Biology subjects

Stucky, C. L.

Publications and source records attributed to Stucky, C. L..

4 recordsLinked to original sources

bioRxiv2021

Piezo2 mechanosensitive ion channel is located to sensory neurons and non-neuronal cells in rat peripheral sensory pathway: implications in pain

Piezo2 mechanotransduction channel is a crucial mediator of sensory neurons for sensing and transducing touch, vibration, and proprioception. We here characterized Piezo2 expression and cell specificity in rat peripheral sensory pathway using a validated Piezo2 antibody. Immunohistochemistry using this antibody revealed Piezo2 expression in pan primary sensory neurons (PSNs) of dorsal rood ganglia (DRG) in naive rats, which was actively transported along afferent axons to both central presynaptic terminals innervating the spinal dorsal horn (DH) and peripheral afferent terminals in skin. Piezo2 immunoreactivity (IR) was also detected in the postsynaptic neurons of the DH and in the motor neurons of the ventral horn, but not in spinal GFAP- and Iba1-positive glia. Notably, Piezo2-IR was clearly identified in peripheral non-neuronal cells, including perineuronal glia, Schwann cells in the sciatic nerve and surrounding cutaneous afferent endings, as well as in skin epidermal Merkel cells and melanocytes. Immunoblots showed increased Piezo2 in DRG ipsilateral to plantar injection of complete Freunds adjuvant (CFA), and immunostaining revealed increased Piezo2-IR intensity in the DH ipsilateral to CFA injection. This elevation of DH Piezo2-IR was also evident in various neuropathic pain models and monosodium iodoacetate (MIA) knee osteoarthritis (OA) pain model, compared to controls. We conclude that 1) the pan neuronal profile of Piezo2 expression suggests that Piezo2 may function extend beyond simply touch/proprioception mediated by large-sized low-threshold mechanosensitive PSNs, 2) Piezo2 may have functional roles involving sensory processing in spinal cord, Schwann cells, and skin melanocytes, and 3) aberrant Piezo2 expression may contribute pain pathogenesis.

neuroscience↗

bioRxiv2020

Piezo1 Mediates Keratinocyte Mechanotransduction

Epidermal keratinocytes mediate touch sensation by detecting and encoding tactile information to sensory neurons. However, the specific mechanotransducers that enable keratinocytes to respond to mechanical stimulation are unknown. Here, we found that the mechanically-gated ion channel Piezo1 is the major keratinocyte mechanotransducer. Keratinocyte expression of Piezo1 is critical for normal sensory afferent firing and behavioral responses to mechanical stimuli.

neuroscience↗

bioRxiv2020

Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain

Persistent tactile pain is a poorly managed symptom of inflammatory and neuropathic injury. To develop therapies for this maladaptive sensation, the underlying molecular mediators must be identified. Using knockout mice and pharmacological inhibitors, we identified transient receptor canonical 5 (TRPC5) as a key contributor to the persistent tactile pain that occurs in many inflammatory and neuropathic preclinical rodent models. TRPC5 inhibition was effective in injuries associated with elevated levels of the bioactive phospholipid lysophosphatidylcholine (LPC). Exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain. In vitro, LPC activated both homomeric mouse and human TRPC5 channels, which upon examination of human dorsal root ganglia tissue, were expressed in 75% of human sensory neurons. Based on these results, TRPC5 inhibitors should be pursued as personalized therapy for spontaneous and tactile pain in conditions where elevated LPC is a biomarker.

neuroscience↗

bioRxiv2020

Keratinocytes are required for normal cold and heat sensation

Keratinocytes are the most abundant cell type in the epidermis, the most superficial layer of the skin. Historically, epidermal-innervating sensory neurons were thought to be the exclusive detectors and transmitters of environmental stimuli. However, recent work from our lab and others has demonstrated that keratinocytes are also critical for normal mechanotransduction and mechanically-evoked behavioral responses in mice. Here, we asked whether keratinocyte activity is also required for normal cold and heat sensation. We first observed cold-induced activity in mouse, rat, hibernating 13-lined ground squirrel, and human keratinocytes and determined that keratinocyte cold activity is conserved across mammalian species. Next, using transgenic mouse tissues and pharmacological tools, we determined that keratinocyte cold responses require the release of intracellular calcium through one or more unknown cold-sensitive proteins. This cold-induced keratinocyte activity is required for normal cold sensation as optogenetic inhibition of epidermal cells reduced reflexive behavioral responses to cold stimuli. Keratinocyte inhibition also decreased reflexive behavioral responses to heat stimuli. Lastly, we demonstrated that epidermal ATP-P2X4 signaling is required for normal cold and heat sensation. Based on these data and our previous findings, keratinocyte purinergic signaling is a modality-conserved amplification system that is required for normal somatosensation in vivo.

neuroscience↗