Abstract
The first point of our body's contact with tactile stimuli (innocuous and noxious) is the epidermis, the outermost layer of skin that is largely composed of keratinocytes. Here, we sought to define the role that keratinocytes play in touch sensation in vivo and ex vivo. We show that optogenetic inhibition of keratinocytes decreases behavioral and cellular mechanosensitivity. These processes are inherently mediated by ATP signaling, as demonstrated by complementary cutaneous ATP release and degradation experiments. Specific deletion of P2X4 receptors in sensory neurons markedly decreases behavioral and primary afferent mechanical sensitivity, thus positioning keratinocyte-released ATP to sensory neuron P2X4 signaling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signaling that occurs in cutaneous pain and itch disorders, and ultimately, the development of novel topical therapeutics for these conditions.
Highlights
Peripheral sensory neurons detect external stimuli and transmit this information to spinal cord and brainstem circuits
Keratinocytes were isolated from the glabrous hindpaw skin of transgenic mice that express tdTomato in Keratin14 (K14)-positive cells, the vast majority (~94–97%) of which are keratinocytes (Byrne et al, 1994; Dassule et al, 2000; Wang et al, 1997), with a small percentage (3–6%) being Merkel cells (Moll et al, 1986; Fradette et al, 2003; Halata et al, 2003)
We hypothesized that this depolarization may induce release of keratinocyte-derived factors that subsequently signal to sensory neurons, and we aimed to utilize optogenetic approaches to manipulate this process
Summary
Peripheral sensory neurons detect external stimuli and transmit this information to spinal cord and brainstem circuits Despite their location below the epidermal surface, convention proposes that cutaneous sensory nerve terminals are the exclusive transducers of mechanical stimuli. In co-cultures of keratinocytes and dorsal root ganglia (DRG) neurons, mechanical stimulation of keratinocytes evokes inward currents in adjacent sensory neurons, presumably through release of one of the aforementioned metabolites (Klusch et al, 2013). Taken together, these data suggest that sensory neurons may not be the sole transducers of mechanical
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