Some like it hot

Heat receptors provide an important early warning system to allow us to take evasive action to prevent tissue damage. Capsaicin — the 'hot' component of chilli peppers — evokes a sensation of burning pain, so it is not surprising to find that it acts through heat-responsive receptors. One such receptor is the ion channel TRPV1, and in Science, Prescott and Julius report on the identification of a structural motif that is crucial for determining the sensitivity of TRPV1 to hot and spicy stimuli.

TRPV1 is a heat-activated ion channel of the transient receptor potential (TRP) family. The phospholipid molecule phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P₂, PIP₂) inhibits the activation of TRPV1. In the presence of capsaicin or temperatures higher than 43°C, TRPV1 becomes activated. After tissue injury, the release of inflammatory products leads to the activation of phospholipase C, which cleaves PIP₂. The cleavage of PIP₂ relieves the inhibition of TRPV1, which can now be activated at temperatures that are not normally considered to be noxious.

Prescott and Julius identified a motif in the cytoplasmic domain of TRPV1 (amino-acid residues 777–820) that had the structural characteristics of a PIP₂binding site. By expressing mutant forms of TRPV1 in Xenopus oocytes, they examined how the strength of PIP₂ binding influences channel activity.

First, the authors deleted residues 777–820 from the TRPV1 channel. The resulting channel, which they named TRPV1 Δ777–820, was activated at lower temperatures and lower capsaicin concentrations than the wild-type channel. Next, they replaced the TRPV1 PIP₂ binding domain with a domain from the IRK1 channel that binds PIP₂ with relatively high affinity. In this case, the temperature or capsaicin concentration that was required to activate the mutant channel was much higher than normal.

Prescott and Julius concluded that the threshold for TRPV1 activation is determined by the strength of its interaction with PIP₂. This finding raises the possibility that the sensitivity of pain receptors could be regulated by altering their affinity for phospholipids, and this could lead to new clinical strategies for pain management.