Architecture of cannabinoid signaling in mouse retina

Authors

  • Sherry Shu-Jung Hu,

    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
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  • Andy Arnold,

    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
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  • Jacqueline M. Hutchens,

    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
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  • Josh Radicke,

    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
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  • Benjamin F. Cravatt,

    1. Department of Chemical Physiology, the Scripps Research Institute, La Jolla, California 92037
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  • Jim Wager-Miller,

    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
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  • Ken Mackie,

    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
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  • Alex Straiker

    Corresponding author
    1. The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
    • Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th Street, Bloomington, IN 47405
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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 Δ9-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 receptor 1 (CB1) in the retina is known, but recently a constellation of proteins has been identified that produce and break down endocannabinoids (eCBs) and modulate CB1 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 CB1 function; and 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. Our most prominent finding was that DGLα is present in postsynaptic type 1 OFF cone bipolar cells juxtaposed to CB1-containing cone photoreceptor terminals. CRIP1a is reliably presynaptic to DGLα, consistent with a possible role in cannabinoid signaling, and NAAA is restricted to retinal pigment epithelium, whereas DGLβ is limited to retinal blood vessels. These results taken together with previous anatomical 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. J. Comp. Neurol. 518:3848–3866, 2010. © 2010 Wiley-Liss, Inc.

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