Trpa1

Abstract

The transient receptor potential ankyrin subtype 1 protein (TRPA1) is a nonselective cation channel permeable to Ca(2+), Na(+), and K(+). TRPA1 is a promiscuous chemical nocisensor that is also involved in noxious cold and mechanical sensation. It is present in a subpopulation of Aδ- and C-fiber nociceptive sensory neurons as well as in other sensory cells including epithelial cells. In primary sensory neurons, Ca(2+) and Na(+) flowing through TRPA1 into the cell cause membrane depolarization, action potential discharge, and neurotransmitter release both at peripheral and central neural projections. In addition to being activated by cysteine and lysine reactive electrophiles and oxidants, TRPA1 is indirectly activated by pro-inflammatory agents via the phospholipase C signaling pathway, in which cytosolic Ca(2+) is an important regulator of channel gating. The finding that non-electrophilic compounds, including menthol and cannabinoids, activate TRPA1 may provide templates for the design of non-tissue damaging activators to fine-tune the activity of TRPA1 and raises the possibility that endogenous ligands sharing binding sites with such non-electrophiles exist and regulate TRPA1 channel activity. TRPA1 is promising as a drug target for novel treatments of pain, itch, and sensory hyperreactivity in visceral organs including the airways, bladder, and gastrointestinal tract.

Streptozotocin Stimulates the Ion Channel TRPA1 Directly

“…However, it is not likely that species differences in the TRPA1 sequence are responsible for this discrepancy. TRPA1 is highly conserved between rats and mice (97% identity), and the residues previously proposed to be important for channel activation are identical (6). Previous reports of thermal and mechanical hyperalgesia, which develop both in hyperglycemic and normoglycemic STZ-treated rats, therefore support our behavioral findings (43,44).…”

“…The major current treatments target the management of pain with anti-convulsant, anti-depressant, and opioid drugs that often have limited efficacy or unacceptable side effects (4). The ion channel TRPA1 is expressed in a subset of nociceptive sensory neurons where it acts as a promiscuous receptor for oxidants and electrophilic agents, but it is also activated by a number of nonreactive compounds (6). Covalent modification of cysteine residues present in the intracellular N terminus of TRPA1 is thought to underlie the agonist activity of oxidants and electrophilic agonists (7,8).…”

The N-terminal Ankyrin Repeat Domain Is Not Required for Electrophile and Heat Activation of the Purified Mosquito TRPA1 Receptor

“…Importantly, the authors concluded that this could best be explained by an effect on the coupling of temperature to channel gating rather than altering the nature of the thermosensitive domain itself (30). This reasoning is in line with our view that conformational changes of the N-terminal ARD indirectly affect thermo-and chemosensitive structures outside the N-terminal ARD of TRPA1 (10,14). Studies of purified TRPA1 without its N-terminal ARD should therefore be a valuable contribution in the search for TRPA1 thermo-and chemosensory domains (14).…”

“…A role for mammalian TRPA1, and especially the human TRPA1 (hTRPA1), as noxious cold sensors has been controversial ever since it was proposed (13), whereas the heat-sensitive role of TRPA1 homologues in non-mammalians has been easily accepted (5,10). However, we have recently shown that hTRPA1 is indeed an intrinsically cold-sensitive protein (14).…”

“…However, these and similar conclusions have to be regarded with some caution because the use of mutagenic and chimeric strategies results in artificial constructs, which makes it difficult to exclude indirect effects on a temperature sensor located elsewhere in the protein (5,10). Furthermore, each of three single point mutations of amino acids in the N-terminal ARD, not previously regarded critical, like certain cysteine and lysine residues (28,29), changed the mouse TRPA1 from being cold-sensitive to being heat-sensitive (30).…”