Abstract
Fatty acids (FAs) are not only essential components of cellular energy storage and structure, but play crucial roles in signalling. Here we present a toolkit of photoswitchable FA analogues (FAAzos) that incorporate an azobenzene photoswitch along the FA chain. By modifying the FAAzos to resemble capsaicin, we prepare a series of photolipids targeting the Vanilloid Receptor 1 (TRPV1), a non-selective cation channel known for its role in nociception. Several azo-capsaicin derivatives (AzCAs) emerge as photoswitchable agonists of TRPV1 that are relatively inactive in the dark and become active on irradiation with ultraviolet-A light. This effect can be rapidly reversed by irradiation with blue light and permits the robust optical control of dorsal root ganglion neurons and C-fibre nociceptors with precision timing and kinetics not available with any other technique. More generally, we expect that photolipids will find many applications in controlling biological pathways that rely on protein–lipid interactions.
Highlights
Fatty acids (FAs) are essential components of cellular energy storage and structure, but play crucial roles in signalling
We evaluated the photopharmacology of AzCA1–8 using whole-cell electrophysiology in human embryonic kidney (HEK) 293T cells transiently expressing the yellow fluorescent protein (YFP)-tagged ion channel (TRPV1-YFP)[28]
Having demonstrated that AzCA4 acts as a photoswitchable TRPV1 agonist that is relatively inactive in the dark, we evaluated its activity in isolated wild-type mouse dorsal root ganglia (DRG) neurons using both electrophysiology and intracellular Ca2 þ imaging
Summary
Fatty acids (FAs) are essential components of cellular energy storage and structure, but play crucial roles in signalling. Several azo-capsaicin derivatives (AzCAs) emerge as photoswitchable agonists of TRPV1 that are relatively inactive in the dark and become active on irradiation with ultraviolet-A light. This effect can be rapidly reversed by irradiation with blue light and permits the robust optical control of dorsal root ganglion neurons and C-fibre nociceptors with precision timing and kinetics not available with any other technique. TRPV1 is involved in responses to noxious stimuli, but is believed to initiate the neurogenic inflammatory response[19], which has made it an attractive target for novel analgesics[11] These attempts have proven more challenging than anticipated, as TRPV1 is involved in a variety of other biological pathways that can lead to unwanted side effects. Based on the structure of CAP and other TRPV1 agonists, we saw the opportunity to develop a photoswitchable TRPV1 agonist which would permit optical control over the ion channel without the use of a second factor
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