Abstract
The data presented in this paper suggest that we have identified several key steps in the sequence of events occurring between binding of growth factors to their surface receptors and the activation of the Na+-H+ exchange system. Our current working model is shown in Fig. 4. The initial step after binding of peptide rnitogens appears to be the release of inositol trisphosphate from membrane pools of phosphatidylinositol 4′,5′-bisphosphate (PIP2). This inositol trisphosphate then interacts with an internal Ca2+ storage site to mobilize intracellular Ca2+ thereby elevating the intracellular Ca2+ activity. An elevation of Ca2+ activity then acts through a Ca2+-dependent regulatory protein which somehow leads to the activation of the Na+-H+ exchanger. The current data are most consistent with calmodulin being the Ca2+-dependent regulatory protein involved in the activation process; however, the synergism between A23187 and TPA suggests that protein kinase C may also play some role in this process, although the lack of effect of TPA alone suggests that activation of protein kinase C is not a sufficient stimulus for activation of the Na+-H+ exchanger. The current data on phospholipase involvement are most readily explained on the basis of a mitogen activation of phospholipase C activity which acts to release inositol trisphosphate, which in turn mobilizes intracellular Ca2+. However, it should be pointed out that in general the compounds (mepacrine and melittin) that we have used to perturb phospholipase activity have been traditionally thought of as interacting with phospholipase A2 instead of phospholipase C. However, recent results in our laboratory indicate that mepacrine will inhibit the mitogen-induced release of inositol trisphosphate and that melittin will stimulate its release in the absence of mitogens (Jamieson and Villereal, in preparation), suggesting either that these compounds do interact with phospholipase C or that there is some regulation of phospholipase C activity by the breakdown products of phoshpolipase A2 activity. A report from Majerus's laboratory indicating that mepacrine directly inhibits phospholi pase C activity suggests that effects of mepacrine in the HSWP cell are probably at the level of phospholipase C. In the summary scheme (Fig. 4), the possibility that the release of inositol trisphosphate could be potentiated via the stimulation of a kinase activity which would increase the substrate (PIP2) available to phospholipase C is presented. This possibility is suggested by the observation that certain oncogene products with kinase activity can phosphorylate phosphatidylinositol to the polyphosphorylated forms (Sugimoto et al., 1984; Macara et al., 1984).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 175-192 |
| Number of pages | 18 |
| Journal | Current Topics in Membranes and Transport |
| Volume | 26 |
| Issue number | C |
| DOIs | |
| State | Published - 1986 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
Chapter 10 Mechanisms of Growth Factor Stimulation of Na+-H+ Exchange in Cultured Fibroblasts. / Villereal, Mitchel L.; Muldoon, Leslie; Vicentini, Lucia M.; Jamieson, Gordon A.; Owen, Nancy E.
In: Current Topics in Membranes and Transport, Vol. 26, No. C, 1986, p. 175-192.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chapter 10 Mechanisms of Growth Factor Stimulation of Na+-H+ Exchange in Cultured Fibroblasts
AU - Villereal, Mitchel L.
AU - Muldoon, Leslie
AU - Vicentini, Lucia M.
AU - Jamieson, Gordon A.
AU - Owen, Nancy E.
