Merkel Cells Sense Cooling with TRPM8 Channels

Abstract

In the skin, Merkel cells connect with keratinocytes and Aβ nerve fibers to form a touch receptor that functions as a slow adapting mechanoreceptor (slow adapting type 1). In human and mouse Merkel cells, we observed an increased concentration of intracellular Ca ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 agonists occurred after the addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current that was inhibited by a TRPM8 antagonist. Our results indicate that Merkel cells sense cooling through TRPM8 channels. We hypothesized that cooling modulates the slow adapting type 1 receptor response. Cooling mouse skin to 22°C reduced the slow adapting type 1 receptor discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22°C applied to the slow adapting type 1 receptive field reduced the spiking discharge. Altogether, our results indicate that Merkel cells are polymodal sensory cells that respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of Merkel cells, and possibly other TRPM8-expressing non-neuronal cells, such as keratinocytes, potentially adapts the discharge of slow adapting type 1 receptors during cooling.

Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions

“…TRP cation channel subfamily M member 8 (TRPM8) channels are located on the end of epidermal nerve fibres and Merkel cells (107). TRPM8 channels are cold-gated ion channels that inhibit both the histaminergic and non-histaminergic itch sensory pathways when activated (108).…”

Lifting the veil on the keratinocyte contribution to cutaneous nociception

“…First, for several decades, the dogma underlying cutaneous somatosensation stated that nociceptive sensory neurons were the sole cutaneous nociceptors, thus discouraging the emergence of alternative view. Second, functional receptors harboured by epidermal keratinocytes and classically implicated in noxious perception when expressed by sensory neurons, such as TRP ion channels that include TRPV1 (Denda et al, 2001), TRPV3 (Peier et al, 2002b), TRPV4 (Güler et al, 2002), TRPM8 (Denda et al, 2010a;Bidaux et al, 2015;Bouvier et al, 2018), and TRPA1 (Atoyan et al, 2009), also contribute to the skin homeostasis (Caterina and Pang, 2016 Figure 2. Epidermal keratinocytes modulate nociceptive sensory neuron activity.…”

“…Although TRPM8 is expressed by human keratinocytes (Denda et al, 2010a;Bidaux et al, 2015;Bouvier et al, 2018), little is known about its functions. Keratinocyte-expressed TRPM8 does act as a cold sensor, at least to control the balance between keratinocyte proliferation and differentiation (Bidaux et al, 2015).…”

Keratinocytes contribute to normal cold and heat sensation

“…On average, TRPA1 knockout keratinocytes exhibited cold-induced calcium transients at warmer temperatures than wildtype keratinocytes (21.5°C vs. 20.9°C; Figure 2D ). This lack of TRPA1 involvement was not surprising as we and others have not been able to verify TRPA1 expression or function in mouse epidermal cells ( Bouvier et al, 2018 ; Liu et al, 2013 ; Zappia et al, 2016 ). Additionally, global TRPA1 knockout mice ( Bautista et al, 2006 ) and rats ( Reese et al, 2020 ) exhibit normal cold-induced reflexive behaviors, further suggesting that this channel is not a conserved noxious cold transducer in mammalian skin cells.…”