Regulation of vascular tone by transient receptor potential ankyrin 1 channels

The Ca²⁺-permeable, non-selective cation channel, TRPA1 (transient receptor potential ankyrin 1), is the sole member of the ankyrin TRP subfamily. TRPA1 channels are expressed on the plasma membrane of neurons as well as non-neuronal cell types, such as vascular endothelial cells. TRPA1 is activated by electrophilic compounds, including dietary molecules such as allyl isothiocyanate, a derivative of mustard. Endogenously, the channel is thought to be activated by reactive oxygen species and their metabolites, such as 4-hydroxynonenal (4-HNE). In the context of the vasculature, activation of TRPA1 channels results in a vasodilatory response mediated by two distinct mechanisms. In the first instance, TRPA1 is expressed in sensory nerves of the vasculature and, upon activation, mediates release of the potent dilator, calcitonin gene-related peptide (CGRP). In the second, work from our laboratory has demonstrated that TRPA1 is expressed in the endothelium of blood vessels exclusively in the cerebral vasculature, where its activation produces a localized Ca²⁺ signal that results in dilation of cerebral arteries. In this chapter, we provide an in-depth overview of the biophysical and pharmacological properties of TRPA1 channels and their importance in regulating vascular tone.