The Chemical Biology of Phosphoinositide 3‐Kinases

Wymann, Matthias P.; Schultz, Carsten

doi:10.1002/cbic.201200089

Cited by 38 publications

(22 citation statements)

References 196 publications

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“…One note of caution when using these lipids is that they could in principle insert into all lipid bilayers and may thus not faithfully reproduce effects caused by the heterogeneous subcellular distribution typically observed for endogenous PIs. The major challenge in the synthesis of these lipids is that all negative charges on the inositol head-group must be neutralized in order to allow diffusion over cellular membranes [88]. However, membrane permeable analogs of several PIs have been synthesized and successfully used.…”

Section: Manipulating Phosphoinositide Levelsmentioning

confidence: 99%

Detection and manipulation of phosphoinositides

Idevall‐Hagren

Camilli

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Phosphoinositides (PIs) are minor components of cell membranes, but play key roles in cell function. Recent refinements in techniques for their detection, together with imaging methods to study their distribution and changes, have greatly facilitated the study of these lipids. Such methods have been complemented by the parallel development of techniques for the acute manipulation of their levels, which in turn allow bypassing the long-term adaptive changes implicit in genetic perturbations. Collectively, these advancements have helped elucidate the role of PIs in physiology and the impact of the dysfunction of their metabolism in disease. Combining methods for detection and manipulation enables the identification of specific roles played by each of the PIs and may eventually lead to the complete deconstruction of the PI signaling network. Here, we review current techniques used for the study and manipulation of cellular PIs and also discuss advantages and disadvantages associated with the various methods. This article is part of a Special Issue entitled Phosphoinositides.

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Section: Manipulating Phosphoinositide Levelsmentioning

confidence: 99%

Detection and manipulation of phosphoinositides

Idevall‐Hagren

Camilli

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Finally, a promising approach has been elaborated by Carsten Schultz and colleagues that developed very elegant strategies to introduce membrane-permeant versions of phosphoinositides into cells so that the lipid is released upon cleavage by cytosolic esterases (Laketa et al 2009;Mentel et al 2011). Such strategies, together with the development of novel chemical biology tools, offer promising new ways to study the function of membrane lipids (Riezman and Johnsson 2011;Wymann and Schultz 2012).…”

Section: Concluding Remarks and Future Challengesmentioning

confidence: 99%

Lipid Sorting and Multivesicular Endosome Biogenesis

Bissig

Grüenberg

2013

Cold Spring Harbor Perspectives in Biology

132

107

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Intracellular organelles, including endosomes, show differences not only in protein but also in lipid composition. It is becoming clear from the work of many laboratories that the mechanisms necessary to achieve such lipid segregation can operate at very different levels, including the membrane biophysical properties, the interactions with other lipids and proteins, and the turnover rates or distribution of metabolic enzymes. In turn, lipids can directly influence the organelle membrane properties by changing biophysical parameters and by recruiting partner effector proteins involved in protein sorting and membrane dynamics. In this review, we will discuss how lipids are sorted in endosomal membranes and how they impact on endosome functions.

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“…Therefore, techniques for rapid intervention into Pi concentrations and their dynamics are required. Unfortunately, with the exception of PI-3-kinase inhibitors (Wymann and Schultz, 2012), potent and specific pharmacological tools that target PI kinases and phosphatases are mostly lacking (Balla, 2013). Several experimental approaches have been developed that allow for different degrees of spatiotemporal control of various PI species.…”

Section: Introductionmentioning

confidence: 99%

Ion channel regulation by phosphoinositides analyzed with VSPs—PI(4,5)P2 affinity, phosphoinositide selectivity, and PI(4,5)P2 pool accessibility

et al. 2015

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The activity of many proteins depends on the phosphoinositide (PI) content of the membrane. E.g., dynamic changes of the concentration of PI(4,5)P2 are cellular signals that regulate ion channels. The susceptibility of a channel to such dynamics depends on its affinity for PI(4,5)P2. Yet, measuring affinities for endogenous PIs has not been possible directly, but has relied largely on the response to soluble analogs, which may not quantitatively reflect binding to native lipids. Voltage-sensitive phosphatases (VSPs) turn over PI(4,5)P2 to PI(4)P when activated by depolarization. In combination with voltage-clamp electrophysiology VSPs are useful tools for rapid and reversible depletion of PI(4,5)P2. Because cellular PI(4,5)P2 is resynthesized rapidly, steady state PI(4,5)P2 changes with the degree of VSP activation and thus depends on membrane potential. Here we show that titration of endogenous PI(4,5)P2 with Ci-VSP allows for the quantification of relative PI(4,5)P2 affinities of ion channels. The sensitivity of inward rectifier and voltage-gated K+ channels to Ci-VSP allowed for comparison of PI(4,5)P2 affinities within and across channel subfamilies and detected changes of affinity in mutant channels. The results also reveal that VSPs are useful only for PI effectors with high binding specificity among PI isoforms, because PI(4,5)P2 depletion occurs at constant overall PI level. Thus, Kir6.2, a channel activated by PI(4,5)P2 and PI(4)P was insensitive to VSP. Surprisingly, despite comparable PI(4,5)P2 affinity as determined by Ci-VSP, the Kv7 and Kir channel families strongly differed in their sensitivity to receptor-mediated depletion of PI(4,5)P2. While Kv7 members were highly sensitive to activation of PLC by Gq-coupled receptors, Kir channels were insensitive even when PI(4,5)P2 affinity was lowered by mutation. We hypothesize that different channels may be associated with distinct pools of PI(4,5)P2 that differ in their accessibility to PLC and VSPs.

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The Chemical Biology of Phosphoinositide 3‐Kinases

Cited by 38 publications

References 196 publications

Detection and manipulation of phosphoinositides

Detection and manipulation of phosphoinositides

Lipid Sorting and Multivesicular Endosome Biogenesis

Ion channel regulation by phosphoinositides analyzed with VSPs—PI(4,5)P2 affinity, phosphoinositide selectivity, and PI(4,5)P2 pool accessibility

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