Eric HONORE
Chef d'équipe

 

 Glogowska E. et al. (2021). Piezo1 and Piezo2 foster mechanical gating of K(2P) channels. Cell Rep

 Wang S. et al. (2020). Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice. Nat Commun

 Douguet D. et al. (2019). Piezo Ion Channels in Cardiovascular Mechanobiology. Trends Pharmacol Sci

 Douguet D. and Honore E. et al. (2019). Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels. Cell

 Arhatte M. et al. (2019). TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells. Nat Commun

 Douguet D. et al. (2019). Structure and function of polycystins: insights into polycystic kidney disease. Nat Rev Nephrol

 

Collectively cells respond to local mechanical stress by activation of specific molecular pathways resulting in macroscopic changes at the organ level. For instance resistance arteries (small diameter) respond to hypertension by a major structural remodeling caused by the repositioning of arterial smooth muscle cells (SMCs) around a smaller lumen diameter (inward eutrophic remodeling). Hypertensive arterial remodeling allows a normalization of the parietal tension because of an increase in wall thickness (although without hypertrophy) and a reduced arterial diameter. Thus, wall tension is restored to a normal level, despite an increase in luminal pressure [Laplace’s law]. We aim at identifying the sensors and effectors that are involved in these specific adaptive responses to chronic mechanical stress [although these can become maladaptive when hypertension is maintained](3, 4).

Our group has been focusing on the role of ion channels in cellular mechanotransduction for the last 20 years. MS ion channels are conserved throughout evolution and are already present in microbes, yeast and plants. For instance, osmotic down-shock opens bacterial MS ion channels, such as the large non-selective conductance MscL, allowing osmolyte efflux, relieving pressure and preventing cell lysis (5).

Additional studies performed on bacterial MS channels have provided strong evidence that its conformation is directly dependent on tension in the lipid bilayer (for review (6)). Our team members discovered, for the first time, the molecular identity of a mammalian MS ion channel (7) (and for review (8)). We reported that the K_2P channel TREK-1 is a MS K⁺-selective ion channel, directly activated by force generated in the lipid bilayer, as confirmed by more recent structural data and reconstitution experiments (7-31). Opening of TREK/TRAAK channels in response to mechanical stress (shear stress, membrane stretch or cell swelling) causes cell hyperpolarization leading to a decrease in cell excitability (for review (8)).
The identity of the non-selective depolarizing MS cationic channels was discovered in 2010 by the Patapoutian group (32-42). Piezo1 is a large trimeric complex, with an N-terminal mechanotransduction module followed by a C-terminal ionic pore (35, 43). Functional reconstitution experiments with purified Piezo1, as well as electrophysiological recordings indicate that membrane tension is the common activating force acting on Piezo1 gating (36, 39, 40, 44). Piezo1 was shown by our group and others to be required for vascular development, flow-mediated dilatation and arterial remodelling (4, 33, 34, 45), while Piezo2 plays a key role in mechanosensory transduction, in particular light touch sensitivity and proprioception (46-51). Recent findings also indicate that Piezo1 is involved in epithelial cell overcrowding/confinement-sensing and cell extrusion (52, 53). Moreover, mechanical stretch triggers rapid epithelial cell division through Piezo1 opening (54).
Notably, Piezo1/2 are implicated in a variety of rare genetic disorders, including xerocytosis (dominant Piezo1 gain-of-function mutations; GOF), lymphatic dysplasia (recessive Piezo1 loss-of-function mutations; LOF), arthrogryposis (dominant Piezo2 GOF) and muscular atrophy with scoliosis and perinatal respiratory distress (recessive Piezo2 LOF)(55-62).

We are currently focusing on four different projects concerning the role of Piezo1 in: 1) obesity; 2) pulmonary hypertension; 3) nephropathies; 4) genetic resistance to malaria.
 
Expected global outcomes:
Our project is intrinsically pluridisciplinary and aggregates state-of-the-art biophysics, molecular and cellular biology, stem cells research, physiology and bio-engineering. This rationalized and integrated collection of experimental data should allow us to gain important new insights into the basic mechanisms of mechanobiology. We expect that our findings will pave the way for the discovery and development of new strategies, based on the pharmacological and/or mechanical modulation of Piezo1 (mechanotherapy).

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PROJECT 3: MECHANO-NEPHROPATHIES
In the kidney, important progress has recently been made in the understanding of flow sensing by tubular epithelial cells (91, 92). Bending of the primary cilium at the apical side of tubular cells induced by the flow of intraluminal urine activates the ciliary polycystin complex (Polycystin-1; PC1 and Polycystin-2; PC2 which are mutated in autosomal dominant polycystic kidney disease, ADPKD), resulting in a calcium influx through the transient receptor potential (TRP) channel PC2 (for reviews: (2, 93-95)). Kidney epithelial cells also respond to changes in intraluminal pressure (2, 94). Normal pressure at rest within the renal pelvis and ureter is in the range of 0-10 mm Hg. However, peristaltic pressures generated by rhythmic papillary contractions required for the transport of urine vary between 15 and 45 mm Hg (2). When a renal tubule is subjected to intraluminal pressure, both apical and basolateral membranes are stretched (96). This physiological transient elevation in pressure is transmitted back to the tubular lumen and leads to repetitive tubular distension and cell stretching. Intraluminal pressure can also be dramatically elevated in kidney disease states (2). Indeed, obstructive uropathy is associated with a major increase in intratubular pressure, in excess of 60 mm Hg, leading to tubular circumferential stretch (97-101). Stretching, as well as compression of renal epithelial cells also occurs in PKD patients (2). Abnormal fluid accumulation in renal cysts causes the cyst wall to stretch (102-104). Moreover, growing cysts compress neighboring tubules with upstream accumulation of urine leading to increased intratubular pressure. Stretch of epithelial cells has been proposed to impact on cell proliferation, fibrosis, as well as apoptosis (28,97-101,104). Thus, pressure-induced stretch of tubular epithelial cells is relevant to both physiological and diseased kidney conditions (2).

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PROJECT 4: OPENING PIEZO1 IN RED BLOOD CELLS TO FIGHT MALARIA
In our group, Dominique Douguet develops computational methods and creates databases for virtual screening and de novo molecular design, drug re-purposing and knowledge-based design of drug-like compounds (LEA3D suite of tools). We are analyzing the current FDA approved drug chemical space from various dimensions: chemical structures, privileged structures, physicochemical properties, pharmacodynamic and pharmacokinetic properties (our own database e-Drug3D http://chemoinfo.ipmc.cnrs.fr/edrug3d.html; Inter Deposit Digital Number IDDN.FR.001.240001.000.S.P.2017.000.31235). Such structure-activity/property collections allow retrospective analyses of past successes and to foster the development of improved predictive methods relevant to the drug discovery and optimization process and, in particular, methods for assessing pharmacokinetic properties directly from molecular structures. These knowledge-based models and guidelines are associated with conventional ligand- and structure-based virtual screening methods (fingerprint, pharmacophore, shape-matching, docking…) to optimally identify and optimize bioactive small molecules.