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The Journal of Neuroscience, March 11, 2009, 29(10):3120-3131; doi:10.1523/JNEUROSCI.4778-08.2009

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Cellular/Molecular
Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels

Rodolfo Madrid,^1,2 * Elvira de la Peña,^1 * Tansy Donovan-Rodriguez,¹ Carlos Belmonte,¹ and Félix Viana¹

¹Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain, and ²Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile

Correspondence should be addressed to Dr. Félix Viana, Universidad Miguel Hernández, Instituto de Neurociencias-CSIC, Apartado 18, San Juan de Alicante, 03550 Spain. Email: felix.viana{at}umh.es

Molecular determinants of threshold differences among cold thermoreceptors are unknown. Here we show that such differences correlate with the relative expression of I_KD, a current dependent on Shaker-like Kv1 channels that acts as an excitability brake, and I_TRPM8, a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression of I_KD. In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent I_KD. Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade of I_KD shifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of I_KD blockade were observed in TRPA1^–/– mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.

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Received Oct. 2, 2008; revised Jan. 28, 2009; accepted Feb. 6, 2009.

Correspondence should be addressed to Dr. Félix Viana, Universidad Miguel Hernández, Instituto de Neurociencias-CSIC, Apartado 18, San Juan de Alicante, 03550 Spain. Email: felix.viana{at}umh.es

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				P. Orio, R. Madrid, E. de la Peña, A.és Parra, Víc. Meseguer, D. A. Bayliss, C. Belmonte, and Fél. Viana Characteristics and physiological role of hyperpolarization activated currents in mouse cold thermoreceptors J. Physiol., May 1, 2009; 587(9): 1961 - 1976. [Abstract] [Full Text] [PDF]

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