Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation

Figures

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  Figure 1. Cryo-EM structure of the open capsaicin-bound rat TRPV1 channel at 48 °C (redrawn from pdb: 7LPE, [4]). (A) shows the side view of the TRPV1 channel, and (B) shows the bird’s eye view of the channel. (C,D) show the magnified views of the capsaicin binding site from the side and from the top, respectively. The key residues that are important for coordinating capsaicin are shown in blue. S3 and S5 transmembrane domains are colored in orange, and capsaicin molecules are shown as red sticks.

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  Figure 2. Membrane topology of rat TRPV1. The TRPV1 channel becomes sensitized if it is phosphorylated by either PKA or PKC at the indicated sites within the intracellular N- and C-termini. Sensitization of TRPV1 means that a higher cation influx through the channel is observed when it is activated by any of the natural stimuli, such as heat, H+, or capsaicin, compared to its unsensitized state. Cap = capsaicin.

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  Figure 3. Expression pattern of TRPV1. TRPV1 channels are expressed in nociceptive, sensory nerve fibers innervating the skin and visceral sensory nerve fiber endings, smooth muscle, and endothelial cells within the vascular wall. TRPV1 activation in visceral sensory nerve endings leads to calcitonin gene related peptide (CGRP) release. CGRP then acts on vascular smooth muscle cells, causing vasodilation. Activation of postganglionic sympathetic nerve fibers results in noradrenaline (NA) release, which results in vasoconstriction.

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  Figure 4. Vascular wall inflammation may sensitize TRPV1 channels expressed in vascular smooth muscle cells. PKC activity is low in healthy vessels. However, when the blood vessel becomes inflamed, the PKC is activated and PKC-dependent phosphorylation of many intracellular proteins occurs. TRPV1 channels are expressed in both endothelial and smooth muscle cells. The upper panel shows a resting smooth muscle cell (SMC)/endothelial cell (EC) in a healthy artery. In this case, the TRPV1 channel is not phosphorylated (is not sensitized). The middle panel demonstrates the phosphorylated TRPV1 channel in an inflamed vessel, capable of carrying a greater cation influx because it is sensitized. The lower panel illustrates that the excess of capsaicin may precipitate vasoconstriction overpowering capsaicin-induced dilations in the inflamed arteries. The boxed inset shows an isometric tension recording illustrating capsaicin-induced responses in a PGF2α-precontracted dog coronary artery ring [24]. Horizontal bars show the times when PGF2α and capsaicin were added to the tissue bath. cap = capsaicin.