Abstract
Menthol-sensitive/capsaicin-insensitive neurons (MS/CI) and menthol-sensitive/capsaicin-sensitive neurons (MS/CS) are thought to represent two functionally distinct populations of cold-sensing neurons that use TRPM8 receptors to convey innocuous and noxious cold information respectively. However, TRPM8-mediated responses have not been well characterized in these two neuron populations. Using rat dorsal root ganglion neurons, here we show that MS/CI neurons had larger menthol responses with greater adaptation. In contrast, MS/CS neurons had smaller menthol responses with less adaptation. All menthol-sensitive neurons showed significant reduction of menthol responses following the treatment of cells with the protein kinase C (PKC) activator PDBu (Phorbol 12,13-dibutyrate). PDBu-induced reduction of menthol responses was completely abolished in the presence of PKC inhibitors BIM (bisindolylmaleimide) or staurosporine. When menthol responses were examined in the presence of protein kinase inhibitors, it was found that the adaptation was significantly attenuated by either BIM or staurosporine and also by the Ca2+/calmodulin-dependent protein kinase (CamKII) inhibitor KN62 (N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine) in MS/CI neurons. In contrast, in MS/CS neurons menthol response was not affected significantly by BIM, staurosporine or KN62. In both MS/CI and MS/CS neurons, the menthol responses were not affected by PKA activators forskolin and 8-Br-cAMP (8-Bromoadenosine-3', 5'-cyclic monophosphate) or by protein kinase A (PKA) inhibitor Rp-cAMPs (Rp-Adenosine-3',5'-cyclic monophosphorothioate). Taken together, these results suggest that TRPM8-mediated responses are significantly different between non-nociceptive-like and nociceptive-like neurons.
Highlights
Transient receptor potential M8 (TRPM8) receptor, first cloned by MacKemy and colleagues [1] as well as Peier and colleagues [2] from primary afferent neurons of rats and mice, is a principal sensor for cold temperature and belongs to the transient receptor potential (TRP) protein family
We tested these menthol-sensitive neurons with capsaicin (0.5 μM, 10 sec) and AIT (100 μM, 10 sec) in order to see if, in some of them, TRPM8 receptors were co-expressed with TRPV1 and TRPA1, two receptors believed to be expressed in nociceptive primary afferent neurons [12,27,28]
Of 71 menthol-sensitive neurons tested with capsaicin, 56% (40/71) were Menthol-sensitive/capsaicin-insensitive neurons (MS/CI) neurons and 44% (31/71) were menthol-sensitive/capsaicin-sensitive neurons (MS/CS) neurons (Figure 1D)
Summary
Transient receptor potential M8 (TRPM8) receptor, first cloned by MacKemy and colleagues [1] as well as Peier and colleagues [2] from primary afferent neurons of rats and mice, is a principal sensor for cold temperature and belongs to the transient receptor potential (TRP) protein family. Like most of other members in TRP family, TRPM8 is a membrane ion channel that can allow positively charged ions (Na+, Ca2+, K+) to flow through cell membranes when the channel opens. The TRPM8 channel opens when temperature drops below 26 ± 2°C, resulting in depolarizing membrane currents [1,2,3]. Membrane currents flowing through TRPM8 channels increase with decreasing temperature and reach. The percentage of mentholsensitive cells in acutely dissociated rat DRG neurons is similar to that of TRPM8-expressing DRG neurons [9,10].
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