Skip to main content Accessibility help

Vanilloid receptor 1 (TRPV1/VR1) co-localizes with fatty acid amide hydrolase (FAAH) in retinal amacrine cells

  • SARAH ZIMOV (a1) (a2) and STEPHEN YAZULLA (a3)


Fatty acid amide hydrolase (FAAH) is the degradative enzyme for anandamide (AEA), an endogenous ligand for the vanilloid receptor (TRPV1) and cannabinoid receptor 1. As FAAH and TRPV1 are integral membrane proteins, FAAH activity could modulate the availability of AEA for TRPV1 activation. Previous studies in this laboratory reported an extensive endocannabinoid system in goldfish retina. Immunocytochemistry was used to determine the relative distributions of FAAH-immunoreactivity (IR) and TRPV1-IR in goldfish retina. Here, we show the first example in an intact neural system in which TRPV1-IR co-localizes in subpopulations of FAAH-immunoreactive neurons, in this case amacrine cells. These cells are rare and consist of three subtypes: 1. ovoid cell with granular-type dendrites restricted to sublamina a, 2. pyriform cell with smooth processes in sublamina b, and 3. fusiform cell with smooth processes that project to sublaminae a and b. The varied appearances of reaction product in the dendrites suggest different subcellular localization of TRPV1, and hence function of FAAH activity regarding TRPV1 stimulation among the cell types. Ovoid and pyriform amacrine cells, but not fusiform cells, labeled with GAD-IR and constituted subsets of GABAergic amacrine cells. TRPV1 amacrine cells, though rare, are represented in the ON, OFF and ON/OFF pathways of the retina. As TRPV1 stimulation increases intracellular calcium with numerous downstream effects, co-localization of TRPV1 and FAAH suggests an autoregulatory function for anandamide. Due to the rarity of these cells, the three vanilloid amacrine cell types may be involved in global effects rather than feature extraction, for example: sampling of ambient light or maintaining homeostasis.


Corresponding author

Address correspondence and reprint requests to: Stephen Yazulla, Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794-5230. E-mail:


