Architecture of cannabinoid signaling in mouse retina

Abstract

Cannabinoid receptors and their ligands constitute an endogenous signaling system that is found throughout the body, including the eye. This system can be activated by Δ 9 -tetrahydrocannabinol, a major drug of abuse. Cannabinoids offer considerable therapeutic potential in modulating ocular immune and inflammatory responses and in regulating intraocular pressure. The location of cannabinoid receptors 1 (CB 1 ) in the retina is known, but recently a constellation of proteins has been identified that produce and break down endocannabinoids (eCBs) and modulate CB 1 function. Localization of these proteins is critical to defining specific cannabinoid signaling circuitry in the retina.Here we show the localization of diacylglycerol lipase α and β (DGLα/β), implicated in the production of the eCB 2-arachidonoyl glycerol (2-AG); monoacylglycerol lipase (MGL) and α/β-hydrolase domain 6 (ABHD6), both implicated in the breakdown of 2-AG; cannabinoid receptor interacting protein 1a (CRIP1a), a protein that may modulate CB 1 function; Fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) which have been shown to break down the eCB anandamide and related acyl amides. In our most prominent finding, DGLα is present in post-synaptic Type 1 OFF cone bipolar cells juxtaposed to CB 1 -containing cone photoreceptor terminals. Interestingly, CRIP1a is reliably presynaptic to DGLα, consistent with a possible role in cannabinoid signaling, NAAA is restricted to retinal pigment epithelium (RPE), while DGLβ is limited to retinal blood vessels. These results taken together with previous anatomic and functional studies define specific cannabinoid circuitry likely to modulate eCB signaling at the first synapse of the retina as well as in the inner plexiform layer (IPL).

The Cannabinoid Receptor Interacting Proteins 1 of zebrafish are not required for morphological development, viability or fertility

“…Cnrip1 expression is observed in the outer plexiform layer (OPL) of the mouse retina 36 and morpholino loss of function studies have suggested that Xenopus laevis cnrip1 regulates eye development 35 . However, we detected no eye defects in our maternal/zygotic cnrip1a;cnrip1b double mutants.…”

Cannabinoid receptor interacting protein (CRIP1a) attenuates CB1R signaling in neuronal cells

“…CRIP1a was initially characterized for its ability to bind to a segment of the distal C-terminal of the CB 1 R [1]. Following that report, studies of retinal circuitry showed that CRIP1a could be found in amacrine cells, and in certain cone (but not rod) terminals [33]. The CB 1 R-CRIP1a presynaptic co-localization was juxtaposed across from postsynaptic diacylglycerol lipase at photoreceptor/Type1 OFF cone-bipolar cell synapses.…”

In silico interaction analysis of cannabinoid receptor interacting protein 1b (CRIP1b) – CB1 cannabinoid receptor

“…Although CRIP1a is conserved among mammals and fish, the presence of CRIP1b is limited to primates [11]. CRIP1 proteins have been has been identified immunologically in neurons in the superior cervical ganglion [11], striatum [17], glutamatergic CA3 pyramidal neurons in the hippocampus [18, 19] and retina [20]. …”