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Functional expression and pharmacological modulation of TRPM3 in human sensory neurons
Author(s) -
Vangeel Laura,
Benoit Melissa,
Miron Yannick,
Miller Paul E.,
De Clercq Katrien,
Chaltin Patrick,
Verfaillie Catherine,
Vriens Joris,
Voets Thomas
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14994
Subject(s) - dorsal root ganglion , transient receptor potential channel , neuroscience , damgo , agonist , nociceptor , trpv1 , chemistry , receptor , biology , sensory system , opioid receptor , nociception , biochemistry
Background and Purpose The transient receptor potential (TRP) ion channel TRPM3 functions as a noxious heat sensor, plays a key role in acute pain sensation and inflammatory hyperalgesia in rodents. Despite its potential as a novel analgesic drug target, little is known about the expression, function and modulation in the humans. Experimental Approach We studied TRPM3 in freshly isolated human dorsal root ganglion (hDRG) neurons and human stem cell‐derived sensory (hSCDS) neurons. Expression was analysed at the mRNA level using RT‐qPCR. Channel function was assessed using Fura‐2‐based calcium imaging and whole‐cell patch‐clamp recordings. Key Results TRPM3 was detected at the mRNA level in both hDRG and hSCDS neurons. The TRPM3 agonists pregnenolone sulphate (PS) and CIM0216 evoked robust intracellular Ca 2+ responses in 52% of hDRG and 58% of hSCDS neurons. Whole‐cell patch‐clamp recordings in hSCDS neurons revealed pregnenolone sulphate (PS)‐ and CIM0216‐evoked currents exhibiting the characteristic current–voltage relation of TRPM3. PS‐induced calcium responses in hSCDS neurons were reversed in a dose‐dependent manner by the flavonoid isosakuranetin and by antiseizure drug primidone. Finally, the μ‐opioid receptor agonist DAMGO and the GABA B receptor agonist baclofen inhibited PS‐evoked TRPM3 responses in a subset of hSCDS neurons. Conclusion and Implications These results provide the first direct evidence of functional expression of the pain receptor TRPM3 in human sensory neurons, largely mirroring the channel's properties observed in mouse sensory neurons. hSCDS neurons represent a valuable and readily accessible in vitro model to study TRPM3 regulation and pharmacology in a relevant human cellular context.