Merkel Cells Release Glutamate Following Mechanical Stimulation: Implication of Glutamate in the Merkel Cell-Neurite Complex

Abstract

Merkel cells (MCs) have been proposed to form a part of the MC-neurite complex with sensory neurons through synaptic contact. However, the detailed mechanisms for intercellular communication between MCs and neurons have yet to be clarified. The present study examined the increases in intracellular free Ca 2+ concentration ([Ca 2+ ] i ) induced by direct mechanical stimulation of MCs. We also measured [Ca 2+ ] i in the trigeminal ganglion neurons (TGs) following direct mechanical stimulation to the MCs in an MC-TGs coculture. The MCs were isolated from hamster buccal mucosa, while TGs were isolated from neonatal Wistar rats. Both cell populations showed depolarization-induced [Ca 2+ ] i . Direct mechanical stimulation to MCs increased [Ca 2+ ] i , showing stimulation strength dependence. In the MC-TGs coculture, the application of direct mechanical stimulation to MCs resulted in increased [Ca 2+ ] i in the TGs. These changes were significantly suppressed by antagonists of glutamate-permeable anion channels (4,4′-diisothiocyanato-2,2′-stilbenedisulfonic acid; DIDS), and non-competitive antagonist of the N -methyl- D -aspartate (NMDA) receptors (MK801). Apyrase, an ATP-degrading enzyme, and suramin, a non-selective P2 purinergic receptor antagonist, did not exert inhibitory effects on these [Ca 2+ ] i increases in the TGs following MC stimulation. These results indicated that MCs are capable of releasing glutamate, but not ATP, in response to cellular deformation by direct mechanical stimulation. The released glutamate activates the NMDA receptors on TGs. We suggest that MCs act as mechanoelectrical transducers and establish synaptic transmission with neurons, through the MC-neurite complex, to mediate mechanosensory transduction.

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“…However, there is still controversy about the type of neurotransmitter release that mediates prolonged static-phase firing in Merkel cell afferents [ 75 , 79 ]. The author emphasizes the importance of glutamate release, as demonstrated by Higashikwa et al [ 75 , 80 ]. Glutamate is the likely candidate due to its contribution to neural injury signaling and pain sensation.…”

Less Is More: Rare Pulmonary Neuroendocrine Cells Function as Critical Sensors in Lung

“…They have recently been found to be innervated by sensory neurons and can activate neurons through enteroendocrine secretion of glutamate and serotonin (Bellono et al, 2017;Kaelberer et al, 2018).In contrast, some epithelial receptor cells for canonical senses are found to also possess endocrine features. For example, Merkel cells, the epithelial sensors for gentle touch, produces not only neurotransmitters such as glutamate and norepinephrine but also neuropeptides such as CGRP (Higashikawa et al, 2019;Lucarz and Brand, 2007). These observations suggest that the ability to produce, store, and release both fast-acting neurotransmitters and slow-acting local hormones or neuropeptides may be shared by multiple tissue-resident sensory cell types.…”

Reducing Merkel cell activity in the whisker follicle disrupts cortical encoding of whisker movement amplitude and velocity

“…Among the most prominent whisker mechanoreceptors is the Merkel cell-neurite complex ( Gottschaldt and Vahle-Hinz, 1981 , Halata et al, 2003 , Iggo and Muir, 1969 , Woo et al, 2015 ) in which mechanically excitable cells (i.e. Merkel cells, MCs) synaptically excite primary trigeminal afferent neurons to fire SA impulses ( Chang et al, 2016 , Higashikawa et al, 2019 , Hoffman et al, 2018 , Ikeda et al, 2014 , Ikeda et al, 1994 , Maksimovic et al, 2014 , Maricich et al, 2009 , Nakatani et al, 2015 , Woo et al, 2014 , Woo et al, 2015 ). The activity of MCs strongly correlates with whisker displacement amplitude ( Ikeda et al, 2014 ), and MC-associated afferents show robust coding of whisker self-movement, angle, and whisk-phase during whisking ( Furuta et al, 2020 , Severson et al, 2017 ).…”