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      Dual Regulation of Calcium Mobilization by Inositol 1,4,5-Trisphosphate in a Living Cell

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          Abstract

          Changes in cytosolic free calcium ([Ca 2+] i) often take the form of a sustained response or repetitive oscillations. The frequency and amplitude of [Ca 2+] i oscillations are essential for the selective stimulation of gene expression and for enzyme activation. However, the mechanism that determines whether [Ca 2+] i oscillates at a particular frequency or becomes a sustained response is poorly understood. We find that [Ca 2+] i oscillations in rat megakaryocytes, as in other cells, results from a Ca 2+-dependent inhibition of inositol 1,4,5-trisphosphate (IP 3)–induced Ca 2+ release. Moreover, we find that this inhibition becomes progressively less effective with higher IP 3 concentrations. We suggest that disinhibition, by increasing IP 3 concentration, of Ca 2+-dependent inhibition is a common mechanism for the regulation of [Ca 2+] i oscillations in cells containing IP 3-sensitive Ca 2+ stores.

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          Calcium--a life and death signal.

          M J Berridge, M Bootman, P. Lipp (1998)
          Article 0 comments Cited 317 times – based on 0 reviews     Review now
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            Calcium oscillations increase the efficiency and specificity of gene expression.

            R Dolmetsch, K. Xu, R Lewis (1998)
            Cytosolic calcium ([Ca2+]i) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells. Although Ca2+ is known to mediate a diverse array of cell functions, it is not known whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback control of [Ca2+]i. We have developed a Ca2+ clamp technique to investigate the roles of oscillation amplitude and frequency in regulating gene expression driven by the proinflammatory transcription factors NF-AT, Oct/OAP and NF-kappaB. Here we report that oscillations reduce the effective Ca2+ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, specificity is encoded by the oscillation frequency: rapid oscillations stimulate all three transcription factors, whereas infrequent oscillations activate only NF-kappaB. The genes encoding the cytokines interleukin (IL)-2 and IL-8 are also frequency-sensitive in a way that reflects their degree of dependence on NF-AT versus NF-kappaB. Our results provide direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+ signals that lead to gene expression and cell differentiation.
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              The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.

              E Boursier, D Toullec, P Pianetti … (1991)
              Staurosporine is the most potent inhibitor of protein kinase C (PKC) described in the literature with a half-maximal inhibitory concentration (IC50) of 10 nM. Nevertheless, this natural product is poorly selective when assayed against other protein kinases. In order to obtain specific PKC inhibitors, a series of bisindolylmaleimides has been synthesized. Structure-activity relationship studies allowed the determination of the substructure responsible for conferring high potency and lack of selectivity in the staurosporine molecule. Several aminoalkyl bisindolylmaleimides were found to be potent and selective PKC inhibitors (IC50 values from 5 to 70 nM). Among these compounds GF 109203X has been chosen for further studies aiming at the characterization of this chemical family. GF 109203X was a competitive inhibitor with respect to ATP (Ki = 14 +/- 3 NM) and displayed high selectivity for PKC as compared to five different protein kinases. We further determined the potency and specificity of GF 109203X in two cellular models: human platelets and Swiss 3T3 fibroblasts. GF 109203X efficiently prevented PKC-mediated phosphorylations of an Mr = 47,000 protein in platelets and of an Mr = 80,000 protein in Swiss 3T3 cells. In contrast, in the same models, the PKC inhibitor failed to prevent PKC-independent phosphorylations. GF 109203X inhibited collagen- and alpha-thrombin-induced platelet aggregation as well as collagen-triggered ATP secretion. However, ADP-dependent reversible aggregation was not modified. In Swiss 3T3 fibroblasts, GF 109203X reversed the inhibition of epidermal growth factor binding induced by phorbol 12,13-dibutyrate and prevented [3H] thymidine incorporation into DNA, only when this was elicited by growth promoting agents which activate PKC. Our results illustrate the potential of GF 109203X as a tool for studying the involvement of PKC in signal transduction pathways.
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                Author and article information

                Contributors
                :
                Dept. of Physiology, University of Connecticut Health Center, Farmington CT, 06030-3505.860-679-1269
                Journal
                Journal ID (nlm-ta): J Gen Physiol
                Title: The Journal of General Physiology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1295
                ISSN (Electronic): 1540-7748
                Publication date (Print): 1 April 2000
                Volume: 115
                Issue: 4
                Pages: 481-490
                Affiliations
                [a ]From the Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030-3505
                Article
                Publisher ID: 8090
                PMC ID: 2233754
                PubMed ID: 10736314
                SO-VID: 80f15168-df46-49cd-924e-e5eeb2135cdf
                Copyright © © 2000 The Rockefeller University Press
                History
                Date received : 29 September 1999
                Date revision requested : 22 February 2000
                Date accepted : 28 February 2000
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: pleckstrin,protein kinase c,platelets,ip3-5-phosphatase,megakaryocyte
                Data availability:
                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: pleckstrin, protein kinase c, platelets, ip3-5-phosphatase, megakaryocyte

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