Helix 8 is the essential structural motif of mechanosensitive GPCRs

Erdogmus, Serap; Storch, Ursula; Danner, L.; Becker, Jasmin; Winter, Michaela; Ziegler, Nicole; Wirth, Angela; Offermanns, Stefan; Hoffmann, Carsten; Gudermann, Thomas; Schnitzler, Michael Mederos y

doi:10.1038/s41467-019-13722-0

Cited by 92 publications

(81 citation statements)

References 67 publications

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“…It seems therefore tempting to propose that changes in lateral pressure of the surrounding bilayer could differentially stabilise certain conformations of the receptors and thereby either stimulate or impede GPCR activation. These mechanistic considerations have so far been suggested for some mechanosensitive GPCRs [ 47 , 48 ], but might have a much broader implication also for other GPCRs in general.…”

Section: Interactions Of Gpcrs With Their Membrane Environmentmentioning

confidence: 91%

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

et al. 2020

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Over the past decade, the vast amount of information generated through structural and biophysical studies of GPCRs has provided unprecedented mechanistic insight into the complex signalling behaviour of these receptors. With this recent information surge, it has also become increasingly apparent that in order to reproduce the various effects that lipids and membranes exert on the biological function for these allosteric receptors, in vitro studies of GPCRs need to be conducted under conditions that adequately approximate the native lipid bilayer environment. In the first part of this review, we assess some of the more general effects that a membrane environment exerts on lipid bilayer-embedded proteins such as GPCRs. This is then followed by the consideration of more specific effects, including stoichiometric interactions with specific lipid subtypes. In the final section, we survey a range of different membrane mimetics that are currently used for in vitro studies, with a focus on NMR applications.

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Section: Interactions Of Gpcrs With Their Membrane Environmentmentioning

confidence: 91%

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

et al. 2020

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“…The AC consists of the plasma membrane and the underlying actin cytoskeleton, linked together by a rich pool of transmembrane and adaptor proteins [10]. The structure and biomechanics of the AC are tightly intertwined [11,12] and they in turn influence the functionality of molecular mechanosensors, such as Piezo mechanosensitive ion channels [13,14] or G-protein coupled receptors [15,16]. These are incorporated into the plasma membrane and directly convert mechanical stimuli into downstream biochemical signals.…”

Section: Introductionmentioning

confidence: 99%

Elasticity spectra as a tool to investigate actin cortex mechanics

et al. 2020

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Background The mechanical properties of single living cells have proven to be a powerful marker of the cell physiological state. The use of nanoindentation-based single cell force spectroscopy provided a wealth of information on the elasticity of cells, which is still largely to be exploited. The simplest model to describe cell mechanics is to treat them as a homogeneous elastic material and describe it in terms of the Young’s modulus. Beside its simplicity, this approach proved to be extremely informative, allowing to assess the potential of this physical indicator towards high throughput phenotyping in diagnostic and prognostic applications. Results Here we propose an extension of this analysis to explicitly account for the properties of the actin cortex. We present a method, the Elasticity Spectra, to calculate the apparent stiffness of the cell as a function of the indentation depth and we suggest a simple phenomenological approach to measure the thickness and stiffness of the actin cortex, in addition to the standard Young’s modulus. Conclusions The Elasticity Spectra approach is tested and validated on a set of cells treated with cytoskeleton-affecting drugs, showing the potential to extend the current representation of cell mechanics, without introducing a detailed and complex description of the intracellular structure.

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“…A different mechanism of mechanical GPCR activation has been reported in a very recent article investigating the activation of endothelial histamine H 1 receptors (H 1 Rs) by shear stress and membrane stretch 25 . Mechanical activation of H 1 Rs was found to be agonist-independent, insensitive to inverse agonists, and G 11/q protein dependent, resulting in NO production.…”

Section: Gpcr Participation In Mechano-transductionmentioning

confidence: 95%

Mechanical GPCR Activation by Traction Forces Exerted on Receptor N-Glycans

Marullo

Doly

Saha

et al. 2020

ACS Pharmacol. Transl. Sci.

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Cells are sensitive to chemical stimulation, which is converted into intracellular biochemical signals by the activation of specific receptors. Mechanical stimulations can also induce biochemical responses via the activation of various mechanosensors. Although principally appreciated for their chemosensory function, G proteincoupled receptors (GPCRs) may participate in mechano-transduction. They are indirectly activated by the paracrine release of chemical compounds secreted in response to mechanical stimuli, but they might additionally behave as mechanosensors that are directly stimulated by mechanical forces. Although several studies are consistent with this latter hypothesis, the molecular mechanisms of a potential direct mechanical activation of GPCRs have remained elusive until recently. In particular, investigating the activation of the catecholamine β 2 -adrenergic receptor by a pathogen revealed that traction forces directly exerted on the N-terminus of the receptor via N-glycan chains activate specific signaling pathways. These findings open new perspectives in GPCR biology and pharmacology since most GPCRs express N-glycan chains in their N-terminus, which might similarly be involved in the interaction with cell surface glycan-specific lectins in the context of cell-to-cell mechanical signaling.

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Helix 8 is the essential structural motif of mechanosensitive GPCRs

Cited by 92 publications

References 67 publications

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

Elasticity spectra as a tool to investigate actin cortex mechanics

Mechanical GPCR Activation by Traction Forces Exerted on Receptor N-Glycans

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