Mechanical Stretch Redefines Membrane Gαq–Calcium Signaling Complexes

Qifti, Androniqi; Garwain, Osama; Scarlata, Suzanne

doi:10.1007/s00232-019-00063-8

Cited by 10 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…of caveolae, and these regions also have increased levels of Gα q -dependent PLCβ activation. 53,54 In the cell, this localization could in turn regulate other signaling proteins and processes dependent upon PIP 2 , including ion channel and transporter activity, cell motility, and vesicular trafficking. 55−62 PLCβ is also regulated by the Gβγ heterodimer, but the prenylation of the Gγ subunit would result in exclusion from PIP 2 -enriched regions, 22,26−28 which may impact the amplitude or duration of PLCβ-dependent PIP 2 hydrolysis.…”

Section: ■ Discussionmentioning

confidence: 99%

“…As Gα q increases specific adsorption of PLCβ3, an additional component in its activation of PLCβ may include targeting of the complex to regions enriched with PIP 2 (Figure ). Recent studies have found that PIP 2 is highly concentrated at the rim of caveolae, and these regions also have increased levels of Gα q -dependent PLCβ activation. , In the cell, this localization could in turn regulate other signaling proteins and processes dependent upon PIP 2 , including ion channel and transporter activity, cell motility, and vesicular trafficking. − PLCβ is also regulated by the Gβγ heterodimer, but the prenylation of the Gγ subunit would result in exclusion from PIP 2 -enriched regions, ,− which may impact the amplitude or duration of PLCβ-dependent PIP 2 hydrolysis. Future studies exploring the spatial component of PLCβ activity, alone and following GPCR stimulation, will be essential for understanding the role of the membrane in these dynamic processes.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gα_q and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

et al. 2019

View full text Add to dashboard Cite

Phospholipase Cβ (PLCβ) enzymes are peripheral membrane proteins required for normal cardiovascular function. PLCβ hydrolyzes phosphatidylinositol 4,5-bisphosphate, producing second messengers that increase intracellular Ca2+ level and activate protein kinase C. Under basal conditions, PLCβ is autoinhibited by its C-terminal domains and by the X–Y linker, which contains a stretch of conserved acidic residues required for interfacial activation. Following stimulation of G protein-coupled receptors, the heterotrimeric G protein subunit Gαq allosterically activates PLCβ and helps orient the activated complex at the membrane for efficient lipid hydrolysis. However, the molecular basis for how the PLCβ X–Y linker, its C-terminal domains, Gαq, and the membrane coordinately regulate activity is not well understood. Using compressed lipid monolayers and atomic force microscopy, we found that a highly conserved acidic region of the X–Y linker is sufficient to regulate adsorption. Regulation of adsorption and activity by the X–Y linker also occurs independently of the C-terminal domains. We next investigated whether Gαq-dependent activation of PLCβ altered interactions with the model membrane. Gαq increased PLCβ adsorption in a manner that was independent of the PLCβ regulatory elements and targeted adsorption to specific regions of the monolayer in the absence of the C-terminal domains. Thus, the mechanism of Gαq-dependent activation likely includes a spatial component.

show abstract

Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gα_q and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Caveolae are prominent in smooth muscle cells and provide mechanical strength by flattening during stretch to provide more membrane area . We have found that the flattening of these domains by mechanical stretch or hypo‐osmotic conditions eliminates stabilization of activated Gαq by caveolin molecules reducing Ca 2+ signals . Additionally, osmotic stress reduces the cytosolic level of PLCβ eliminating its cytosolic function .…”

Section: Controlling the Transition Of Plcβ's Plasma Membrane Versus mentioning

confidence: 97%

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

et al. 2019

Self Cite

View full text Add to dashboard Cite

Some proteins can serve multiple functions depending on different cellularconditions. An example of a bifunctional protein is inositide-specific mammalian phospholipase Cβ (PLCβ). PLCβ is activated by G proteins in response to hormones and neurotransmitters to increase intracellular calcium. Recently, alternate cellular function(s) of PLCβ have become uncovered. However, the conditions that allow these different functions to be operative are unclear. Like many mammalian proteins, PLCβ has a conserved catalytic core along with several regulatory domains. These domains modulate the intensity and duration of calcium signals in response to external sensory information, and allow this enzyme to inhibit protein translation in a noncatalytic manner. In this review, we first describe PLCβ's cellular functions and regulation of the switching between these functions, and then discuss the thermodynamic considerations that offer insight into how cells manage multiple and competitive associations allowing them to rapidly shift between functional states.

show abstract

“…Deformation of caveolae by mild osmotic stress disrupts this stabilization and returns calcium signals to levels observed in the absence of caveolae (Guo et al, 2011; Guo et al, 2015; Yang and Scarlata, 2017). Additionally, when cells are subjected to either bi-directional static or oscillating mechanical stretch, calcium release through activation of Gαq/PLCβ is intact, but contacts between Gαq and caveolin are disrupted (Aisiku et al, 2011; Qifti et al, 2019a). In another series of studies, we found that activation of the Gαq/PLCβ pathway is linked to regulation of GAPDH protein production but not Hsp90 (see (Philip et al, 2012)).…”

Section: Introductionmentioning

confidence: 99%

Caveolae Impacts Cellular RNA Levels through Transcription and Translational Processes

Qifti

Balaji

Scarlata

2021

Preprint

Self Cite

View full text Add to dashboard Cite

Caveolae are membrane domains that provide mechanical strength to cells and localize signaling molecules. Caveolae are composed of caveolin-1 or -3 (Cav1/3) molecules that assemble into domains with the help of cavin-1. Besides organizing caveolae, cavin-1, also known as Polymerase I and Transcript Release Factor (PTRF), promotes ribosomal RNA transcription in the nucleus. Cell expression of Cav1 and cavin-1 are linked. Here, we find that deforming caveolae by subjecting cells to mild osmotic stress (300 to 150 mOsm), changes the levels of cellular proteins (GAPDH, Hsp90 and Ras) change only when Cav1/cavin-1 levels are reduced suggesting link between caveolae deformation and protein expression. We find that this link may be due to relocalization of cavin-1 from the plasma membrane to the nucleus upon caveolae deformation caused by osmotic stress. Cavin-1 relocalization is also seen when Cav1-Gαq contacts change upon stimulation with carbachol. Cav1 and cavin-1 levels have profound effects on the amount of cytosolic RNA and the size distribution of these RNAs that in turn impact the ability of cells to form stress granules and RNA-processing bodies (p-bodies) that protect mRNA when cells are subjected to environmental stress. Studies using a cavin-1 knock-out cell line show adaptive changes in cytosolic RNA levels but a reduced ability to form stress granules. Our studies show that caveolae, through release of cavin-1, communicates mechanical and chemical cues to the cell interior to impact transcriptional and translational processes.

show abstract

Mechanical Stretch Redefines Membrane Gαq–Calcium Signaling Complexes

Cited by 10 publications

References 21 publications

Gα_q and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

Gα_q and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

Caveolae Impacts Cellular RNA Levels through Transcription and Translational Processes

Contact Info

Product

Resources

About

Mechanical Stretch Redefines Membrane Gαq–Calcium Signaling Complexes

Cited by 10 publications

References 21 publications

Gαq and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

Gαq and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

Caveolae Impacts Cellular RNA Levels through Transcription and Translational Processes

Contact Info

Product

Resources

About

Gα_q and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers

Gα_q and the Phospholipase Cβ3 X–Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers