Bradykinin inhibits cyclic AMP accumulation in D384-human astrocytoma cells via a calcium-dependent inhibition of adenylyl cyclase

doi:10.1016/0898-6568(93)90018-H

Cellular Signalling

Volume 5, Issue 3, May 1993, Pages 279-288

https://doi.org/10.1016/0898-6568(93)90018-H Get rights and content

Abstract

Bradykinin causes a concentration-dependent, transient rise in intracellular Ca²⁺ and a sustained inhibition of forskolin-, dopamine- and 5′-N-ethyl-carboxamidoadenosine (NECA)-stimulated cAMP accumulation in D384 astrocytoma cells. Chelation of intracellular calcium abolished bradykinin's inhibitory effect on cAMP accumulation. Chelating extracellular Ca²⁺ did not block the initial, but eliminated the sustained inhibition of cAMP accumulation. Increasing Ca²⁺ influx by calcium ionophore A23187 caused a concentration-dependent inhibition of stimulated cAMP accumulation. A hydroquinone derivative 2,5-di(tert-butyl)-1,4-benzohydroquinone (tBuBHQ), which inhibits microsomal Ca²⁺ sequestration, did not mimic the effect of bradykinin, although it increased [Ca²⁺]_i even more than A23187 did. The inhibitory effect of bradykinin was not mediated by Ca²⁺/CaM-dependent stimulation of phosphodiesterase (PDE). Forskolin-stimulated adenylyl cyclase activity was inhibited by Ca²⁺ (10⁻⁷ to 10⁻³ M), both in ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) washed and native D384 plasma membranes. This effect was not altered by calmodulin (CaM) or CaM-antagonists. Bradykinin treatment, which attenuates cAMP accumulation in intact cells, did not do so in plasma membranes. These findings suggest that bradykinin-induced inhibition of cAMP formation in D384 cells requires mobilization of [Ca²⁺]_i and subsequent entry of Ca²⁺ which directly interacts with a component of the adenylyl cyclase system.

