Investigations of the first human with a loss of function mutation in the TRPV1 channel

TRPV1 is a polymodal channel that is natively expressed in nociceptor neurons. It is activated directly by noxious-heat and by several molecules such as endovaniloids, protons and a variety of toxins, such as capsaicin (the pungent ingredient of “hot” pepper). Our recent study identified an individual who showed no aversion towards eating “hot” peppers. Whole exome sequencing identified a novel homozygous missense mutation (N331K) at the ankyrin-repeat-domain (ARD) of the TRPV1 channel. The affected individual demonstrated no sensitivity to capsaicin, reduced sensitivity to noxious-heat, an elevated noxious-cold threshold and extensive flare and pain-response to AITC, a TRPA1 channel activator. Functional assays of the expressed hTRPV1^N331K, revealed a non-functional, but normally expressed, localized and assembled channel. Interestingly, the activity of the mutated channel was not rescued by mutations causing constitutive-activity, suggesting a potential role of the ARD in the gating mechanism of the TRPV1 channel. Several of the observed phenotypes, such as hypersensitivity to AITC are inconsistent with results obtained from TRPV1-KO mice, while other phenotypes, such as hypersensitivity to noxious-cold were neither observed in humans harboring mutations that reduce expression of hTRPV1 nor in TRPV1-KO mice. The above observations raise critical questions of whether the observed phenotypes are individual-specific, species-specific or mutation-specific. Furthermore, although the binding of several ligands to the ARD of the TRPV1 regulate channel activity, this binding was not related to the gating mechanism of the channel. The present work has generated several promising tools, which are expected to give answers to the above fundamental questions.