Cold receptor confirmed

An ion channel long-suspected to play a key role in sensing cold does, indeed, drive response to low temperatures in mice, according to a paper published online this week in Nature. The researchers found that mice without a functioning receptor called TRPM8 show deficits in their ability to detect cold temperatures. Two papers in this month's Neuron support the findings, reporting cold detection deficiencies in TRPM8-knockout mice."I think things are pretty clear," senior author David Julius of the University of California, San Francisco (UCSF) told The Scientist. "TRPM8 is the major detector of cold stimuli."Previous work has suggested that different transient receptor potential (TRP) ion channels are involved in thermal detection at different temperatures. One of these channels, TRP melastatin 8 (TRPM8), is activated by chemical cooling agents like menthol, as well as by low environmental temperatures. However, some studies have suggested that TRPM8 may not comprise the principal mechanism of cold detection, Julius said.To isolate TRPM8's role in cold detection, the authors, led by Diana Bautista and Jan Siemens of UCSF and Joshua Glazer of the Medical College of Wisconsin in Milwaukee, analyzed TRPM8-deficient mice. Neurons from these mice were completely unresponsive to menthol as well as to another cooling agent. Intact sensory nerve fibers in these mice exhibited a dramatically reduced sensitivity to cold.The TRPM8-deficient mice also displayed behavioral deficits in cold detection. When researchers apply acetone to mice's paws, they normally flinch in response to the cool sensation as the acetone evaporates. Knockout mice, however, showed a diminished response during this experiment. TRPM8 knockouts also failed to discriminate between adjacent surfaces of different temperatures. Wild-type mice prefer to remain on a surface heated to 30°C if the adjacent surface is cooler. As the temperature of the cooler surface drops, they spend more time on the warmer surface. TRPM8 knockouts showed no such preference until the temperature of the cool surface dropped below 15°C. Even at the lowest temperatures, knockouts spent more time on the cool surface than wild-types did.The TRPM8-deficient animals did display some awareness of cold temperatures below 15°C, a threshold which may act as a cutoff between innocuous cool and noxious cold temperatures."There are diminished responses to noxious cold in the TRPM8 mice, but they still do respond," said David McKemy of the University of Southern California in Los Angeles, who was not involved in the study. The receptor "is not the only thing that appears to be detecting cold.""The emerging picture is one of complexity. Eliminating TRPM8 strongly reduces, without abolishing, cold-evoked activity, pointing towards additional mechanisms," noted Félix Viana of the Spanish Council for Scientific Research in Madrid, also not a co-author.It's unclear which other mechanisms may be operating at very low temperatures, Julius said, although they could relate to tissue injury or vascular changes. "That's still the question that looms out there," he said. "Is there really a difference mechanistically between cool and noxious cold?" The two Neuron papers present very similar results, except both found a small residual effect of menthol in TRPM8-deficient cells, McKemy said. "What all three papers do show is that there appear to be some alternative, unknown mechanisms but that in general, the majority of cold responses are likely due to TRPM8."Melissa Lee Phillips mail@the-scientist.comLinks within this articleT. Toma, "Cool sensations," The Scientist, February 11, 2002. http://www.the-scientist.com/article/display/20210/D.M. Bautista et al., "The menthol receptor TRPM8 is the principal detector of environmental cold," Nature, published online May 30, 2007. http://www.nature.com/natureR.W. Colburn et al., "Attenuated cold sensitivity in TRPM8 null mice," Neuron, May 3, 2007. http://www.the-scientist.com/pubmed/17481392A. Dhaka et al., "TRPM8 is required for cold sensation in mice," Neuron, May 3, 2007. http://www.the-scientist.com/pubmed/17481391David Julius http://www.ucsf.edu/djlabA. Dhaka et al., "Trp ion channels and temperature sensation," Annual Review of Neuroscience, 2006. http://www.the-scientist.com/pubmed/16776582M.M. Stephan, "Signals from the frontlines," The Scientist, March 28, 2005. http://www.the-scientist.com/article/display/15363/M.M. Stephan, "How hot peppers helped David Julius make the TRP channel connection," The Scientist, March 28, 2005. http://www.the-scientist.com/2005/03/28/S22/1/A.M. Peier et al., "A TRP channel that senses cold stimuli and menthol," Cell, March 8, 2002. http://www.the-scientist.com/pubmed/11893340R. Madrid et al., "Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals," Journal of Neuroscience, November 28, 2006. http://www.the-scientist.com/pubmed/17135413P. Rainville et al., "Psychophysical study of noxious and innocuous cold discrimination in monkey," Experimental Brain Research, March 1999. http://www.the-scientist.com/pubmed/10100973David McKemy http://www.usc.edu/programs/neuroscience/faculty/profile.php?fid=55Félix Viana http://in.umh.es/?page=personalsg&key=54

Cold receptor confirmed

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