Piezo channels: from structure to function.

International audienceMechanotransduction is the conversion of mechanical stimuli into biological signals. It is involved in the modulation of diverse cellular functions such as migration, proliferation, differentiation, and apoptosis as well as in the detection of sensory stimuli such as air vibration and mechanical contact. Therefore, mechanotransduction is crucial for organ development and homeostasis and plays a direct role in hearing, touch, proprioception, and pain. Multiple molecular players involved in mechanotransduction have been identified in the past, among them ion channels directly activated by cell membrane deformation. Most of these channels have well-established roles in lower organisms but are not conserved in mammals or fail to encode mechanically activated channels in mammals due to non-conservation of mechanotransduction property. A family of mechanically activated channels that counts only two members in human, piezo1 and 2, has emerged recently. Given the lack of valid mechanically activated channel candidates in mammals in the past decades, particular attention is given to piezo channels and their potential roles in various biological functions. This review summarizes our current knowledge on these ion channels

Piezo channels: from structure to function.

International audienceMechanotransduction is the conversion of mechanical stimuli into biological signals. It is involved in the modulation of diverse cellular functions such as migration, proliferation, differentiation, and apoptosis as well as in the detection of sensory stimuli such as air vibration and mechanical contact. Therefore, mechanotransduction is crucial for organ development and homeostasis and plays a direct role in hearing, touch, proprioception, and pain. Multiple molecular players involved in mechanotransduction have been identified in the past, among them ion channels directly activated by cell membrane deformation. Most of these channels have well-established roles in lower organisms but are not conserved in mammals or fail to encode mechanically activated channels in mammals due to non-conservation of mechanotransduction property. A family of mechanically activated channels that counts only two members in human, piezo1 and 2, has emerged recently. Given the lack of valid mechanically activated channel candidates in mammals in the past decades, particular attention is given to piezo channels and their potential roles in various biological functions. This review summarizes our current knowledge on these ion channels

Piezo1 ion channel pore properties are dictated by C-terminal region

International audiencePiezo1 and Piezo2 encode mechanically activated cation channels that function as mechano-transducers involved in vascular system development and touch sensing, respectively. Structural features of Piezos remain unknown. Mouse Piezo1 is bioinformatically predicted to have 30–40 transmembrane (TM) domains. Here, we find that nine of the putative inter-transmembrane regions are accessible from the extracellular side. We use chimeras between mPiezo1 and dPiezo to show that ion-permeation properties are conferred by C-terminal region. We further identify a glutamate residue within a conserved region adjacent to the last two putative TM domains of the protein, that when mutated, affects unitary conductance and ion selectivity, and modulates pore block. We propose that this amino acid is either in the pore or closely associates with the pore. Our results describe important structural motifs of this channel family and lay the groundwork for a mechanistic understanding of how Piezos are mechanically gated and conduct ions

Patch-seq of mouse DRG neurons reveals candidate genes for specific mechanosensory functions

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PACAP-LOADED LIPOSOME DELIVERY ACROSS THE BBB: A LIGHT-SHEET MICROSCOPY STUDY

The blood-brain barrier (BBB) impermeability and selectivity prevent the transport of many therapeutic molecules into the brain, making ineffective their use for treatment of neurological diseases.1 Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide proposed for treatment of central nervous system (CNS) diseases.2 However, its clinical use is limited by the efflux component of peptide transport system-6 (PTS-6), which reduces its brain uptake3, and also for its low stability in human plasma, rapid degradation and peripheral actions.4 Nanocarrier-mediated method is a non-invasive strategy to explore for brain drug delivery; among them, liposomes are attractive tools that can be easily modified to improve their delivery. 5 We developed liposomes loaded with PACAP and functionalized on the surface with gH625 peptide, a membrane-perturbing domain in glycoprotein H of Herpes simplex virus 1. gH625 can traverse the membrane bilayer and deliver several cargoes across cell membranes in vitro6 and crosses the BBB in vivo.7We evaluated the efficiency of gH625-liposomes to deliver PACAP to the brain in Swiss CD1 mice after intravenous administration using light sheet fluorescence microscopy. Our results show that gH625-liposomes ameliorate both PACAP reaching and crossing the BBB, increasing the number of neuronal cells labeled with PACAP. These data suggest that gH625-liposomes represent a promising strategy to deliver therapeutic agents to CNS for the treatment of neurological diseases but also to provide an effective imaging and/or diagnostic tool for the brain

A NEW STRATEGY TO DELIVER PACAP TO THE BRAIN

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide, but its brain uptake is limited by the blood-brain barrier (BBB) component, such as peptide transport system-6 (PTS-6) [1]. The liposomes represent an attractive tool to deliver molecules across the BBB; they can be easily modified on surface to improve their delivery. The peptide gH625, a membrane-perturbing domain in glycoprotein H of Herpes Simplex virus 1, has been extensively used for vector-mediated strategies that enable passage of several cargoes across cell membranes in vitro [2] and crosses the BBB [3]. We evaluated the efficiency of liposomes functionalized with gH625 to deliver PACAP to the brain of Swiss CD1 mice after intravenous injection using light sheet fluorescence microscopy. gH625 liposomes improves both PACAP reaching and crossing the BBB, with a higher number of PACAP labeled neuronal cells. This study suggests a promising strategy to deliver PACAP to CNS for brain diseases treatment