Biology subjects

Taberner, F. J.

Publications and source records attributed to Taberner, F. J..

6 recordsLinked to original sources

bioRxiv2024

PIEZO1 and PIEZO2 Blade domains are differentially required for channel localization and function.

PIEZO1 and PIEZO2 are critical force-gated ion channels, detecting and transducing mechanical forces into ionic currents in many eukaryotic cell types, serving essential physiological roles. CryoEM and structure-function studies have revealed that three PIEZO monomers assemble as a 3-blade propeller, highlighting essential structural aspects for channel function. One of the most prominent features in PIEZO architecture is the Blade, a large membrane embedded domain that comprises 36 transmembrane fragments organized in 9 THU (Transmembrane Helix Units). Despite its suggested role in force transduction, the contribution of the Blade domain in channel physiology remains unclear. By systematically generating different truncated versions of PIEZO1 and PIEZO2, lacking parts of the Blade, we show the intact PIEZO1 Blade is essential for proper localization and function. Conversely, our results indicate the PIEZO2 Distal Blade segments (THU1-3) are dispensable for normal mechanical sensitivity. However, it plays a central role in channel stability and localization, containing a region that mediates the intracellular retention of a chimeric membrane protein. Our study indicates that, in addition to their biophysical properties, PIEZO1 and PIEZO2 also differ in the regulation of their localization, adding a new layer of control on PIEZO2 activity.

neuroscience↗

bioRxiv2022

PRE-INJURY MECHANORECEPTOR ABLATION REDUCES NOCICEPTOR-DRIVEN SPINAL CORD INJURY-INDUCED NEUROPATHIC PAIN

Evidence from previous studies supports the concept that spinal cord injury (SCI) induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree nociceptors and mechanoreceptors contribute. Sensorimotor activation-based interventions (e.g. treadmill training) have been shown to reduce NP following experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. At the same time, nociceptors have been shown to become hyperexcitable early after SCI and peptidergic axons sprout into deeper laminae of the below injury level dorsal horn. The aim of the present study is to comprehensively understand the relative contribution of each pathway in respect to NP presentation in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B (TrkB) expressing mechanoreceptors before SCI mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. CGRP sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. Moreover, detection of hyperexcitability in nociceptors, not in mechanoreceptors, in skin-nerve preparations of contusion SCI mice 7 days after injury makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. SNS reporter mice allowing specific visualization of the entire nociceptor population confirmed significant sprouting of respective neurons into laminae III/IV as early as 5 days post-injury. Genetic ablation of SNS-Cre mice severely affected their overall health condition, which precluded them to undergo experimental SCI and subsequent further analysis. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors with consecutive peptidergic fiber sprouting in the dorsal horn are confirmed as the likely main driver of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

neuroscience↗

bioRxiv2022

The molecular mechanism and physiological role of silent nociceptor activation

Silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation selectively upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors. Moreover, we show that mice lacking TMEM100 do not develop secondary allodynia - i.e. pain hypersensitivity that spreads beyond the site of inflammation - in a mouse model of knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce allodynia in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary allodynia during inflammation.

neuroscience↗

bioRxiv2021

An intrinsically disordered intracellular domain of PIEZO2 is required for force-from-filament activation of the channel

A central question in mechanobiology is how mechanical forces acting in or on a cell are transmitted to mechanically-gated PIEZO channels that convert these forces into biochemical signals. Here we show that PIEZO2 is sensitive to force-transmission via the membrane (force-from-lipids) as well as force transmission via the cytoskeleton (force-from-filament) and demonstrate that the latter requires the intracellular linker between the transmembrane helices nine and ten (IDR5). Moreover, we show that rendering PIEZO2 insensitive to force-from-filament by deleting IDR5 abolishes PIEZO2-mediated inhibition of neurite outgrowth, which relies on the detection of cellgenerated traction forces, while it only partially affects its sensitivity to cell indentation and does not at all alter its sensitivity to membrane stretch. Hence, we propose that PIEZO2 is a polymodal mechanosensor that detects different types of mechanical stimuli via different force transmission pathways, which highlights the importance of utilizing multiple complementary assays when investigating PIEZO channel function.

neuroscience↗

bioRxiv2020

Identification of a novel population of peripheral sensory neuron that regulates blood pressure

The vasculature is innervated by a network of peripheral afferents that sense and regulate blood flow. Here, we describe a system of non-peptidergic sensory neurons with cell bodies in the spinal ganglia that regulate vascular tone in the distal arteries. We identify a population of mechanosensitive neurons marked by TrkC and Tyrosine hydroxylase in the dorsal root ganglia that project to blood vessels. Local stimulation of these neurons decreases vessel diameter and blood flow, while systemic activation increases systolic blood pressure and heart rate variability via the sympathetic nervous system. Chemogenetic inactivation or ablation of the neurons provokes variability in local blood flow leading to a reduction in systolic blood pressure, increased heart rate variability and ultimately lethality within 48 hours. Thus, TrkC/Tyrosine hydroxylase positive sensory neurons form part of a sensory feedback mechanism that maintains cardiovascular homeostasis through the autonomic nervous system.

neuroscience↗

bioRxiv2017

Control of mechanical pain hypersensitivity through ligand-targeted photoablation of TrkB positive sensory neurons

SummaryMechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury. Mice in which TrkB-Cre expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.\n\nHighlightsO_LITrkB+ neurons detect light touch under basal conditions\nC_LIO_LITrkB+ neurons convey mechanical allodynia in neuropathic pain states\nC_LIO_LIA photosensitizing derivative of BDNF allows for photoablation of TrkB+ neurons\nC_LIO_LIBDNF-guided photoablation reverses allodynia in multiple types of neuropathic pain\nC_LI

neuroscience↗