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      Bradykinin Induces a Calcium-Store- Dependent Calcium Influx in Mouse Mesangial Cells

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          Bradykinin (BK) elicits extracellular-dependent [Ca<sup>2+</sup>]<sub>i</sub> elevations in mouse mesangial cells (MMC) that are not blocked by verapamil, nifedipine, L-nicardipine, NiCl<sub>2</sub>, or LaCl<sub>3</sub>. The aim of the present study was to evaluate the mechanisms involved in calcium influx induced by BK in MMC. [Ca<sup>2+</sup>]<sub>i</sub> was analyzed through spectrofluorometry employing fura-2-AM, and the data were expressed as [Ca<sup>2+</sup>]<sub>i </sub>obtained/[Ca<sup>2+</sup>]<sub>i </sub>basal ratio. Heparin (IP<sub>3</sub>, a receptor antagonist) almost abolished the effects of BK in MMC (1.85 ± 0.15 vs. 1.13 ± 0.02, n = 4, p = 0.001). Following external and intracellular calcium store depletion, BK’s effect was absent even after successful extracellular calcium replenishment. ML-7 (a myosin light chain kinase inhibitor) blocked responses to thapsigargin (2.62 ± 0.13 vs. 1.11 ± 0.04, n = 4, p < 0.001), but not those of BK (6.51 ± 0.39, n = 6, vs. 5.86 ± 1.17, n = 4, p = 0.39). On the other hand, genistein (a tyrosine kinase inhibitor) was able to inhibit thapsigargin (3.12 ± 0.22, n = 5, vs. 1.28 ± 0.16, n = 4, p < 0.001) as well as BK responses (6.46 ± 0.66 vs. 2.89 ± 0.61, n = 4, p < 0.05). Econazole (a P-450 monooxygenase inhibitor) inhibited the responses to both thapsigargin (3.45 ± 0.16 vs. 1.03 ± 0.03, n = 4, p < 0.001) and BK (6.49 ± 0.83, n = 6, vs. 1.17 ± 0.08, n = 4, p = 0.01). Finally, responses to BK were not affected by indomethacin (6.69 ± 0.66 vs. 6.57 ± 0.87, n = 4, p = 0.916). Thus, BK promotes an IP<sub>3</sub>-sensitive store-dependent calcium influx in MMC. This phenomenon seems to involve tyrosine kinase and P-450 monooxygenase products in its transduction pathway.

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          Most cited references 10

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          Calcium--a life and death signal.

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            Regulation by cAMP-dependent protein kinease of a G-protein-mediated phospholipase C.

             M. Liu,  D. Simon (1996)
            The heterotrimeric G proteins mediate a variety of cellular processes by coupling transmembrane receptors to different effector molecules, including adenylyl cyclases and inositol-phospholipid-specific phospholipase C (PLC)1-3. Activation of adenylyl cyclases results in the production of cyclic AMP and activation of cAMP-dependent protein kinase (PKA). Phospholipase C catalyses the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdInsP2) to generate diacylglycerol and inositol-1,4,5-triphosphate (InsP2), leading to the activation of protein kinase C (PKC) and the mobilization of intracellular calcium. The various PLC isoforms appear to be activated by different receptors, and in some cases by different G-protein components. There are four well-characterized forms of PLC-beta and all of them are activated to various extents by the G alpha q family of G proteins. Specific activation of PLC isoforms beta 2 and beta 3 by G-protein beta gamma subunits has also been reported. Although it has been suggested that PLC activity might be modulated by the adenylyl cyclase pathway, no clear link has been established between the two pathways. Here we report that cAMP-dependent protein kinase specifically inhibits G beta gamma-activated PLC-beta 2 activity but not that of the G alpha-activated PLC isoforms, and that the effect of PKA is not mimicked by PKC isozymes. Furthermore, we show that PKA directly phosphorylates serine residues of the PLC-beta 2 protein both in vivo and in vitro. Our results provide an insight into the specificity and nature of the crosstalk between the two G-protein-coupled signal transduction pathways.
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              Functional co-localization of transfected Ca(2+)-stimulable adenylyl cyclases with capacitative Ca2+ entry sites.

              Three adenylyl cyclases (ACI, ACIII, and ACVIII) have been described, which are putatively Ca(2+)-stimulable, based on in vitro assays. However, it is not clear that these enzymes can be regulated by physiological rises in [Ca2+]i when expressed in intact cells. Furthermore, it is not known whether transfected adenylyl cyclases might display the strict requirement for capacitative Ca2+ entry that is shown by the Ca(2+)-inhibitable ACVI, which is indigenous to C6-2B glioma cells (Chiono, M., Mahey, R., Tate, G., and Cooper, D. M. F. (1995) J. Biol. Chem. 270, 1149-1155). In the present study, ACI, ACIII, and ACVIII were heterologously expressed in HEK 293 cells, and conditions were devised that distinguished capacitative Ca2+ entry from both internal release and nonspecific elevation in [Ca2+]i around the plasma membrane. Remarkably, not only were ACI and ACVIII largely insensitive to Ca2+ release from stores, but they were robustly stimulated only by capacitative Ca2+ entry and not al all by a substantial increase in [Ca2+]i at the plasma membrane elicited by ionophore. (ACIII, reflecting its feeble in vitro sensitivity to Ca2+, was unaffected by any [Ca2+]i rise.) These results suggest a quite unsuspected, essential association of Ca(2+)-sensitive adenylyl cyclases with capacitative Ca2+ entry sites, even when expressed heterologously.

                Author and article information

                S. Karger AG
                June 2002
                03 June 2002
                : 91
                : 2
                : 308-315
                aNephrology Division, Department of Medicine, Universidade Federal de São Paulo, and bPharmacology Division, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
                58409 Nephron 2002;91:308–315
                © 2002 S. Karger AG, Basel

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                Figures: 5, References: 28, Pages: 8
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