Biology subjects

Begay, V.

Publications and source records attributed to Begay, V..

5 recordsLinked to original sources

bioRxiv2022

Piezo2 voltage-block regulates mechanical pain sensitivity

PIEZO2 mechanosensitive channels are required for normal touch sensation. However, PIEZO2 channels are almost completely blocked at negative resting membrane potentials. We show that PIEZO2 voltage-block can be relieved by mutations at a conserved Arginine (R2756) which dramatically sensitizes the channel to mechanical stimuli. We generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to ask how voltage regulates the endogenous mechanosensitivity of sensory neurons. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but touch receptors were largely unaffected. Piezo2 knock-in mice were hypersensitive to noxious mechanical stimuli as their nociceptors acquired properties similar to ultrasensitive touch receptors. Thus, mechanical pain sensitivity can be tuned by voltage-block of PIEZO2 channels, a channel property potentially amenable for pharmacological modulation.

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↗

bioRxiv2022

Lack of evidence for participation of TMEM150c/TENTONIN3 in sensory mechanotransduction.

The membrane protein TMEM150c has been proposed to form a mechanosensitive ion channel that is required for normal proprioceptor function. Here we examined whether expression of TMEM150c in neuroblastoma cells lacking Piezo1 is associated with the appearance of mechanosensitive currents. Using three different modes of mechanical stimuli, indentation, membrane stretch and substrate deflection we could not evoke mechanosensitive currents in cells expressing TMEM150c. We next asked if TMEM150c is necessary for the normal mechanosensitivity of cutaneous sensory neurons. We used an available mouse model in which the Tmem150c locus was disrupted through the insertion of a LacZ cassette with a splice acceptor that should lead to transcript truncation. Analysis of these mice indicated that ablation of the Tmem150c gene was not complete in sensory neurons of the dorsal root ganglia (DRG). Using a Crispr/cas9 strategy we made a second mouse model in which a large part of the Tmem150c gene was deleted and established that these Tmem150c-/- mice completely lack TMEM150c protein in the DRGs. We used an ex vivo skin nerve preparation to characterize the mechanosenstivity of mechanoreceptors and nociceptors in the glabrous skin of the Tmem150c-/- mice. We found no quantitative alterations in the physiological properties of any type of cutaneous sensory fiber in Tmem150c-/- mice. Since it has been claimed that TMEM150c is required for normal proprioceptor function we made a quantitative analysis of locomotion in Tmem150c-/- mice. Here again we found no indication that there was altered gait in Tmem150c-/- mice compared to wild type controls. In summary, we conclude that existing mouse models that have been used to investigate TMEM150c function in vivo are problematic. Furthermore, we could find no evidence that TMEM150c forms a mechanosensitive channel or that it is necessary for the normal mechanosensitivity of cutaneous sensory neurons.

neuroscience↗

bioRxiv2021

Immune competence and spleen size scale with colony status in the naked mole-rat

Naked mole-rats (NM-R; Heterocephalus glaber) live in multi-generational colonies with a social hierarchy, show low cancer incidence and long life-spans. Here we asked if such extreme physiology might have an immune component. The spleen is the largest lymphoid organ and plays an essential role in response to immunological insults and may participate in combating cancer and slowing ageing. We investigated the anatomy, molecular composition and function of the NM-R spleen using RNA-sequencing and histological analysis in healthy animals. We found that spleen size in healthy NM-Rs varies considerably. We therefore classified NM-Rs according to spleen size as NM-Rs with small spleens or enlarged spleens. Animals with enlarged spleens showed potentially better anti-microbial profiles and were much more likely to have a high rank within the colony. Splenomegaly was associated with infection in sick NM-Rs, but not in NM-Rs with enlarged spleens. In all healthy NM-Rs splenic erythropoiesis, megakaryopoiesis and myelopoiesis were increased, but B lymphopoiesis was reduced and splenic marginal zone showed markedly altered morphology when compared to other rodents. However, in NM-Rs lymphocytes were found in secondary sites such as lymph nodes, gut lymphoid nodules and thymus. Thus, the NM-R spleen is a major site of adult hematopoiesis under normal physiological conditions. Overall, the NM-R immune system seems to rely mainly on innate immune responses with a more restricted adaptive immune response. We propose that the anatomical plasticity of the spleen might be regulated by social interaction and gives immunological advantage to increase the life-span of higher ranked animals.

immunology↗

bioRxiv2020

USH2A is a Meissner corpuscle end-organ protein necessary for vibration sensing in mice and humans

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive vibration-sensing neurons are associated with Meissners corpuscles and Pacinian corpuscles1. Such end-organ structures have been recognized for more than 160 years, but their exact functions have remained a matter of speculation. Here we examined the role of USH2A in touch sensation in humans and mice. The USH2A gene encodes a transmembrane protein with a very large extracellular domain. Pathogenic USH2A mutations cause Usher syndrome associated with hearing loss and visual impairment2. We show that patients with biallelic pathogenic USH2A mutations also have profound impairments in vibrotactile touch perception. Similarly, mice lacking the USH2A protein showed severe deficits in a forepaw vibrotactile discrimination task. Forepaw rapidly-adapting mechanoreceptors (RAMs) recorded from Ush2a-/- mice innervating Meissners corpuscles showed profound reductions in their vibration sensitivity. However, the USH2A protein was not expressed in sensory neurons, but was found in specialized terminal Schwann cells in Meissners corpuscles. Loss of this large extracellular tether-like protein in corpuscular end-organs innervated by RAMs was sufficient to reduce the vibration sensitivity of mechanoreceptors. Thus, USH2A expressed in corpuscular end-organs associated with vibration sensing is required to properly perceive vibration. We propose that cells within the corpuscle present a tether-like protein that may link to mechanosensitive channels in sensory endings to facilitate small amplitude vibration detection essential for the perception of fine textured surfaces.

neuroscience↗