| First Author | Andrianov YE | Year | 2025 |
| Journal | J Physiol | Volume | 603 |
| Issue | 20 | Pages | 6365-6389 |
| PubMed ID | 40172079 | Mgi Jnum | J:376639 |
| Mgi Id | MGI:8271101 | Doi | 10.1113/JP286407 |
| Citation | Andrianov YE, et al. (2025) Activation of TRPA1 and TRPM3 triggers Ca(2+) waves in central terminals of sensory neurons and facilitates synaptic activity in the spinal dorsal horn. J Physiol 603(20):6365-6389 |
| abstractText | Transient receptor potential ankyrin 1 (TRPA1) and melastatin 3 (TRPM3) are transduction channels of sensory neurons that play major roles in peripheral mechanisms of somatosensation, including thermosensation, chemosensation and nociception. Recent studies suggest that both channels also contribute to central mechanisms of pain processing at the spinal cord level. TRPA1 and TRPM3 are highly permeable for Ca(2+), suggesting that they could regulate Ca(2+) signalling at spinal synapses. However, information about TRPA1- and TRPM3-induced Ca(2+) signalling in the dorsal horn (DH) of the spinal cord is lacking. Here, we describe a dual-colour technique for simultaneously measuring Ca(2+) concentration ([Ca(2+)](i)) in central terminals of sensory neurons and in spinal DH neurons by green (GCaMP3) and red (jRGECO1a) Ca(2+) indicators, using two-photon imaging in isolated mouse spinal cord with attached dorsal roots (DR). DR stimulation elicited [Ca(2+)](i) transients in axonal boutons of primary afferents and in cell bodies of DH neurons. The antagonists of AMPA and NMDA glutamate receptors, CNQX and AP5, inhibited [Ca(2+)](i) transients in DH neurons, but not in sensory axonal boutons. Selective agonists of TRPA1 and TRPM3, ASP7663 and CIM0216, induced complex [Ca(2+)](i) responses in distinct but partially overlapping subsets of sensory axonal boutons. Concomitant [Ca(2+)](i) elevations were observed in DH neurons, which were blocked by CNQX and AP5. Patch clamp recordings from DH neurons showed that ASP7663 and CIM0216 markedly enhanced excitatory synaptic activity. In summary, our findings suggest that TRPA1 and TRPM3 on central terminals of sensory neurons regulate presynaptic [Ca(2+)](i) and synaptic transmission in the spinal DH. KEY POINTS: Transient receptor potential ankyrin 1 (TRPA1) and melastatin 3 (TRPM3) are transduction channels of sensory neurons that play major roles in peripheral mechanisms of somatosensation and central mechanisms of pain processing. These two receptors are highly permeable for Ca(2+), suggesting that they could regulate Ca(2+) signalling at spinal synapses. This study uses a dual-colour technique to simultaneously measure Ca(2+) changes in response to electrical and chemical stimulation in the central terminals of sensory neurons and in spinal dorsal horn neurons in an intact, ex vivo spinal cord with attached dorsal roots. Selective agonists of TRPA1 and TRPM3 induced complex Ca(2+) responses in sensory boutons and evoked synaptically-driven Ca(2+) changes in dorsal horn neurons. These results help us to better understand TRPA1 and TRPM3 mediated synaptic transmission in the spinal cord, potentially explaining the role of these channels in pain processing. |
