Merkel Cells Activate Sensory Neural Pathways through Adrenergic Synapses

• Published in: Neuron (Cambridge, Mass.) Vol. 100; no. 6; pp. 1401 - 1413.e6
• Main Authors: Hoffman, Benjamin U., Baba, Yoshichika, Griffith, Theanne N., Mosharov, Eugene V., Woo, Seung-Hyun, Roybal, Daniel D., Karsenty, Gerard, Patapoutian, Ardem, Sulzer, David, Lumpkin, Ellen A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-12-2018; Elsevier Limited
• Subjects: Action Potentials - physiology; Adrenergic Agents - metabolism; Adrenergic receptors; Adrenergic transmission; Afferent Pathways - physiology; Animals; Bacterial Capsules - metabolism; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Catecholamines; Clonal deletion; Enzymes; Excitability; Female; Ganglia, Spinal - cytology; Gene expression; Genomics; Male; Merkel Cells - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neurotransmission; Neurotransmitter receptors; Neurotransmitters; Pain perception; Receptors, Adrenergic, beta-2; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Serotonin, 5-HT3 - genetics; Receptors, Serotonin, 5-HT3 - metabolism; Ribonucleic acid; RNA; Skin; Skin - cytology; Skin - innervation; SNAP receptors; Software; Synapses - physiology; Synaptic transmission; Synaptic Transmission - physiology; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Vesicular Monoamine Transport Proteins - genetics; Vesicular Monoamine Transport Proteins - metabolism; Wnt1 Protein - genetics; Wnt1 Protein - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.10.034

Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of β2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch.
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•Epidermal Merkel cells form adrenergic synapses with Aβ mechanosensory afferents•Norepinephrine directly activates action potentials in Merkel-cell afferents•Merkel cells employ SNARE-dependent vesicular release to excite tactile afferents•Neuronal β2-adrenergic receptors are required for slowly adapting type I responses
Hoffman et al. reveal the molecular machinery underlying neurotransmission at a gentle-touch receptor. Employing Eccles’s classical criteria for a chemical synapse, they show that epithelial Merkel cells communicate with sensory neurons through β2-adrenergic receptors at excitatory synapses.