Phosphatidylinositol 4,5-Bisphosphate Modifies Tubulin Participation in Phospholipase Cβ<sub>1</sub>Signaling

Popova, J.; Greene, Arin K.; Wang, Jia; Rasenick, Mark M.

doi:10.1523/jneurosci.22-05-01668.2002

Cited by 44 publications

(40 citation statements)

References 70 publications

(95 reference statements)

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“…However, microtubule is a cytosolic structure protein, and PLD 2 a membrane-bound protein. Although, membrane-and phospholipid-associated tubulin have been reported (55)(56)(57), it appears that this membrane tubulin is similar to the monomeric form (55,57,59). This notion is supported by observations of the COS-7 cells treated with the microtubule stability regulating pharmacological agents nocodazole and Taxol.…”

Section: Figmentioning

confidence: 86%

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Chae

Lee

et al. 2005

Journal of Biological Chemistry

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Mammalian phospholipase D (PLD) is considered a key enzyme in the transmission signals from various receptors including muscarinic receptors. PLD activation is a rapid and transient process, but a negative regulator has not been found that inhibits signal-dependent PLD activation. Here, for the first time, we report that tubulin binding to PLD 2 is an inhibition mechanism for muscarinic receptor-linked PLD 2 activation. Tubulin was identified in an immunoprecipitated PLD 2 complex from COS-7 cells by peptide mass fingerprinting. The direct interaction between PLD 2 and tubulin was found to be mediated by a specific region of PLD 2 (amino acids 476 -612). PLD 2 was potently inhibited (IC 50 <10 nM) by tubulin binding in vitro. In cells, the interaction between PLD 2 and tubulin was increased by the microtubule disrupting agent nocodazole and reduced by the microtubule stabilizing agent Taxol. Moreover, PLD 2 activity was found to be inversely correlated with the level of monomeric tubulin. In addition, we found that interaction with and the inhibition of PLD 2 by monomeric tubulin is important for the muscarinic receptor-linked PLD signaling pathway. Interaction between PLD 2 and tubulin was increased only after 1-2 min of carbachol stimulation when carbachol-stimulated PLD 2 activity was decreased. The expression of the tubulin binding region of PLD 2 blocked the later decrease in carbachol-induced PLD activity by masking tubulin binding. Taken together, these results indicate that an increase in local membrane monomeric tubulin concentration inhibits PLD 2 activity, and provides a novel mechanism for the inhibition of muscarinic receptor-induced PLD 2 activation by interaction with tubulin. Mammalian phospholipase D (PLD)1 hydrolyzes membrane phosphatidylcholine to generate phosphatidic acid and choline. PLD activity is dramatically activated in response to a variety of signals, including hormones, neurotransmitters, and growth factors (1). PLD products, phosphatidic acid itself or the hydrolyzed product diacylglycerol, have been known to act as intracellular lipid second messengers and to be involved in multiple physiological events, such as, the promotion of mitogenesis, stimulation of respiratory bursts, secretory processes, and actin cytoskeletal reorganization (2-7). Therefore, signal-dependent PLD activity must be tightly controlled in cells.Many reports have been issued about the mechanisms of receptor-mediated PLD activation. Although the mammalian PLD isozymes, PLD 1 and PLD 2 , have some different regulatory properties, in general, agonist-induced PLD is activated by various protein kinases, including protein kinase C, proteintyrosine kinase, and the MAP kinase family, in addition to small G proteins of the ARF, Rho, and Ras families (8 -13). The signal-dependent activation of PLD is rapid and transient. Although, the activation kinetics depend on the stimulus and cell type, the PLD signal is usually diminished within 10 min (14). However, the mechanisms involved in PLD signal inhibition remain unknow...

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Section: Figmentioning

confidence: 86%

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Chae

Lee

et al. 2005

Journal of Biological Chemistry

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“…Although transactivation seems pertinent to the regulation of adenylyl cyclase or phospholipase C by tubulin (16,20), its role in regulation of microtubule dynamics is unknown. Nevertheless, it is noteworthy that activation of G i ␣ and G s ␣ has been linked to a rapid increase in microtubule depolymerization (29,30).…”

Section: Discussionmentioning

confidence: 99%

A Specific Domain of Giα Required for the Transactivation of Giα by Tubulin Is Implicated in the Organization of Cellular Microtubules

