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Andrew Oh Jo, Daniel A Ryskamp, Sarah Redmon, Peter Barabas, David Krizaj; NONRETROGRADE ENDOCANNABINOID SIGNALING MODULATES RETINAL GANGLION CELL CALCIUM HOMEOSTASIS THROUGH THE TRPV1 CATION CHANNEL. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3021.
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© ARVO (1962-2015); The Authors (2016-present)
Endocannabinoids are widely distributed across ocular tissues with effects ranging from regulation of IOP to photosensitivity and color discrimination. While these endogenous lipid precursors of arachidonic acid are known to retrogradely modulate synaptic transmission, they also influence neuronal function through nonretrograde targeting of TRPV1 (transient receptor potential vanilloid 1), a polymodal cation channel implicated in nociceptive sensitization and synaptic depotentiation. Here, we examined whether the known physiological effects of endocannabinoids on retinal function could be partly mediated through TRPV1 channels.
Acutely dissociated mouse retinal cells were exposed to endocannabinoids and TRP channel agonists/antagonists. Calcium dynamics were imaged with Fura-2 AM. Response selectivity was assessed with selective antagonists and knockout mice.
We found that retinal ganglion cells (RGCs) respond to the TRPV1 agonist capsaicin and “endovanilloid” cannabinoid receptor type 1 (CB1) agonists N-arachidonoyl dopamine (NADA), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), with [Ca2+]i elevations. For example, NADA evoked significant (845 ± 198 nM) [Ca2+]i increases in a subset (52 ±17 %) of RGCs. The amplitudes of endocannabinoid-evoked [Ca2+]i signals were reduced by the selective TRPV1 antagonist capsazepine. Sustained exposure of retinal wholemounts to capsaicin was associated with RGC degeneration. This effect was occluded by co-application of 2-AG. As endocannabinoid receptor and TRPV1 channel activation modulate inflammation, we examined the effects of TRPV1 antagonists on Toll-like receptor 4 (TLR4)-mediated responses in RGCs. Capsazepine suppressed TLR4-mediated signals; moreover, inflammatory sensitization was depressed in TRPV1 knockout mice.
We show that natural lipids (AEA, 2-AG) modulate RGC calcium homeostasis and survival in part through low affinity activation of TRPV1. This mechanism, acting in conjunction with CB1 receptors, is well placed to modulate RGC excitability and combine synaptic responses with inflammatory signals involving the TLR4 pathway. Our data suggest that the effects of exogenous cannabinoids on visual function, immune responses and retinal pathology/neuroprotection might be mediated in part through direct modulation of nociceptive TRP channels intrinsic to RGCs.
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