ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures

Abstract

Mammals detect temperature with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temperatures that activate these channels covers a majority of the relevant physiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temperature compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.

TRPA1 channel activation induces cholecystokinin release via extracellular calcium

“…Transient receptor potential ankyrin 1 (TRPA1) channels, members of transient receptor potential (TRP) superfamily, are calcium permeable non-selective cation channels originally reported to sense noxious cold temperatures [1]. Since their discovery TRPA1 channels have also been implicated in a number of sensory functions including the mediation of nociceptive and inflammatory signals in response to pungent ingredients [2][3][4][5], involvement in the development of cold hyperalgesia following inflammation and nerve injury [6], as well as a role in mechanosensation [7,8].…”

Temperature sensing across species

“…Subsequently, we identified a cold and menthol receptor, TRPM8, from TG neurons using a similar paradigm, thereby establishing that members of the TRP family of ion channels play an important role in thermosensation [47]. Subsequently, four additional TRP channels have been implicated in temperature sensation both in vitro and in vivo, and their properties, along with TRPV1 and TRPM8, can conceivably account for the entire spectrum of perceived temperatures [48][49][50][51][52][53][54][55] (Fig. 3).…”

“…TRPA1 was first reported by Story et al [55] to be activated in vitro by cold temperatures near that considered noxious (<17°C). However, the hypothesis that TRPA1 mediates perceptual responses to noxious cold was contradicted by at least two laboratories that could not reproduce cold activation of the channel in vitro [40,101].…”

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

“…Icilin is a cold-inducing agent that activates two transient receptor potential channels, TRPM8 and TRPA1, in the dorsal root ganglia and trigeminal neurons of the periphery (McKemy et al, 2002;Peier et al, 2002;Reid et al, 2002;Story et al, 2003;Bandell et al, 2004;Jordt et al, 2004;Liu et al, 2006). Upon application to the skin or on the tongue, icilin produces "mild, pleasant sensations of coolness, similar to menthol but discrete and non-irritating" and is 400-600 times more potent than menthol (Wei and Seid, 1983;Behrendt et al,2004;Wei, 2005).Icilin may potentially be used in the treatment of pruritus, hemorrhoids, canker sores, arthritis and pain (Wei and Seid, 1983;Wei, 2005).…”

“…TRPM8 is activated by cool temperatures (<25°C), menthol and icilin (McKemy et al, 2002;Peier et al, 2002); whereas TRPA1 is activated by noxious cold (<17°C), icilin, pungent natural compounds (mustard oil, wintergreen oil, clove oil, cinnamon oil, ginger oil) (Bandell et al, 2004), and raw garlic (Bandell et al, 2004;Bautista et al, 2005;Macpherson et al, 2005), but not by menthol (Story et al, 2003;Jordt et al, 2004). Activation of these channels by their respective agonists results in calcium ion influx and desensitization (McKemy et al, 2002;Peier et al, 2002;Story et al, 2003;Jordt et al, 2004;Liu et al, 2006). Investigation of the downstream effect of channel activation remains unclear, supporting the need to investigate the pharmacology of cold-inducing compounds in vivo.…”