Proceedings of The Physiological Society
Durham University (2010) Proc Physiol Soc 21, C10 and PC10
The physiological basis of acid insensitivity in the African naked mole rat
E. St. John Smith1, D. Omerbasic1, G. Anirudhan1, S. G. Lechner1, G. R. Lewin1
1. Dept. of Neuroscience, Max-Delbr?ck Centre for Molecular Medicine, Berlin, Germany.
Nociceptors are somatic sensory neurons activated by noxious stimuli. Perhaps uniquely among mammals, the African naked mole-rat (NMR, Heterocephalus glaber) displays neither nocifensive behaviour to acid, nor possesses acid-sensitive C-fibre nociceptors (Park et al. 2008, Smith and Lewin 2009). Insensitivity to acid could be explained by a lack of expression of proton-gated ion channels, which we investigated using whole-cell patch clamp to measure proton-gated currents in nociceptor cell bodies (isolated from the dorsal root ganglia, DRG). By recording from NMR sensory neurones we observed that pH5 evoked transient inward currents in 32% of DRG neurones (peak current density: 52±11 pA/pF, n=22) and sustained inward currents in the remaining 68% (32±9 pA/pF, n=36). We observed similar, but smaller, currents in mouse DRG neurones (Mus musculus): 15% transient (12±3 pA/pF, n=11) and 85% sustained (19±4 pA/pF, n=63). We next cloned two NMR ion channels, which are proton-sensitive, present in DRG neurons and thought to play a role in acid-mediated pain, transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 1a (ASIC1a). Both nmrTRPV1 and nmrASIC1a exhibit a similar pH50 compared to other rodent TRPV1s and ASIC1as (nmrTRPV1 = pH5.50 and nmrASIC1a = pH5.64). Interestingly, in DRG neurones proton-gated inward currents did not correlate with action potential (AP) generation as examined in current-clamp, pH5 evoked APs in only 6% of mouse neurones (n=49) and only 19% of NMR neurones. Although acid causes depolarisation, subsequent AP initiation is mediated by voltage-gated sodium channels (NaV) that are inhibited by acid. Total voltage-gated inward currents in mouse DRG neurones were indeed inhibited by acid (IC50 = 5.97) and pH6 inhibited Gmax by 45%. Furthermore, using the in-vitro skin-nerve preparation, the spike rate of mechanically evoked APs in mouse C-fibre nociceptors was also inhibited over time by a pH4.0 solution to ~50% of control levels. NaV currents mediate the bulk of voltage-gated inward current in DRG neurones and pH6 inhibited isolated NaV current Gmax by 46%. Interestingly, voltage-gated inward currents in NMR DRG neurones are significantly more sensitive to acid: pH6 caused 63% inhibition (significantly different from in the mouse, p<0.01, Mann Whitney test). Greater inhibition of NMR NaVs may explain their lack of acid-induced nocifensive behaviour. Thus acid induces inward currents in NMR nociceptors, but larger NaV inhibition compared to mouse prevents AP generation. In conclusion, proton-evoked currents are present in NMR DRG neurones, but voltage-gated inward currents are more sensitive to acid-inhibition, which may explain the lack of acid-induced nocifensive behaviour in NMRs.
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