De rol van TRP kanalen in het voelen van pijnlijke hitte

Abstract

Although several members of the transient receptor potential (TRP) superfamily of cation channels have been implicated in somatosensation, the expression levels of TRP channel genes in the individual sensory ganglia have never been systematically studied. In the first part of this thesis, we developed, compared, and refined techniques to quantitatively analyse the relative mRNA expression of all TRP channels in trigeminal and individual dorsal root ganglia from 27 anatomically defined segments of the spinal cord of the mouse. At the mRNA level, 17 of the 28 TRP channel genes, TRPA1, TRPC1, TRPC3, TRPC4, TRPC5, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV4, TRPML1, and TRPP2, were detectable in every tested ganglion. Notably, four TRP channels, TRPC4, TRPM4, TRPM8, and TRPV1, showed statistically significant variation in mRNA levels between dorsal root ganglia from different segments, suggesting ganglion-specific regulation of TRP channel gene expression. This study provides for the first time a comparative mRNA distribution profile in TG and DRG along the entire vertebral column for the mammalian TRP channel family. Furthermore, although it is well-known that acute heat sensing in mammals is performed by a subset of sensory neurons expressing the heat sensor TRPV1, genetic ablation of TRPV1 or other candidate heat sensors, such as TRPM3, only resulted in small deficits in noxious heat sensing. So, the molecular basis of noxious heat sensing remained largely unresolved. In the second part of this thesis, we demonstrate that acute noxious heat sensing is mediated by a set of three TRP ion channels. We compared the sensitivity to heat in wild type mice and mice deficient for TRPV1, TRPM3, and TRPA1 in combined knockouts. We found that all double knockout mice retain robust heat responses at the cellular and behavioural level. In contrast, Trpa1-/-/Trpm3-/-/Trpv1-/- mice lack heat responses in isolated sensory neurons, and show a striking deficit in the heat sensitivity of intact C and Aδ nerve fibres and in the nociceptive responses to painfully hot temperatures. Reintroducing any of the three TRP channels into triple knockout sensory neurons restores heat responsiveness. Together, these data indicate that TRPA1, TRPV1, and TRPM3 have critical but redundant roles in acute noxious heat sensing. This redundancy could be a fail-safe mechanism allowing heat avoidance, even when the function of one or two molecular heat sensors is compromised.status: publishe