACh, possibly by an action that alters ChAT activity.
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PMID:Vasoactive intestinal peptide increases acetylcholine synthesis by rat hippocampal slices. 282 90

In Xenopus laevis oocytes, adenosine and other purinergic agonists induce a K+-conductance increase that is fully mimicked by intracellular application of cAMP. Acetylcholine suppresses the K+-conductance increase caused by adenosine, by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, or by intracellular injection of cAMP. This effect of acetylcholine is not mimicked by intracellular injection of Ca2+ or of the Ca-mobilizing agent inositol 1,4,5-trisphosphate. However, adenosine and cAMP responses are inhibited by 4 beta-phorbol 12,13-dibutyrate and 4 beta-phorbol 12-myristate 13-acetate. These results suggest that, in Xenopus oocytes, the muscarinic inhibition of purinergic and cAMP responses is mediated through the activation of the phospholipid-dependent, Ca-activated protein kinase (protein kinase C).
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PMID:Acetylcholine and phorbol esters inhibit potassium currents evoked by adenosine and cAMP in Xenopus oocytes. 299 58

The relaxation of phenylephrine-contracted blood vessels by acetylcholine, nitroprusside, or atrial natriuretic factor has been linked to elevations in cyclic guanosine 3',5'-monophosphate (cGMP). Also, 8-bromo-cGMP can induce vascular relaxation in isolated vascular smooth muscle contracted with phenylephrine. We determined whether these cGMP-dependent vasodilators could relax isolated rat aortas contracted with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. cGMP was measured by radioimmunoassay. Acetylcholine, nitroprusside, and atrial natriuretic factor induced relaxation in vascular smooth muscle contracted by 12-O-tetradecanoylphorbol-13-acetate. These relaxation responses were accompanied by elevations of cGMP. However, the sensitivity to these vasodilators was markedly decreased in phorbol ester-contracted vessels compared to phenylephrine-contracted vessels. Nifedipine and superoxide dismutase induced small but significant relaxations in phorbol ester-contracted vessels; however, blood vessels contracted with phenylephrine and phorbol ester relaxed completely with papaverine. There was a marked decrease in sensitivity to 8-bromo-cGMP in phorbol ester-treated vessels compared to phenylephrine-contracted vessels. Contractions induced by phorbol ester were not inhibited by amiloride or chlorpromazine. Also, following incubation in potassium-free salt solution, vessels incubated with phenylephrine or phenylephrine and phorbol ester underwent similar relaxations when exposed to potassium chloride. The contractile state induced by phorbol ester has decreased sensitivity to cGMP-dependent vasodilators. This may be due to nonspecific effects of the phorbol ester or to the mechanism by which protein kinase C activation maintains vascular tone.
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PMID:Phorbol ester, vascular relaxation, and cyclic guanosine 3',5'-monophosphate. 303 7

Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na+ conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C.
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PMID:Pertussis toxin-insensitive phosphoinositide hydrolysis, membrane depolarization, and positive inotropic effect of carbachol in chick atria. 304 Feb 95

Acetylcholine (ACh) causes vascular smooth muscle relaxation by releasing endothelium-derived relaxing factor (EDRF) from endothelial cells (EC). Although a pivotal role for cytosolic free Ca2+ ([Ca2+]i) has been implicated in the generation and/or release of EDRF by various agonists, there is no conclusive evidence showing that ACh increases [Ca2+]i in EC. In the present study, using the Ca2+-sensitive fluorescent indicator fura-2, we show for the first time that ACh (10(-5) M) increases [Ca2+]i six- to sevenfold above prestimulus levels in primary cultures of rabbit aortic EC (RbAEC). ACh effects are dose dependent [effective concentration producing 50% of the maximum response (EC50) approximately 9 X 10(-7) M] and are blocked by atropine, a selective muscarinic receptor antagonist. The [Ca2+]i increase is due both to the mobilization of intracellular Ca2+ and to the influx of extracellular Ca2+. A 5-min incubation of RbAEC with 4 beta-phorbol 12-myristate 13-acetate (10(-7) M) inhibits ACh-induced [Ca2+]i transients, suggesting that the signaling pathway involved in ACh receptor signal transduction may be modulated via protein kinase C. These cultured EC provide a unique in vitro model system for studying mechanisms involved in ACh-induced EDRF release.
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PMID:ACh-induced calcium transients in primary cultures of rabbit aortic endothelial cells. 320 14

1. The major purpose of this study was to investigate cellular regulation of the ductal transport processes in salivary glands which act to modify the electrolyte composition of primary saliva and cause it to become hypotonic. This was achieved using an isolated mandibular gland preparation by observing the effect of different stimuli on the electrolyte composition of saliva secreted at the same flow rate, on the assumption that these stimuli do not influence primary saliva composition. The effects of the same stimuli on the volume of primary fluid secretion and on protein secretion were also observed. Proteins were measured in total and as individual components after their separation by high-performance liquid chromatography. 2. Acetylcholine was used as a 'Ca2+-mobilizing' agonist (i.e. one which both elevates intracellular Ca2+ concentration and activates protein kinase C). Isoprenaline was initially used to elevate intracellular cyclic AMP concentration but was subsequently abandoned in favour of forskolin. 3. Acetylcholine was a very potent stimulus of primary fluid secretion. By contrast, isoprenaline and forskolin were essentially without effect, even when superimposed on acetylcholine stimulation. 4. As judged by saliva electrolyte composition, increasing the concentration of acetylcholine enhanced ductal absorption of Na+ and Cl- and secretion of K+ (and presumably HCO3-). Forskolin had the opposite effect: when superimposed on submaximal acetylcholine stimulation it caused saliva concentrations of Na+ and Cl- to remain high and K+ low (i.e. it inhibited ductal transport processes). The inhibitory effect of forskolin on ductal transport could be overcome by increasing the concentration of acetylcholine, and vice versa. 5. Acetylcholine, isoprenaline and forskolin each increased salivary protein secretion, although the kinetics of secretion differed. The spectrum of proteins secreted in response to the three stimuli was the same. The relative proportions of the individual proteins was influenced by the strength of stimulation (i.e. the proportions at high total protein output differed from those at low total protein output) but not apparently by the nature of the stimulus. 6. Thus, the three major secretory processes in the rabbit mandibular salivary gland respond differently to the two major signal transduction mechanisms. For primary fluid secretion, Ca2+ is stimulatory and cyclic AMP almost without effect; for ductal transport, Ca2+ is stimulatory and cyclic AMP inhibitory; and for protein secretion both Ca2+ and cyclic AMP are stimulatory.
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PMID:Effects of acetylcholine, isoprenaline and forskolin on electrolyte and protein composition of rabbit mandibular saliva. 325 19


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