FIGURE 1.

Merkel cells are touch-sensing and touch-transducing cells. (A) Depiction of a Merkel cell (green) and LTMR (purple) complex. Merkel cells are epidermal cells that form synapses with slowly adapting LTMR and are responsible for the detection of light touch. They are found in abundance in fingers and around the lips, and are associated with hair follicles. Merkel cells respond to mechanical stimulation by activation of the mechanosensitive cationic channel Piezo2 (Ikeda et al., 2014; Ranade et al., 2014; Woo et al., 2014). Consequently, membrane depolarization and Ca²⁺ influx induce neurotransmitter (NT) release by way of SNARE-mediated vesicle release (Hoffman et al., 2018). There is controversy about which neurotransmitter is released by Merkel cells, with serotonin, glutamate, and adrenaline all being implicated (Chang et al., 2016, 2017; Hoffman et al., 2018; Higashikawa et al., 2019; Sonekatsu et al., 2019; Chang and Gu, 2020a). Finally, the neurotransmitter interacts with G-protein-coupled receptors (GPCR) or ionotropic receptors on the afferent fibers leading to increased firing of action potentials. The postulated receptors for serotonin, glutamate, and adrenaline are the 5-HT3 receptor, the NMDA and glutamate-permeable anion channels, and the β2 adrenergic receptor, respectively (Chang et al., 2016, 2017; Hoffman et al., 2018; Higashikawa et al., 2019). Piezo2 channels are also expressed on the afferents, thus mediating concomitant mechanical activation of the nerve fibers. Merkel cells also form finger-like projections apically, where they interact with keratinocytes. (B) Schematic representation of the skin-nerve preparation used to record the electrophysiological activity of the nerve endings of the mouse skin upon touch stimulation. Normally, the hindlimb skin and saphenous of the mouse are used and mechanical stimulation is via von Frey monofilaments. (C) Top panel, depiction of a typical response of a LTMR to 1 mm indentation. The vertical purple bars represent action potentials. Bottom panel, the same stimulation elicits fewer action potentials in a fiber of a mouse in which the tetanus neuro-toxin light-chain subunit was expressed in the Merkel cells, thus preventing SNARE-dependent vesicular fusion [adapted from Hoffman et al. (2018)]. These results support the idea that Merkel cells regulate LTMRs via release of neurotransmitter.