Various noxious stimuli trigger the depolarization of small-diameter sensory neurons in the trigeminal ganglia and dorsal root ganglia (DRG). Heat activates the cation channel TRPV1; however, Trpv1–/– mice still avoid noxious heat, indicating the presence of other mechanisms that elicit behavioral responses to excessive heat. Cho et al. (see also Bandell and Patapoutian) characterized the Ca2+-activated Cl– channel anoctamin 1 (ANO1) as a heat sensor. Cells ectopically expressing mouse ANO1 produced Cl– currents in response to temperatures over 44°C, which was the thermal threshold of activation for ANO1. Furthermore, increasing the intracellular Ca2+ concentration enhanced the magnitude of heat-induced currents and reduced the temperature threshold for activation. Immunocytochemistry indicated the presence of ANO1 in small-diameter nociceptive neurons. Inward Cl– currents were detected in cultured DRG neurons from wild-type and Trpv1–/– mice upon application of a heat ramp (from 23 to 48°C), and DRG neurons from wild-type and Trpv1–/– mice depolarized in response to the heat ramp when assayed with a physiological intracellular concentration of Cl–. The frequency of heat-induced action potential spikes was higher in DRG neurons from wild-type mice than in those from Trpv1–/– mice, and pharmacologically blocking TRVP1 and ANO1 activity (with capsazepine and mefloquine, respectively) substantially attenuated heat-induced currents in wild-type DRG neurons. Rats treated with mefloquine took longer to withdraw their tails from radiant heat than saline-treated rats. Intraplantar injection of carrageenan causes inflammation and sensitization to heat-induced pain (called heat-induced hyperalgesia), an effect that was prevented in rats by treatment with mefloquine. Wild-type or Trpv1–/– mice treated intrathecally with small-interfering RNA (siRNA) against ANO1 took longer to withdraw their tails from radiant heat than those treated with scrambled siRNA. DRG neurons from mice in which Ano1 was knocked down specifically in trigeminal neurons and DRG neurons showed decreased inward Cl– current in response to heat, and these mice were less sensitive to heat-induced pain as assessed by various tests. The authors note that ANO1 agonists have been considered as a treatment for cystic fibrosis, and their results suggest that these compounds might cause heat sensitivity.
H. Cho, Y. D. Yang, J. Lee, B. Lee, T. Kim, Y. Jang, S. K. Back, H. S. Na, B. D. Harfe, F. Wang, R. Raouf, J. N. Wood, U. Oh, The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons. Nat. Neurosci. 15, 1015–1021 (2012). [PubMed]
M. Bandell, A. Patapoutian, A hot new channel. Nat. Neurosci. 15, 931–933 (2012). [PubMed]