Activation and desensitization mechanisms of muscarinic current response in single pancreatic acinar cells of rats.

Maruyama, Yoshio

doi:10.1113/jphysiol.1989.sp017805

Cited by 41 publications

(52 citation statements)

References 32 publications

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“…9B). The present finding that Ca2+ oscillations subsist after protein kinase C inhibition is in agreement with a recent report that H7 does not affect Ca2+ waves in the exocrine pancreas (Maruyama, 1989). appears more reliable than the first, probably because onset kinetics reflect more directly the first steps of the Ca2+ release response than does the peak Ca2+ value (Horn & Marty, 1988).…”

Section: Lack Of Effect Of Protein Kinase C On Calcium Oscillationssupporting

confidence: 82%

“…rat hippocampal slices: Labarca, Janowsky, Patel & Paul, 1984;human platelets: MacIntyre, McNicol & Drummond, 1985;Zavoico, Halenda, Sha'afi & Feinstein, 1985;PC12 cells: Vicentini, Virgilio, Ambrosini, Pozzan & Meldolesi, 1985; murine neuroblastoma cells: Kanba, Kanba & Richelson, 1986; exocrine glands: Llano & Marty, 1987;Sugiya, Obie & Putney, 1988; Maruyama, 1989; but see Gray, 1988), it has been found that protein kinase C activators inhibit the production of inositol trisphosphate and the ensuing Ca2+ rise, thus suggesting the presence of a negative feedback due to the production of diacylglycerol by phospholipase C. Whether or not this inhibition actually participates in desensitization is, however, unclear. In a liver cell line, downregulation of protein kinase C induced by prolonged treatment with phorbol esters has recently been shown to potentiate and to prolong the inositide response, suggesting that protein kinase C inhibition may play a role in agonist-induced desensitization (Hepler, Earp & Harden, 1988).…”

Section: Y P Tan and A Martymentioning

confidence: 99%

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Protein kinase C‐mediated desensitization of the muscarinic response in rat lacrimal gland cells.

Tan

Marty

1991

The Journal of Physiology

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SUMMARY1. Desensitization of the Ca2+ release response evoked by acetylcholine in acinar cells from rat lacrimal glands was studied using the Ca2+-sensitive dye Fura-2. The evolution of the amplitude and half-maximal rise time (t1) of the Ca2+ response was followed as a function of trial number in a series of stimulations.2. Under control conditions repetitive applications of acetylcholine (15 s long applications every minute) led to a linear decrease of the amplitude and to a linear increase of ti with trial number. Both amplitude and ti recovered their control values after 20 min of washing.3. Staurosporine (02-1 ,lM), an inhibitor of protein kinase C, was found to decrease the slopes of the variation of amplitude and ti with trial number.4. Prolonged treatment with 12-O-tetradecanoyl phorbol 13-acetate (TPA), an activator of protein kinase C (100-250 nm for 2-4 h), also led to a markedly decreased desensitization, presumably as a result of down-regulation of protein kinase C. On the other hand moderate pre-treatments with TPA (16-32 nm for 10 min) strongly inhibited the response, most probably as a result of protein kinase C activation.5. Application of oleoylacetylglycerol (50 /LM), a weaker activator of protein kinase C, inhibited the response and enhanced desensitization. These effects were, however, not obtained after down-regulation of protein kinase C with strong exposure to TPA.6. We conclude that protein kinase C activation following the ACh-induced Ca2+ rise and the concomitant diacylglycerol production mediates desensitization of the response. 7. Arachidonic acid (100 ICM) inhibited the ACh-induced response and enhanced desensitization. However, this effect did not appear to be mediated by protein kinase C since it was also obtained with docosahexaenoic acid, an analogue of arachidonic acid which does not activate protein kinase C.

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Section: Lack Of Effect Of Protein Kinase C On Calcium Oscillationssupporting

confidence: 82%

Section: Y P Tan and A Martymentioning

confidence: 99%

Protein kinase C‐mediated desensitization of the muscarinic response in rat lacrimal gland cells.

Tan

Marty

1991

The Journal of Physiology

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“…This has already been shown for M 3 receptors in other cell systems (Yamatani et al 1988, Maruyama 1989, Tan & Marty 1991, reviewed by Berrie & Elliott 1994. However, the observation that desensitization of PLC-coupled muscarinic receptors is mediated by PKC (Haga et al 1990) is not supported by all studies as described by Benya et al (1995).…”

Section: Pkc Involvement In Desensitizationsupporting

confidence: 60%

The role of protein kinase C in the desensitization of rat pancreatic islets to cholinergic stimulation

