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Helix 8 Is the Essential Structural Motif of Mechanosensitive Gpcrs

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Helix 8 Is the Essential Structural Motif of Mechanosensitive Gpcrs ARTICLE https://doi.org/10.1038/s41467-019-13722-0 OPEN Helix 8 is the essential structural motif of mechanosensitive GPCRs Serap Erdogmus1,10, Ursula Storch1,2,10, Laura Danner1, Jasmin Becker1, Michaela Winter1, Nicole Ziegler3, Angela Wirth4,5, Stefan Offermanns4,6, Carsten Hoffmann 7, Thomas Gudermann1,8,9*& Michael Mederos y Schnitzler1,8* G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but 1234567890():,; also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology. 1 Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336 Munich, Germany. 2 Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Pettenkoferstr. 9, 80336 Munich, Germany. 3 Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany. 4 Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstraße 43, 61231 Bad Nauheim, Germany. 5 Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. 6 J. W. Goethe University Frankfurt, Medical Faculty, 60590 Frankfurt, Germany. 7 Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Hans Knoell Str. 2, 07745 Jena, Germany. 8 DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. 9 Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany. 10These authors contributed equally: Serap Erdogmus, Ursula Storch. *email: [email protected] muenchen.de; [email protected] NATURE COMMUNICATIONS | (2019) 10:5784 | https://doi.org/10.1038/s41467-019-13722-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13722-0 PCRs serve as molecular targets for about 30% of all dynamics of mechanically induced conformational changes and approved drugs1. They are versatile cellular sensors acti- the structural motifs mediating mechanosensation in GPCRs have G fi vated not only by hormones and neurotransmitters, but not been identi ed yet. Indeed, it is not even clear whether also by physical and chemical stimuli such as voltage2–6, ions7, mechanical force acts directly or indirectly on these GPCRs. and mechanical forces8,9. Until now, several GPCRs like apelin To address these questions on a molecular level, we employ the 10,11 12 fl receptors , sphingosine 1-phosphate receptors (S1PR) , para- technique of intramolecular dynamic uorescence energy transfer 13 thyroid hormone 1 receptors (PTH1R) , dopamine D5 receptors (FRET) to monitor conformation changes of H1R in order to 14 15–18 (D5R) , angiotensin II AT 1 receptors (AT1R) , GPR68 analyze whether mechanical forces and agonists foster distinct 19 20 receptors , cysteinyl leukotriene 1 receptors (CysLT1R) ,bra- active receptor conformations. In addition, we aim to identify 21 22 dykinin B2 receptors (B2R) , formyl peptide 1 receptors , molecular structures that are essential for mechanosensation 15 15 endothelin ETA receptors , muscarinic M5 receptors , and of GPCRs. 15 fi fi fi vasopressin V1A receptors have been identi ed as mechan- We nd that the H1R undergoes stimulus-speci c patterns of osensors involved in physiological settings like vascular conformational changes, and we identify the C-terminal helix 8 15,16,18–20 regulation as well as in pathophysiological circumstances (H8) as the essential structural motif endowing H1R and other like cardiac hypertrophy17 and preeclampsia23. Thus, dissecting GPCRs with mechanosensitivity. On the physiological level, we – fl the structure function relationship of mechanosensitive GPCRs is identify H1R as a sensor of uid shear stress in the endothelium a crucial first step towards a deeper understanding of their roles in contributing to flow-induced vasodilation. physiology and pathophysiology and might help improve pharmacotherapy. It is well known that in blood vessels, mechanical forces can Results 24 elicit biological responses essential for autoregulatory vessel The endothelial H1R is a sensor of shear stress. To investigate a fl function. Increased blood pressure can activate smooth muscle potential physiological role for the mechanosensitive H1Rin ow- cells resulting in myogenic vasoconstriction known as the