The menthol receptor TRPM8 is the principal detector of environmental cold

Citation metadata

From: Nature(Vol. 448, Issue 7150)
Publisher: Nature Publishing Group
Document Type: Report
Length: 5,823 words
Lexile Measure: 1550L

Document controls

Main content

Article Preview :

Author(s): Diana M. Bautista [1, 2, 7]; Jan Siemens [1, 2, 7]; Joshua M. Glazer [5, 7]; Pamela R. Tsuruda [1, 2]; Allan I. Basbaum [3, 4]; Cheryl L. Stucky (corresponding author) [5]; Sven-Eric Jordt [6]; David Julius (corresponding author) [1, 2]

Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels [1, 2, 3, 4]. One such channel--TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)--is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below [similar]26 [degrees]C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons [5, 6]. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo [7, 8, 9, 10]. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 [degrees]C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis [2] that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.

We generated TRPM8-deficient mice through targeted deletion of a genomic region encoding amino acids 594-661 within the presumptive cytoplasmic amino-terminal domain. In addition to removing coding information, this manipulation introduced a stop codon before and a frameshift after the deleted segment (Fig. 1a). Successful targeting was verified by Southern blotting and RT-PCR analysis of transcripts from trigeminal ganglia of wild-type and mutant mice (Fig. 1b). The resulting TRPM8 -/- mice were normal in overall appearance and viability, and matings between heterozygous animals produced siblings with normal mendelian distributions for gender and genotype. Moreover, mutant and wild-type littermates showed no differences in core body temperature (37.4 [plus or minus] 0.15 [degrees]C and 37.4 [plus or minus] 0.13 [degrees]C, respectively; n = 11 mice per genotype).

Sensory ganglia from TRPM8-deficient mice appeared anatomically normal, as was assessed by staining with a variety of immunological probes that label peptidergic, unmyelinated or vanilloid-responsive neurons (Fig. 1c, d). Thus, antibodies directed against substance P (peripherin) or the capsaicin receptor (TRPV1) revealed an identical prevalence of labelled cells in trigeminal ganglia from wild-type and mutant mice. In contrast, TRPM8 immunoreactivity was specifically absent from trigeminal ganglia or the peripheral free nerve endings of adult mutant mice. Central projections of primary afferent fibres to the spinal cord of TRPM8 -/- mice were also devoid of TRPM8 immunoreactivity, while those from wild-type littermates showed a robust pattern of staining that was confined to the most superficial layer of...

Source Citation

Source Citation   

Gale Document Number: GALE|A185560788