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Review
. 2020:85:119-150.
doi: 10.1016/bs.ctm.2020.01.009. Epub 2020 Feb 29.

Regulation of vascular tone by transient receptor potential ankyrin 1 channels

Pratish Thakore  1 , Sher Ali  1 , Scott Earley  2
Affiliations
Review

Regulation of vascular tone by transient receptor potential ankyrin 1 channels

Pratish Thakore et al. Curr Top Membr. 2020.

Abstract

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.

Keywords: Endothelium; Perivascular nerves; TRP channels; TRPA1; Vasodilation.

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Conflict of interest statement

Disclosures The authors have no conflicts of interest, financial or otherwise, to report.

Figures

Fig. 1
Fig. 1
High resolution cryo-EM structure of TRPA1. (A) Representative cryo-EM 2-dimensional image of TRPA1 (left and middle, side view; right, end-on view). (B) Representative image of negative stain particles. (C) 3-Dimensional density map of TRPA1 with each subunit color coded (left, side view; middle, top view; right, bottom view). Figure derived from Paulsen, C. E., Armache, J. P., Gao, Y., Cheng, Y., & Julius, D. (2015). Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature, 520(7548), 511–517. https://doi.org/10.1038/nature14367.
Fig. 2
Fig. 2
Sensory nerve TRPA1-dependent vasodilation. Activation of TRPA1 channels on pre-synaptic sensory nerves leads to Ca2+ influx. This causes the release of CGRP, which binds CGRP receptors on vascular smooth muscle cells and mediates hyperpolarization and relaxation.
Fig. 3
Fig. 3
TRPA1 activation causes endothelium-dependent vasodilation in cerebral arteries. (A) (Top) Immunolabeling for TRPA1 (red) in rat coronary, renal, mesenteric and cerebral arteries (scale bar, 10 μm). Green is autofluorescence produced by the internal elastic lamina. TRPA1 was only detected in the endothelium of the cerebral vasculature and not in other vascular beds. Bottom: omission of primary antibody. (B) Representative trace and summary data demonstrating that the TRPA1 agonist AITC (100 μM) induces vasodilation of rat cerebral arteries, which was significantly reduced following disruption of the endothelium (n = 3, *P ≤ 0.05 vs control). (C) Representative trace and summary data showing the vasodilation to AITC is blocked by the selective TRPA1 antagonist HC-030031 (3 μM) (n = 3, *P ≤ 0.05 vs control). Panel (A) image derived from Sullivan, M. N., Gonzales, A. L., Pires, P. W., Bruhl, A., Leo, M. D., Li, W., et al. (2015). Localized TRPA1 channel Ca2+ signals stimulated by reactive oxygen species promote cerebral artery dilation. Science Signaling, 8(358), ra2. doi: https://doi.org/10.1126/scisignal.2005659 (web archive link), Panels (B and C) images derived from Earley, S., Gonzales, A. L., & Crnich, R. (2009). Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-activated K+ channels. Circulation Research, 104(8), 987–994. https://doi.org/10.1161/CIRCRESAHA.108.189530 (web archive link).
Fig. 4
Fig. 4
Endothelial TRPA1-dependent dilation of cerebral arteries. Activation of TRPA1 channels present in myoendothelial projections (MEPs) causes Ca2+ influx. Ca2+ is released from the endothelial cell ER through IP3Rs via a Ca2+-induced Ca2+-release mechanism. Intermediate conductance Ca2+-activated K+ channels (KCa3.1) are activated and the resulting K+ efflux causes hyperpolarization of the endothelial cell plasma membrane (EC PM). The change in membrane potential (ΔEM) is conducted to the underling smooth muscle through myoendothelial gap junctions (MEGJs), resulting in hyperpolarization of the smooth muscle plasma membrane (SM PM) and relaxation.
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