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The Journal of Neuroscience, March 1, 2002, 22(5):1668-1678

Phosphatidylinositol 4,5-Bisphosphate Modifies Tubulin Participation in Phospholipase C₁ Signaling

Juliana S. Popova¹, Arin K. Greene¹, Jia Wang¹, and Mark M. Rasenick^{1, 2}

Departments of ¹ Physiology and Biophysics and ² Psychiatry, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612-7342

Tubulin forms the microtubule and regulates certain G-protein-mediated signaling pathways. Both functions rely on the GTP-binding properties of tubulin. Signal transduction through Gq-regulated phospholipase C₁ (PLC₁) is activated by tubulin through a direct transfer of GTP from tubulin to Gq. However, at high tubulin concentrations, inhibition of PLC₁ is observed. This report demonstrates that tubulin inhibits PLC₁ by binding the PLC₁ substrate phosphatidylinositol 4,5-bisphosphate (PIP₂). Tubulin binding of PIP₂ was specific, because PIP₂ but not phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-phosphate, phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, or inositol 1,4,5-trisphosphate inhibited microtubule assembly. PIP₂ did not affect GTP binding or GTP hydrolysis by tubulin. Muscarinic agonists promoted microtubule depolymerization and translocation of tubulin to the plasma membrane. PIP₂ augmented this process in both Sf9 cells, containing a recombinant PLC₁ pathway, and SK-N-SH neuroblastoma cells. Colocalization of tubulin and PIP₂ at the plasma membrane was demonstrated with confocal laser immunofluorescence microscopy. Although tubulin bound to both Gq and PLC₁, PIP₂ facilitated the interaction between tubulin and PLC₁ but not that between tubulin and Gq. However, PIP₂ did augment formation of tubulin-Gq-PLC₁ complexes. Subsequent to potentiating PLC₁ activation, sustained agonist-independent membrane binding of tubulin at PIP₂- and PLC₁-rich sites appeared to inhibit Gq coupling to PLC₁. Furthermore, colchicine increased membrane-associated tubulin and also inhibited PLC₁ activity in SK-N-SH cells. Thus, tubulin, depending on local membrane concentration, may serve as a positive or negative regulator of phosphoinositide hydrolysis. Rapid changes in membrane lipid composition or in the cytoskeleton might modify neuronal signaling through such a mechanism.

Key words: tubulin; phospholipid; microtubule; cytoskeleton; G-protein; phospholipase C; muscarinic receptor; acetylcholine; G-protein-coupled receptor; calcium; protein kinase C

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2251668-11$05.00/0

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