Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1

Abstract

Photosensitization, an exaggerated sensitivity to harmless light, occurs genetically in rare diseases, such as porphyrias, and in photodynamic therapy where short-term toxicity is intended. A common feature is the experience of pain from bright light. In human subjects, skin exposure to 405 nm light induced moderate pain, which was intensified by pretreatment with aminolevulinic acid. In heterologous expression systems and cultured sensory neurons, exposure to blue light activated TRPA1 and, to a lesser extent, TRPV1 channels in the absence of additional photosensitization. Pretreatment with aminolevulinic acid or with protoporphyrin IX dramatically increased the light sensitivity of both TRPA1 and TRPV1 via generation of reactive oxygen species. Artificial lipid bilayers equipped with purified human TRPA1 showed substantial single-channel activity only in the presence of protoporphyrin IX and blue light. Photosensitivity and photosensitization could be demonstrated in freshly isolated mouse tissues and led to TRP channel-dependent release of proinflammatory neuropeptides upon illumination. With antagonists in clinical development, these findings may help to alleviate pain during photodynamic therapy and also allow for disease modification in porphyria patients.

Calcium activates purified human TRPA1 with and without its N-terminal ankyrin repeat domain in the absence of calmodulin

“…A-967079 inhibits hTRPA1 with an IC50 value of 67 nM and is about 100 times more potent than HC030031 (15,16), which was used in this study at a concentration that abolished purified hTRPA1 and Δ1-688 hTRPA1 single-channel activity evoked by chemical ligands, temperature and mechanical stimuli (17)(18)(19)(20). As also reported previously (17)(18)(19)(20), no basal TRPA1 activity was observed at 20-22°C (not shown). Likewise, no channel activity was observed in membranes without the purified hTRPA1 proteins exposed to 10 and 100 µM calcium (n=3, not shown).…”

TRP Channels in Skin Biology and Pathophysiology

“…Patients bearing an N855S gain-of-function mutation in this channel are afflicted with Familial Episodic Pain Disorder, a condition associated with upper body pain that can be triggered by stressful stimuli such as fatigue, cold, or fasting [175]. Reactive oxygen species acting at TRPA1 may also be responsible for the augmented cutaneous sensitivity to ambient light in patients with porphyria, a potential contributor to pain in that condition [176]. …”

Photodynamic Physiology—Photonanomanipulations in Cellular Physiology with Protein Photosensitizers

“…In contrast to the inhibitory effect on the voltage-gated channels Na v and K v , photo-oxidation has been found to activate the calcium-permeant sensory channels TRPA1 and TRPV1 (Hill and Schaefer, 2009; Babes et al, 2016). Photodynamic action with photosensitizers acridine orange (490 nm), or hypericin (590 nm) was found to activate TRPA1 expressed in HEK293 cells (Hill and Schaefer, 2009).…”

“…Photodynamic action with photosensitizer protoporphyrin IX was found to drastically activate both TRPA1 and TRPV1. Purified human TRPA1 inserted in artificial lipid bilayers was found to be activated only after photodynamic action with protoporphyrin IX and blue light (Babes et al, 2016) (Figure 3). Similar works involving the protein photosensitizers both ex vivo and in vivo are eagerly awaited.…”

“…Scale bars indicate 2 pA current and 1 s. Only simultaneous presence of light and PPIX (photodynamic action) led to channel opening. From Babes et al (2016). …”