Accepted

PIEZO1 is a mechanosensitive channel that converts applied force into electrical signals. Partial molecular structures show that PIEZO1 is a bowl-shaped trimer with extended arms. Here we use cryo-electron microscopy to show that PIEZO1 adopts different degrees of curvature in lipid vesicles of different sizes. We also use high-speed atomic force microscopy to analyse the deformability of PIEZO1 under force in membranes on a mica surface, and show that PIEZO1 can be flattened reversibly into the membrane plane. By approximating the absolute force applied, we estimate a range of values for the mechanical spring constant of PIEZO1. Both methods of microscopy demonstrate that PIEZO1 can deform its shape towards a planar structure. This deformation could explain how lateral membrane tension can be converted into a conformation-dependent change in free energy to gate the PIEZO1 channel in response to mechanical perturbations.

HCN ion channels conducting the I current control the frequency of firing in peripheral sensory neurons signalling pain Previous studies have demonstrated a major role for the HCN2 subunit in chronic pain but a potential involvement of HCN3 in pain has not been investigated HCN3 was found to be widely expressed in all classes of sensory neurons (small, medium, large) where it contributes to I HCN3 deletion increased the firing rate of medium, but not small, sensory neurons Pain sensitivity both acutely and following neuropathic injury was largely unaffected by HCN3 deletion, with the exception of a small decrease of mechanical hyperalgesia in response to a pinprick We conclude that HCN3 plays little role in either acute or chronic pain sensation HCN ion channels generate an inward current that can regulate action potential firing in somatosensory nerve fibres and can play an important role in pain sensation. The HCN1 isoform plays a limited role only in cold sensation following nerve injury. HCN2, on the other hand, is a key regulator of excitability in nociceptive nerve fibres, and controls the perception of inflammatory and neuropathic pain, but has no influence on acute pain sensation. Here we examine a potential role for the HCN3 isoform in neuronal excitability and pain. HCN3 is widely expressed in somatosensory neurons, and contributes to the regulation of firing of action potentials in medium-sized neurons, amongst which many have a nociceptive function. Genetic deletion of HCN3, however, had little impact on acute pain sensation, on inflammatory pain, nor on pain following nerve injury (neuropathic pain). We conclude that HCN3 does not play an important role in pain sensation.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required.