Chen

Skiba

et al. 2003

Journal of Biological Chemistry

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␣ subunits bind tubulin with high affinity, whereas transducin (G t ␣) does not. The interaction between tubulin and G␣, which also involves the direct transfer of GTP from tubulin to G␣ (transactivation), is not yet fully understood. This study, using chimeras of G i ␣ and G t ␣, showed that the G i ␣ (215-295) segment converted G t ␣ to bind to tubulin and this chimera (chimera 1) could be transactivated by tubulin. Insertion of G t ␣ (237-270) into chimera 1 to form chimera 2 resulted in a protein that, like G t ␣, did not bind tubulin. Thus, it was thought that the G i ␣ (237-270) domain was essential to modulate the binding of G i ␣ 1 to tubulin. Surprisingly, when domain (237-270) of G i ␣ was replaced by G t ␣ (237-270) to form chimera 3, the chimera bound to tubulin with a similar affinity (K D Х120 nM) as wild-type G i ␣ 1 . However, even though chimera 3 displayed normal GTP binding, it was not transactivated by GTP-tubulin. Furthermore, when these chimeras were expressed in COS-1 cells, cellular processes in cells overexpressing G i ␣ 1 or chimera 1 were more abundant and longer than those in native cells. G␣ was seen throughout the length of the process. Morphology of cells expressing chimera 2 was identical to controls. Consistent with the role of Chimera 3 as a "dominant negative" G␣, cells transfected with chimera 3 had only few truncated processes. This study demonstrates that although G i ␣ (237-270) is not obligatory for the binding of G i ␣ to tubulin, it is crucial for the transactivation of G␣ by tubulin. These results also suggest that the transactivation of G␣ by tubulin may play an important role in modulating microtubule organization and cell morphology.G proteins act as intracellular transducers to propagate a variety of signals across the plasma membrane. Due to their interaction with transmembrane receptors and lipid modification, G proteins are usually associated with the plasma membrane. Recently, increasing evidence has emerged that G proteins are also present at intracellular areas such as Golgi apparatus, endoplasmic reticulum, cytoskeleton, and even the nucleus (1-5). Moreover, some studies have also shown that activated G␣s can be released from the plasma membrane to the cytoplasm (6 -9). Thus, it is possible that G proteins exist in several different cellular locations and play roles in various physiologic processes.Microtubules, a major component of the cytoskeleton, are involved in many cellular functions including chromosome movements during mitosis, intracellular transport, and the modulations of cell morphology. The biological function of microtubules is based, in significant part, on the ability of tubulin to polymerize and depolymerize. A heterodimer of ␣-and ␤-tubulin is the basic building block of microtubules. Tubulin is a GTP-binding protein, two GTP molecules are bound noncovalently in exchangeable (E-site on ␤-tubulin) and nonexchangeable (N-site on ␣-tubulin) sites. Both G␣ subunits and tubulin have intrinsic GTPase activity but that of tubulin is activated durin...

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“…It is known that Gsα proteins in concert with tubulin promote GTPase activity and increase the dynamical behavior of MTs (Wang, 1991;Layden, 2008). Tubulin activates signal transduction in 5-HT receptors coupled to protein Gq/11α through a direct transfer of GTP from tubulin to Gq/11α (Popova, 2002).…”

Section: Quantitative and Quantum Approaches To Psychopathologymentioning

confidence: 99%

Consciousness and Hallucinations: Molecular Considerations and Theoretical Questions

et al. 2011

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This paper focuses on aspects of quantitative and quantum approaches to the phenomenon of hallucination. Consideration is given to the molecular hypothesis of consciousness, to consciousness as perception of the self, and to hallucinatory perception as consciousness detached from reality. The possible transitional sequence viscosity of membrane / GS-alpha protein / tubulin in altered states of consciousness is explored.

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Phosphatidylinositol 4,5-Bisphosphate Modifies Tubulin Participation in Phospholipase Cβ₁Signaling

Cited by 44 publications

References 70 publications

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

A Specific Domain of Giα Required for the Transactivation of Giα by Tubulin Is Implicated in the Organization of Cellular Microtubules

Consciousness and Hallucinations: Molecular Considerations and Theoretical Questions

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Phosphatidylinositol 4,5-Bisphosphate Modifies Tubulin Participation in Phospholipase Cβ1Signaling

Cited by 44 publications

References 70 publications

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

A Specific Domain of Giα Required for the Transactivation of Giα by Tubulin Is Implicated in the Organization of Cellular Microtubules

Consciousness and Hallucinations: Molecular Considerations and Theoretical Questions

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Phosphatidylinositol 4,5-Bisphosphate Modifies Tubulin Participation in Phospholipase Cβ₁Signaling