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Rhythmic expression of adenylyl cyclase VI contributes to the differential regulation of serotonin N-acetyltransferase by bradykinin in rat pineal glands
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The rhythmic nocturnal production of melatonin in pineal glands is controlled by the periodic release of norepinephrine from the superior cervical ganglion. Norepinephrine binds to the β-adrenergic receptor and stimulates an increase in intracellular cAMP levels, leading to the transcriptional activation of serotonin N-acetyltransferase, which in turn promotes melatonin production. In the present study, we report that bradykinin inhibits basal- and forskolin-stimulated adenylyl cyclase activity, norepinephrine-induced cAMP generation, and N-acetyltransferase expression in a calcium-dependent manner. These effects were blocked by pretreatment with U73122 (a selective phospholipase C inhibitor), and 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (a Ca²⁺ chelator), but not pertussis toxin. The calcium ionophore, ionomycin, inhibited isoproterenol-mediated cAMP generation, similar to bradykinin. Interestingly, the inhibitory effect of bradykinin was evident only during the daytime. At midday, bradykinin inhibited the cAMP level by ∼50% but markedly stimulated cAMP production (by ∼50%) at night. Northern blotting and immunoblotting data disclosed circadian expression of calcium-inhibitable adenylyl cyclase type 6. Expression of adenylyl cyclase type 6 was maximal at Zeitgeber Time (ZT) 01 and very low at ZT 13. Our results suggest that bradykinin-induced calcium inhibits melatonin synthesis through the mediation of adenylyl cyclase type 6 expression.
Dependence of the Ca2+-inhibitable adenylyl cyclase of C6-2B glioma cells on capacitative Ca2+ entry
1998, Journal of Biological Chemistry
The ability of adenylyl cyclases to be regulated by physiological transitions in Ca²⁺ provides a key point for integration of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) and cAMP signaling. Ca²⁺-sensitive adenylyl cyclases, whether endogenously or heterologously expressed, require Ca²⁺ entry for their regulation, rather than Ca²⁺ release from intracellular stores (Chiono, M., Mahey, R., Tate, G., and Cooper, D. M. F. (1995) J. Biol. Chem. 270, 1149–1155; Fagan, K., Mahey, R., and Cooper, D. M. F. (1996) J. Biol. Chem. 271, 12438–12444). The present study compared the regulation by capacitative Ca²⁺ entry versusionophore-mediated Ca²⁺ entry of an endogenously expressed Ca²⁺-inhibitable adenylyl cyclase in C6–2B cells. Even in the face of a dramatic [Ca²⁺]_i rise generated by ionophore, Ca²⁺ entry via capacitative Ca²⁺entry channels was solely responsible for the regulation of the adenylyl cyclase. Selective efficacy of BAPTA over equal concentrations of EGTA in blunting the regulation of the cyclase by capacitative Ca²⁺ entry defined the intimacy between the adenylyl cyclase and the capacitative Ca²⁺ entry sites. This association could not be impaired by disruption of the cytoskeleton by a variety of strategies. These results not only establish an intimate spatial relationship between an endogenously expressed Ca²⁺-inhibitable adenylyl cyclase with capacitative Ca²⁺ entry sites but also provide a physiological role for capacitative Ca²⁺ entry other than store refilling.
Capacitative Ca2+ entry exclusively inhibits cAMP synthesis in C6-2B glioma cells. Evidence that physiologically evoked Ca2+ entry regulates Ca2+-inhibitable adenylyl cyclase in non-excitable cells
1995, Journal of Biological Chemistry
Elevation of cytosolic free Ca ²⁺ inhibits the type VI adenylyl cyclase that predominates in C6-2B cells. However, it is not known whether there is any selective requirement for Ca ²⁺ entry or release for inhibition of cAMP accumulation to occur. In the present study, the effectiveness of intracellular Ca ²⁺ release evoked by three independent methods (thapsigargin, ionomycin, and UTP) was compared with the capacitative Ca ²⁺ entry that was triggered by these treatments. In each situation, only Ca ²⁺ entry could inhibit cAMP accumulation (La ³⁺ ions blocked the effect); Ca ²⁺ release, which was substantial in some cases, was without effect. A moderate inhibition, as was elicited by a modest degree of Ca ²⁺ entry, could be rendered substantial in the absence of phosphodiesterase inhibitors. Such conditions more closely mimic the physiological situation of normal cells. These results are particularly significant, in demonstrating not only that Ca ²⁺ entry mediates the inhibitory effects of Ca ²⁺ on cAMP accumulation, but also that diffuse elevations in [Ca ²⁺] _i are ineffective in modulating cAMP synthesis. This property suggests that, as with certain Ca ²⁺-sensitive ion channels, Ca ²⁺-sensitive adenylyl cyclases may be functionally colocalized with Ca ²⁺ entry channels.
Ca2+-sensitive adenylyl cyclases
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Modulation of nerve and glial function by adenosine-role in the development of ischemic damage
1994, International Journal of Biochemistry
Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A₁ receptor enhances the K⁺ and Cl conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca²⁺ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A₁ receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca²⁺ channels. The A₁ and A₂ receptors, coupled to G₁/G_o and G_s proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A₁ receptor may mimic metabotropic receptor stimulation in activating intracellular Ca²⁺ mobilization and PKC. A₂ receptor mediated cAMP formation is depressed by high intracellular Ca²⁺ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A₁ and A₂. receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.
Adenosine A<inf>2B</inf> receptor signalling is altered by stimulation of bradykinin or interleukin receptors in astroglioma cells
1994, Neurochemistry International
The human astroglioma cell D384 possesses adenosine A_2B receptors coupled to the formation of cyclic AMP. These cells also possess bradykinin B₂ receptors coupled to phospholipase C and consequent increases in intracellular calcium and protein kinase C. Interleukin 1β causes an increase in c-fos, AP-1 transcriptional activity and an increased expression of several genes including NGF, but the initial signalling events are unknown. Bradykinin causes a rapid decrease in A_2B receptor mediated cAMP formation, via a mechanism that involves calcium, but not cGMP, and appears to depend upon a direct decrease in adenylyl cyclase, II-1β causes a slowly developing (18–24 h) increase in A_2B receptor signalling. The results indicate that adenosine effects in glial cells, believe to be important in neuroprotection, are modified in the short and long-term by inflammatory mediators.

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Cellular Signalling

Abstract

References (37)

Expl Cell Res.

Endocrinology

Cell Calcium

FEBS Lett.

Molec. Pharmac.

J. biol. Chem.

Eur. J. Biochem.

Naunyn-Schmiedeberg's Arch. Pharmac.

Acta. physiol. scand.

Neurochem. Int.

J. cell. Biochem.

Biochemistry

Cited by (18)

Rhythmic expression of adenylyl cyclase VI contributes to the differential regulation of serotonin N-acetyltransferase by bradykinin in rat pineal glands

Dependence of the Ca<sup>2+</sup>-inhibitable adenylyl cyclase of C6-2B glioma cells on capacitative Ca<sup>2+</sup> entry

Capacitative Ca<sup>2+</sup> entry exclusively inhibits cAMP synthesis in C6-2B glioma cells. Evidence that physiologically evoked Ca<sup>2+</sup> entry regulates Ca<sup>2+</sup>-inhibitable adenylyl cyclase in non-excitable cells

Ca<sup>2+</sup>-sensitive adenylyl cyclases

Modulation of nerve and glial function by adenosine-role in the development of ischemic damage

Adenosine A<inf>2B</inf> receptor signalling is altered by stimulation of bradykinin or interleukin receptors in astroglioma cells