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E-Conference: Defining Calcium Entry Signals

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GTP-gamma(S), small G-proteins, and SOC- Any connection?

3 June 2004

Randen L. Patterson

One of most fascinating observations during my career as a graduate student learning about calcium entry was that GTP-gamma(S) was capable of inhibiting SOC. I was amazed by this, because at the time (1997) there were very few things that were capable of inhibiting SOC (which is still true today). Obviously, GTP-gamma(S) inhibits essentially all G-proteins at some level, so this is equivalent to hitting the cell with a sledgehammer. BUT, G-proteins are also the major component of most trafficking systems. It is surprising that this line of research has not progressed significantly since 1997. Small G-proteins such as Rac, Rho, and Cdc42 are all directly linked to intracellular trafficking, as well as cytoskeletal remodeling. Cytoskeletal remodeling has also been effective in disrupting SOC, as reported by numerous laboratories.

This begs the question, are small G-proteins an avenue for mapping the activation of SOC?

Yao et al (Cell 1999) demonstrated that SOC could be inhibited by constitutively active Rho, and potentiated when Rho was inhibited. Consistent with this idea, Ito et al (Am J Respir Cell Mol Biol. 2002) and Ghisdal et al (J. Physiol 2003) performed studies which supported these findings. They demonstrated that noradreniline activation of agonist-induced calcium entry required rho-dependent kinase activation, but SOC did not. Furthermore, TRPC1 association with the IP3-receptor has been demonstrated to be regulated by rhoA in endothelial cells (Mehta et al, JBC 2003).

From this data, it seems reasonable that Rho signaling pathways are a key regulator of calcium entry, and perhaps are a discriminating factor between agonist-induced calcium entry and calcium entry induced by pathophysiological store depletion.

Is Rho activity down -regulated in response to calcium store depletion? If so, could this be used as a way of increasing the protein(s) responsible for SOC in the plasma membrane, which might be identified using S-35 methionine pulse- chase experiments, or some other genomic approach? For example, the TG2 DDT cell line which was developed to be resistant to thapsigargin, and has constitutive SOC. Does this cell line have depressed rho activity versus control?

It is also surprising that the TG2 DDT cell line has never been analyzed by microarray versus the control cell line. This might provide candidate genes which could be tested for SOC activity.

Finally, could a trafficking event indeed be why SOC is slow to activate after calcium store depletion? Further investigation of the Rho pathway will likely shed new light on the activation mechanism of not only SOC, but agonist-mediated calcium entry as well.

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