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Pacinian corpuscles detect transient touch and vibration in vertebrates. Corpuscles are composed of a mechanoreceptor afferent surrounded by lamellar Schwann cells (LSCs), enclosed by a multilayered outer core. The spatial arrangement of these components and their contribution to sensory tuning are unclear. We report the three-dimensional architecture of the Pacinian corpuscle and reveal the role of its cellular components in touch detection. In the prevailing model, the outer core acts as a mechanical filter that limits static and low-frequency stimuli from reaching the afferent terminal—the presumed sole site of touch detection. We show that the outer core is dispensable for the sensory tuning to transient touch and vibration; instead, these properties arise from the inner core. By acting as additional touch sensors, LSCs potentiate mechanosensitivity of the terminal, which detects touch via fast inactivating ion channels. Thus, functional tuning of the Pacinian corpuscle is enabled by an interplay between mechanosensitive LSCs and the afferent terminal in the inner core. 

Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5–7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24–48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center. 

Abstract Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions. 

Mechanosensory corpuscles detect transient touch and vibration in the skin of vertebrates, enabling precise sensation of the physical environment. The corpuscle contains a mechanoreceptor afferent surrounded by lamellar cells (LCs), but corpuscular ultrastructure and the role of LCs in touch detection are unknown. We report the three-dimensional architecture of the avian Meissner (Grandry) corpuscle acquired using enhanced focused ion beam scanning electron microscopy and machine learning-based segmentation. The corpuscle comprises a stack of LCs interdigitated with terminal endings from two afferents. Simultaneous electrophysiological recordings from both cell types revealed that mechanosensitive LCs use calcium influx to trigger action potentials in the afferent and thus serve as physiological touch sensors in the skin. The elaborate architecture and bicellular sensory mechanism in the corpuscles, which comprises the afferents and LCs, create the capacity for nuanced encoding of the submodalities of touch. 

Afferents of peripheral mechanoreceptors innervate the skin of vertebrates, where they detect physical touch via mechanically gated ion channels (mechanotransducers). While the afferent terminal is generally understood to be the primary site of mechanotransduction, the functional properties of mechanically activated (MA) ionic current generated by mechanotransducers at this location remain obscure. Until now, direct evidence of MA current and mechanically induced action potentials in the mechanoreceptor terminal has not been obtained. Here, we report patch-clamp recordings from the afferent terminal innervating Grandry (Meissner) corpuscles in the bill skin of a tactile specialist duck. We show that mechanical stimulation evokes MA current in the afferent with fast kinetics of activation and inactivation during the dynamic phases of the mechanical stimulus. These responses trigger rapidly adapting firing in the afferent detected at the terminal and in the afferent fiber outside of the corpuscle. Our findings elucidate the initial electrogenic events of touch detection in the mechanoreceptor nerve terminal.