PY - 1986
Y1 - 1986
N2 - The data presented in this paper suggest that we have identified several key steps in the sequence of events occurring between binding of growth factors to their surface receptors and the activation of the Na+-H+ exchange system. Our current working model is shown in Fig. 4. The initial step after binding of peptide rnitogens appears to be the release of inositol trisphosphate from membrane pools of phosphatidylinositol 4′,5′-bisphosphate (PIP2). This inositol trisphosphate then interacts with an internal Ca2+ storage site to mobilize intracellular Ca2+ thereby elevating the intracellular Ca2+ activity. An elevation of Ca2+ activity then acts through a Ca2+-dependent regulatory protein which somehow leads to the activation of the Na+-H+ exchanger. The current data are most consistent with calmodulin being the Ca2+-dependent regulatory protein involved in the activation process; however, the synergism between A23187 and TPA suggests that protein kinase C may also play some role in this process, although the lack of effect of TPA alone suggests that activation of protein kinase C is not a sufficient stimulus for activation of the Na+-H+ exchanger. The current data on phospholipase involvement are most readily explained on the basis of a mitogen activation of phospholipase C activity which acts to release inositol trisphosphate, which in turn mobilizes intracellular Ca2+. However, it should be pointed out that in general the compounds (mepacrine and melittin) that we have used to perturb phospholipase activity have been traditionally thought of as interacting with phospholipase A2 instead of phospholipase C. However, recent results in our laboratory indicate that mepacrine will inhibit the mitogen-induced release of inositol trisphosphate and that melittin will stimulate its release in the absence of mitogens (Jamieson and Villereal, in preparation), suggesting either that these compounds do interact with phospholipase C or that there is some regulation of phospholipase C activity by the breakdown products of phoshpolipase A2 activity. A report from Majerus's laboratory indicating that mepacrine directly inhibits phospholi pase C activity suggests that effects of mepacrine in the HSWP cell are probably at the level of phospholipase C. In the summary scheme (Fig. 4), the possibility that the release of inositol trisphosphate could be potentiated via the stimulation of a kinase activity which would increase the substrate (PIP2) available to phospholipase C is presented. This possibility is suggested by the observation that certain oncogene products with kinase activity can phosphorylate phosphatidylinositol to the polyphosphorylated forms (Sugimoto et al., 1984; Macara et al., 1984).
AB - The data presented in this paper suggest that we have identified several key steps in the sequence of events occurring between binding of growth factors to their surface receptors and the activation of the Na+-H+ exchange system. Our current working model is shown in Fig. 4. The initial step after binding of peptide rnitogens appears to be the release of inositol trisphosphate from membrane pools of phosphatidylinositol 4′,5′-bisphosphate (PIP2). This inositol trisphosphate then interacts with an internal Ca2+ storage site to mobilize intracellular Ca2+ thereby elevating the intracellular Ca2+ activity. An elevation of Ca2+ activity then acts through a Ca2+-dependent regulatory protein which somehow leads to the activation of the Na+-H+ exchanger. The current data are most consistent with calmodulin being the Ca2+-dependent regulatory protein involved in the activation process; however, the synergism between A23187 and TPA suggests that protein kinase C may also play some role in this process, although the lack of effect of TPA alone suggests that activation of protein kinase C is not a sufficient stimulus for activation of the Na+-H+ exchanger. The current data on phospholipase involvement are most readily explained on the basis of a mitogen activation of phospholipase C activity which acts to release inositol trisphosphate, which in turn mobilizes intracellular Ca2+. However, it should be pointed out that in general the compounds (mepacrine and melittin) that we have used to perturb phospholipase activity have been traditionally thought of as interacting with phospholipase A2 instead of phospholipase C. However, recent results in our laboratory indicate that mepacrine will inhibit the mitogen-induced release of inositol trisphosphate and that melittin will stimulate its release in the absence of mitogens (Jamieson and Villereal, in preparation), suggesting either that these compounds do interact with phospholipase C or that there is some regulation of phospholipase C activity by the breakdown products of phoshpolipase A2 activity. A report from Majerus's laboratory indicating that mepacrine directly inhibits phospholi pase C activity suggests that effects of mepacrine in the HSWP cell are probably at the level of phospholipase C. In the summary scheme (Fig. 4), the possibility that the release of inositol trisphosphate could be potentiated via the stimulation of a kinase activity which would increase the substrate (PIP2) available to phospholipase C is presented. This possibility is suggested by the observation that certain oncogene products with kinase activity can phosphorylate phosphatidylinositol to the polyphosphorylated forms (Sugimoto et al., 1984; Macara et al., 1984).
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U2 - 10.1016/S0070-2161(08)60732-7
DO - 10.1016/S0070-2161(08)60732-7
M3 - Article
AN - SCOPUS:0006689152
VL - 26
SP - 175
EP - 192
JO - Current Topics in Membranes
JF - Current Topics in Membranes
SN - 1063-5823
IS - C
ER -