The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor Function

• Published in: Cell reports (Cambridge) Vol. 10; no. 3; pp. 370 - 382
• Main Authors: François, Amaury, Schüetter, Niklas, Laffray, Sophie, Sanguesa, Juan, Pizzoccaro, Anne, Dubel, Stefan, Mantilleri, Annabelle, Nargeot, Joel, Noël, Jacques, Wood, John N., Moqrich, Aziz, Pongs, Olaf, Bourinet, Emmanuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2015; Elsevier
• Subjects: Cellular Biology; Life Sciences; Neurobiology; Neurons and Cognition
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.12.042

The T-type calcium channel Cav3.2 emerges as a key regulator of sensory functions, but its expression pattern within primary afferent neurons and its contribution to modality-specific signaling remain obscure. Here, we elucidate this issue using a unique knockin/flox mouse strain wherein Cav3.2 is replaced by a functional Cav3.2-surface-ecliptic GFP fusion. We demonstrate that Cav3.2 is a selective marker of two major low-threshold mechanoreceptors (LTMRs), Aδ- and C-LTMRs, innervating the most abundant skin hair follicles. The presence of Cav3.2 along LTMR-fiber trajectories is consistent with critical roles at multiple sites, setting their strong excitability. Strikingly, the C-LTMR-specific knockout uncovers that Cav3.2 regulates light-touch perception and noxious mechanical cold and chemical sensations and is essential to build up that debilitates allodynic symptoms of neuropathic pain, a mechanism thought to be entirely A-LTMR specific. Collectively, our findings support a fundamental role for Cav3.2 in touch/pain pathophysiology, validating their critic pharmacological relevance to relieve mechanical and cold allodynia. [Display omitted] •Cav3.2 calcium channels are markers of both C- and Aδ- low-threshold mechanoreceptors•Cav3.2 in receptive fields and axons facilitates action potential initiation and conduction•Cav3.2 in C-LTMR governs innocuous touch, noxious mechanical cold, and chemical pain•Cav3.2 channels in C-LTMRs are molecular substrates of allodynia in neuropathic pain François et al. show that Cav3.2 calcium channels are potent and specific regulators of low-threshold mechanoreceptors (LTMRs) setting the efficient detection, conduction, and transfer of tactile/pain information. In C-LTMRs, this mechanism crucially contributes to neuropathic pain, highlighting the utility of a therapeutic Cav3.2-inhibition strategy to improve patient quality of life.