Verspohl

Wienecke²

1998

Journal of Endocrinology

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It is well known that protein kinase C (PKC) plays an important role in mediating insulin secretion in response to cholinergic stimulation. In various cells PKC also mediates a desensitization process. The role of PKC for homologous desensitization of the insulin response to repetitive stimulation with the muscarinic agonist carbachol (CCh) was investigated in perifusion experiments using isolated rat pancreatic islets. Repetitive (six times) stimulation with CCh (100 µM) reduced insulin secretion over time (up to 50% during the second challenge). This was not a toxic effect since the desensitizing effect was mostly washed out after 45 min. When PKC was downregulated by long term preincubation (20 h) with 200 nM phorbol 12-myristate 13-acetate (TPA), the initial stimulation of insulin release by CCh was reduced by 50%, and a desensitization by further CCh stimulation was no longer obvious. In contrast, when other compounds with different mechanisms of actions for inactivating PKC were used, i.e. PKC inhibitors such as staurosporin (100 nM), Ro 31-8220 (5 µM) or PKC peptide(19-31), the insulin secretion in response to CCh was reduced but the desensitization was not abolished. When PKC was downregulated or inhibited by the above methods, the PKC activator phorbol 12-myristate 13-acetate (TPA; 200 nM) was no longer able to evoke an increase in insulin secretion during static incubation, i.e. these control experiments indicate a real PKC inhibition. When heparin (50 µg/ml), an inhibitor of G-protein coupled receptor kinase (GRK), was used, the desensitization of the cholinergic stimulation of insulin release remained unchanged. The data indicate that PKC plays a role in CCh-mediated insulin secretion and also show a desensitization of this effect after repetitive stimulation with CCh. The data further indicate that specific PKC isoenzymes that are inhibited by staurosporin or Ro 31-8220 do not take part in the desensitization process, while isoenzymes that are downregulated by TPA are involved. It may be speculated that a hitherto unknown PKC isoenzyme that is downregulated by TPA but not by the other used PKC inhibitors is involved in the desensitization process, or that a nonspecific effect of TPA is involved. Members of the GRK family are not involved in the desensitization process of CCh.

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“…In rat clonal pituitary cells (Ozawa & Kimura, 1979;Ozawa, 1981;Dubinsky & Oxford, 1985;Ritchie, 1987b;Mollard et al 1988), thyrotrophin-releasing hormone (TRH) initiates an initial activation of Ca2+-dependent K+ current followed by a secondary increase in action potential frequency. A similar transient activation of outward current occurs in response to muscarine in a number of inexcitable secretary cells (Trautman & Marty, 1984;Horn & Marty, 1988;Gray, 1988;Maruyama, 1989). Despite the widespread occurrence of a hyperpolarizing response during the initial stages of secretagogue action, there is no clear functional role for this type of effect in secretary cells (Petersen & Murayama, 1984).…”

mentioning

confidence: 99%

“…Although our results cannot exclude the possibility that a critical dialysissensitive component is slowly lost during our recordings, the fact that the ability of muscarine to produce elevations of cytosolic Ca2+ undergoes some essentially irreversible deterioration even in non-dialysed cells implies that the loss of muscarinic sensitivity may reflect some intrinsic property of the muscarinic response, rather than a limitation of the experimental approach. Such desensitization is not uncharacteristic of muscarinic-mediated processes involving PLC (Llano & Marty, 1987;Maruyama, 1989). …”

mentioning

confidence: 99%

Effects of muscarine on single rat adrenal chromaffin cells.

Neely

Lingle

1992

The Journal of Physiology

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SUMMARY1. The action of muscarine on membrane currents and cytosolic calcium (Ca2") of dissociated rat adrenal chromaffin cells was investigated using standard whole-cell voltage-clamp techniques and microfluorimetry of unclamped single cells.2. In cells held at a constant holding potential negative to -40 mV, brief (5-10 s) applications of muscarine produced a transient activation of outward current. The activation of this current by muscarine also occurs in the presence of 5 mMCo2+. 4. The outward current activated by muscarine is transient even in the continuing presence of muscarine. Complete recovery between pairs of muscarine applications occurs over a 1-2 min period. If sufficient time was allowed for recovery between muscarine applications, the muscarine-activated outward current could be reliably elicited in dialysed cells for periods of 20-30 min.5. Voltage ramps were used to examine effects of muscarine on currents over a range of membrane potentials. Over all potentials, muscarine activates a relatively voltage-independent component which is blocked almost completely by 200 nMapamin and by 200 /LM-curare. At potentials negative to about -40 mV, the apaminand curare-sensitive current accounts for virtually all muscarine-activated current.This current appears to correspond to a Ca2+-activated, voltage-independent current found in these cells. Effects of muscarine on currents activated at potentials positive to 0 mV are complex. At potentials above 0 mV, muscarine can produce either an activation or an inhibition of outward current. The outward current activated at positive potentials was primarily voltage dependent and blocked by 1 mM-TEA. However, in some cells activation of voltage-dependent current was not observed and, in such cases, muscarine produced an inactivation of the voltage-dependent component of current. The inactivation of outward current could also be observed in the presence of 5 mMCo2± indicating that the inactivation does not occur secondarily to an effect of muscarine on Ca2+ current. The possibility is discussed that the

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Activation and desensitization mechanisms of muscarinic current response in single pancreatic acinar cells of rats.

Cited by 41 publications

References 32 publications

Protein kinase C‐mediated desensitization of the muscarinic response in rat lacrimal gland cells.

Protein kinase C‐mediated desensitization of the muscarinic response in rat lacrimal gland cells.

The role of protein kinase C in the desensitization of rat pancreatic islets to cholinergic stimulation

Effects of muscarine on single rat adrenal chromaffin cells.

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