otential (TRP) superfamily of ion channels comprises proteins with six transmembrane domains and cytoplasmic N- and C-termini. TRP proteins assemble as homo- or heterotetramers to form cation-permeable ion channels (Voets et al., 2005
). Currently, 28 TRP channels have been discovered in mammals and based on their sequence homology, are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPP and TRPML (Montell, 2005
). This review highlights recent discoveries describing the roles of TRPV1, TRPM8 and TRPA1 in transduction and sensitization in primary afferent somatosensory neurons. The first TRP channel discovered in mammalian sensory neurons was Transient Receptor Potential Vanilloid 1 (TRPV1). TRPV1 is the obligate receptor for capsaicin, the spicy ingredient in hot chili peppers, and also a key receptor for noxious physical heat (>42 °C; Caterina et al., 1997
). TRPV1 is found on many small-medium-diameter nociceptive sensory neurons which are likely to have C fiber axons (Tominaga et al., 1998
). The identification of TRPV1 was the major catalyst that launched the fields of somatosensory and pain transduction research to the molecular level, and discovery of additional TRP family members rapidly followed.
Transient Receptor Potential Ankyrin 1 (TRPA1) is the only member of the ankyrin subfamily found in mammals. Originally called ANKTM1, TRPA1 was identified by a homology search for ankyrin domains and six transmembrane domains and is 20% homologous at the amino acid level to TRPV1 (Jaquemar et al., 1999
; Story et al., 2003
). Its structure is distinct from other TRP channels as it is the only member with an extended (14–17) ankryin repeat domain in the N-terminus (Clapham, 2003
). TRPA1 channels are expressed in a subpopulation of unmyelinated nociceptors that also express the capsaicin receptor TRPV1, suggesting an important role in nociception. Consistent with this posit, TRPA1 is activated by a diverse assortment of pungent or irritating reactive chemical compounds including those found in mustard oil (allyl isothiocyanate), cinnamon oil (cinnamaldehyde), gas exhaust (acrolein), raw garlic and onions (allicin) and formalin (formaldehyde); all of these elicit a painful burning or prickling sensation (Story et al., 2003
; Bandell et al., 2004
; Jordt et al., 2004
; Macpherson et al., 2005
; Bautista et al., 2006
; McNamara et al., 2007
). Moreover, TRPA1 has been put forth as a putative transducer of natural physical stimuli including both cold and mechanical force (Story et al., 2003
, Corey et al., 2004
). Thus, a common theme has emerged whereby TRPA1 is found in nociceptors and the modality(s) of nociception to which it mechanistically contributes appear to be quite diverse. Like TRPV1 (Caterina et al., 2000
), TRPA1 may be a molecular “switchboard” integrator for a range of diverse noxious stimuli.
In this article, we focus on these three principal sensory transduction channels and their roles in processes that span from whole animal pain behavior down to their molecular modulation by signaling proteins. On an anatomical level, we review recent work illuminating the central and peripheral projections of TRPM8-expressing neurons. At the primary afferent function level, we review the evidence supporting a role for TRPA1 in both cold transduction and mechanotransduction incutaneous sensory neurons. On a cellular level, we discuss recent discoveries of both endogenous inflammatory mediators and exogenous irritating chemicals that activate TRPA1. Finally, on a membrane signaling level, we detail the capacity of growth factors to modulate TRPA1 and TRPV1 channel activity, and discuss the roles of scaffolding proteins that assist kinases and phosphatases in diversely modulating these ion channels.