Bayliss induced endothelial stimulation, we first investigated its expres- effect25. By contrast, blood flow causes shear stress that activates sion levels in primary endothelial cells derived from human endothelial cells resulting in flow-induced vasodilation26–29 umbilical veins (HUVEC) serving as a cell model to analyze the thereby increasing vessel perfusion. Flow-induced vasodilation is mechanosensitivity of endogenously expressed H1Rs. In HUVEC, disturbed in endothelial dysfunction resulting from pathophy- H1R is more abundantly expressed than any other GPCR that we 30 siological states like atherosclerosis . Shear stress increases the tested (Fig. 1a). H1R showed more than 12-fold higher mRNA 2+ intracellular calcium concentration [Ca ]i in endothelial cells expression levels than other Gq/11-protein coupled receptors and 2+ β leading to Ca /calmodulin-dependent activation of endothelial more than 4-fold higher levels than Gs-protein coupled - 31–33 β nitric oxide synthase (eNOS) and to the release of nitric adrenergic receptors ( xR). mRNA expression levels of other 32–35 oxide (NO) responsible for vasodilation . However, the mechanosensitive GPCRs like V1AR, CysLT1R, GPR68, D5R and molecular identity of endothelial mechanosensors is still a matter PTH1R were below the detection limit. mRNA expression of the of debate. mechanosensitive AT1R was more than 400-fold lower than that A large body of evidence suggests the involvement of numer- of H1R suggesting a negligible role of AT1R for mechanosensation ous proteins in mechanosensation and –transduction in endo- in HUVECs. thelial cells. These include apical mechanosensors such as We then performed calcium imaging with HUVEC. Shear primary cilia, the glycocalix, ion channels, GPCRs, receptor tyr- stress of 4 and 20 dyn cm−2 induced calcium transients that were fi osine kinases and caveloae, junctional mechanosensors such as signi cantly, but not fully suppressed by the selective inverse H1R platelet endothelial cell adhesion molecule-1 (PECAM-1), VE- agonist mepyramine (Fig. 1b, c). Endothelial H1R was also Cadherin and VEGF receptors and basal sensors such as integrins sensitive to hypoosmotic membrane stretch induced by short- 36 12 15 (summarized in ). Among the mechanosensitive GPCRs, S1PR , time application (≤60 s) of a hypoosmotic solution (Fig. 1d, e) 21 19 B2R , and GPR68 are discussed as potential endothelial which was used as a different mechanical stimulus. Hypoosmotic mechanosensory proteins. Moreover, ion channels like PIEZO1 membrane stretch similarly caused calcium transients in HEK293 might also act as mechanosensors. Recently, PIEZO1 has been cells heterologously overexpressing H1R (Fig. 1f, g). Mepyramine identified as an endothelial sensor of shear stress that evokes ATP nearly completely abolished hypoosmotically induced calcium and adrenomedullin release causing GPCR and eNOS activation transients (Fig. 1d, e), indicating that H1Rs were responsible for and resultant nitrogen oxide (NO) production thereby leading to these calcium responses. Thus, endogenously expressed H1Rs are vasodilation37,38. sensitive both to membrane stretch and to shear stress. To extend the current knowledge about the physiological role Since HUVEC are of premature nature and not fully of intrinsically mechanosensitive GPCRs, we focus on the differentiated, we next verified our results in a physiological 15,39 fl mechanosensitive Gq/11-protein coupled H1R characterized setting by analyzing ow-induced vasodilation of isolated murine by the most pronounced mechanosensitivity of any GPCR tested mesenteric artery segments. To test whether endothelial H1R 15 fl by us .H1Rs are highly expressed in the endothelium, with might be involved in ow-induced vasodilation of conduit higher expression levels in endothelial than in smooth muscle arteries, mesenteric artery segments from mice were pre- 40 cells . However, a potential physiological role of H1Rs as constricted up to 20% either with the thromboxane A2 receptor endothelial mechanosensors has not been investigated yet. We agonist U46619 (Fig. 1h) or with a bath solution containing
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