Opportunistic activation of TRP receptors by endogenous lipids: Exploiting lipidomics to understand TRP receptor cellular communication

Abstract

Transient receptor potential channels (TRPs) form a large family of ubiquitous non-selective cation channels that function as cellular sensors and in many cases regulate intracellular calcium. Identification of the endogenous ligands that activate these TRP receptors is still under intense investigation with the majority of these channels still remaining “orphans”. That these channels respond to a variety of external stimuli (e.g. plant-derived lipids, changes in temperature, and changes in pH) provides a framework for their abilities as cellular sensors, however, the mechanism of direct activation is still under much debate and research. In the cases where endogenous ligands (predominately lipids) have shown direct activation of a channel, multiple ligands have been shown to activate the same channel suggesting that these receptors are “promiscuous” in nature. Lipidomics of a growing class of endogenous lipids, N-acyl amides, the most famous of which is N-arachidonoyl ethanolamine (the endogenous cannabinoid, Anandamide) is providing a novel set of ligands that have been shown to activate some members of the TRP family and have the potential to deorphanize many more. Here it is argued that activation of TRPV receptors, a subset of the larger family of TRPs, by multiple endogenous lipids that are structurally analogous is a model system to drive our understanding that many TRP receptors are not promiscuous, but are more characteristically “opportunistic” in nature; exploiting the structural similarity and biosynthesis of a narrow range of analogous endogenous lipids. In addition, this manuscript will compare the activation properties of TRPC5 to the activity profile of an “orphan” lipid, N-palmitoyl glycine; further demonstrating that lipidomics aimed at expanding our knowledge of the family of N-acyl amides has the potential to provide novel avenues of research for TRP receptors.

TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

“…Fatty acid acylamides are a group of lipid derivatives related to endogenous cannabinoid mediators. Some fatty acid acylamides were shown to activate TRP ion channels, including TRPV1 and TRPV4 (6,29). Although the injury-induced concentrations of individual injury-induced fatty acid acylamides in BALF or lung tissue samples were low, we found Untreated TRPV6 TRPV5 TRPV4 TRPV3 TRPV2 TRPV1 TRPM8 TRPM7 TRPM6 TRPM5 TRPM4 TRPM3 TRPM2 TRPM1 TRPC7 TRPC6 TRPC5 TRPC4 TRPC3 TRPC2 TRPC1 TRPA1 FPKM 0 almost all tested species (Ͼ10) to be increased.…”

“…In our present study we focused on N-acyl amines, fatty acidderived products related to anandamide and similar endocannabinoids (6). N-acyl amides are known to activate TRP ion channels, including TRPV4 (6,29). Exposure to chlorine, or intratracheal administration of HCl, resulted in increases of almost all N-acyl amides we tested for in both BALF and total lung tissue, suggesting that multiple TRP channel agonists are produced following ALI (Table 3).…”

“…We therefore speculated that pulmonary injury would induce the production of endogenous agonists of TRPV4. In our present study we focused on N-acyl amines, fatty acidderived products related to anandamide and similar endocannabinoids (6). N-acyl amides are known to activate TRP ion channels, including TRPV4 (6,29).…”

Novel endogenous N-acyl amides activate TRPV1-4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation

“…Much work has shown that TRPs respond to a variety of external stimuli (e.g., plant-derived lipids), however, most TRP receptors are expressed in areas that would not come in direct contact with external stimuli (e.g., CNS tissue, internal organs, smooth muscle); therefore, the mechanism of direct activation by cellular messengers is still under much debate and research. In the few cases where endogenous ligands have been identified that drive direct activation of TRPs, the majority of these ligands are small lipid molecules, most of which share structural homology (Bradshaw et al, 2013). …”

Cannabinoids, the Heart of the Matter

“…TRPV1 ion channels have important functions as cellular sensors, and are involved in nociception, taste perception, thermosensation, mechano‐ and osmolarity sensing, and regulation of signal transmission 15, 55, 56. In addition to ECS and physicochemical activators,15, 33, 55, 56, 57, 58 TRPV1 is activated by tetrahydrocannabinol, cannabinol, cannabigerol and some propyl homologs of THC and cannabigerol 59, 60, 61, 62, 63, 64, 65, 66, 67. Cannabichromene (CBC), cannabidiol, and cannabinol are strong TRPA1 agonists and desensitizers, and THCV (from a botanical extract) is a potent regulator of TRPA1 62…”