Hide All


Ahluwalia, J., Urban, L., Bevan, S. & Nagy, I. (2003). Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. European Journal of Neuroscience 17, 26112618.
Al-Hayani, A., Wease, K.N., Ross, R.A., Pertwee, R.G. & Davies, S.N. (2001). The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice. Neuropharmacology 41, 10001005.
Brecha, N., Sharma, S.C. & Karten, H.J. (1981). Localization of substance P like immunoreactivity in the adult and developing goldfish retina. Neuroscience 6, 27372746.
Cortright, D.N. & Szallasi, A. (2004). Biochemical pharmacology of the vanilloid receptor TRPV1. European Journal of Biochemistry 271, 18141819.
Craib, S.J., Ellington, H.C., Pertwee, R.G. & Ross, R.A. (2001). A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig isolated bronchus. British Journal of Pharmacology 134, 3037.
De Petrocellis, L., Bisogno, T., Maccarrone, M., Davis, J.B., Finazzi-Agro, A. & DiMarzo, V. (2001). The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. Journal of Biological Chemistry 276, 1285612863.
Deutsch, D.G. & Chin, S.A. (1993). Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochemical Pharmacology 46, 791796.
Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.S., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A. & Mechoulam, R. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 19461949.
Diana, M.A. & Marty, A. (2004). Endocannabinoid-mediated short-term synaptic plasticity: Depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). British Journal of Pharmacology 142, 919.
Dowling, J.E. & Ehinger, B. (1975). Synaptic organization of the amine-containing interplexiform cells of the goldfish and Cebus monkey retinas. Science 188, 270273.
Fan, S.F. & Yazulla, S. (2003). Biphasic modulation of voltage-dependent currents of retinal cones by cannabinoid CB1 agonist, WIN 55212-2. Visual Neuroscience 20, 177188.
Fan, S.F. & Yazulla, S. (2004). Inhibitory interaction of cannabinoid CB1 receptor and dopamine D2 receptor agonists on voltage-gated currents of goldfish cones. Visual Neuroscience 21, 6979.
Fan, S.F. & Yazulla, S. (2005). Reciprocal inhibition of voltage-gated potassium currents (I K(V)) by activation of cannabinoid CB1 and dopamine D1 receptors in ON bipolar cells of goldfish retina. Visual Neuroscience 22, 5563.
Fan, S.F. & Yazulla, S. (2007). Retrograde endocannabinoid inhibition of goldfish retinal cones in mediated by 2-arachidonoyl glycerol. Visual Neuroscience 24, 249259.
Fride, E. (2002). Endocannabinoids in the central nervous system—an overview. Prostaglandins Leukotrienes and Essential Fatty Acids 66, 221233.
Fride, E. (2005). Endocannabinoids in the central nervous system: From neuronal networks to behavior. Current Drug Targets CNS Neurological Disorders 4, 633642.
Glaser, S.T., Deutsch, D.D., Studholme, K.M., Zimov, S. & Yazulla, S. (2005). Endocannabinoids in the intact retina: 3H-anandamide uptake, fatty acid amide hydrolase immunoreactivity and hydrolysis of anandamide. Visual Neuroscience 22, 693705.
Goparaju, S.K., Ueda, N., Yamaguchi, H. & Yamamoto, S. (1998). Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Letters 422, 6973.
Gulyas, A.I., Cravatt, B.F., Bracey, M.H., Dinh, T.P., Piomelli, D., Boscia, F. & Freund, T.F. (2004). Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. European Journal of Neuroscience 20, 441458.
Huang, S.M., Bisogno, T., Trevisani, M., Al Hayani, A., DePetrocellis, L., Fezza, F., Tognetto, M., Petros, T.J., Krey, J.F., Chu, C.J., Miller, J.D., Davies, S.N., Geppetti, P., Walker, J.M. & DiMarzo, V. (2002). An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proceedings of the National Academy of Science of the USA 99, 84008405.
Hwang, S.W., Cho, H., Kwak, J., Lee, S.Y., Kang, C.J., Jung, J., Cho, S., Min, K.H., Suh, Y.G., Kim, D. & Oh, U. (2000). Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. Proceedings of the National Academy of Science of the USA 97, 61556160.
Jung, J., Hwang, S.W., Kwak, J., Lee, S.Y., Kang, C.J., Kim, W.B., Kim, D. & Oh, U. (1999). Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel. Journal of Neuroscience 19, 529538.
Jung, J., Lee, S.Y., Hwang, S.W., Cho, H., Shin, J., Kang, Y.S., Kim, S. & Oh, U. (2002). Agonist recognition sites in the cytosolic tails of vanilloid receptor 1. Journal of Biochemistry 46, 4444844454.
Karai, L., Russell, J.T., Iadarola, M.J. & Olah, Z. (2004). Vanilloid receptor 1 regulates multiple calcium compartments and contributes to Ca2+-induced Ca2+-release in sensory neurons. Journal of Biological Chemistry 279, 1637716387.
Kedei, N., Szabo, T., Lile, J.D., Treanor, J.J., Olah, Z., Iadarola, M.J. & Blumberg, P.M. (2001). Analysis of the native quaternary structure of vanilloid receptor 1. Journal of Biological Chemistry 276, 2861328619.
Kim, J. & Alger, B.E. (2004). Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nature Neuroscience 7, 697698.
Kozak, K.R. & Marnett, L.J. (2002). Oxidative metabolism of endocannabinoids. Prostaglandins Leukotrienes & Essential Fatty Acids 66, 211220.
Lasater, E.M. & Dowling, J.E. (1982). Carp horizontal cells in culture respond selectively to L-glutamate and its agonists. Proceedings of the National Academy of Science of the USA 79, 936940.
Li, H., Marshak, D.W., Dowling, J.E. & Lam, D.M.K. (1986). Colocalization of immunoreactive substance P and neurotensin in amacrine cells of the goldfish retina. Brain Research 366, 307313.
Liu, M., Liu, M.C., Magoulas, C., Priestley, J.V. & Willmott, N.J. (2003). Versatile regulation of cytosolic Ca2+ by vanilloid receptor I in rat dorsal root ganglion neurons. Journal of Cell Biology 278, 54625472.
Maccarrone, M., Salvati, S., Bari, M. & Finazzi-Agro, A. (2000). Anandamide and 2-arachidonoylglycerol inhibit fatty acid amide hydrolase by activation the lipoxygenase pathway of the arachidonate cascade. Biophysics Research Communications 278, 576583.
Marc, R.E., Liu, W.L.S. & Muller, J.F. (1988). Gap junctions in the inner plexiform layer of the goldfish retina. Vision Research 28, 924.
Marc, R.E., Murry, R.F. & Basinger, S.F. (1995). Pattern recognition of amino acid signatures in retinal neurons. Journal of Neuroscience 15, 51065129.
Marc, R.E., Stell, W.K., Bok, D. & Lam, D.M.K. (1978). GABAergic pathways in the goldfish retina. Journal of Comparative Neurology 182, 221246.
Marshak, D.W., Carraway, R.E. & Ferris, C.F. (1987). Characterization of immunoreactive substance P and neurotensin in the goldfish retina. Experimental Eye Research 44, 839848.
Marshall, I.C.B., Owen, D.E., Cripps, T.V., Davies, J.B., McNulty, S. & Smart, D. (2003). Activation of vanilloid receptor 1 by resiniferatoxin mobilizes calcium from inositol 1,4,5-trisphosphate-sensitive stores. British Journal of Pharmacology 138, 172176.
Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumdky, M., Kaminski, N.E., Shatz, A.R., Gopher, A., Almog, S., Martin, B.R. & Compton, D.R. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology 50, 8390.
Millns, P.J., Chimenti, M., Ali, N., Ryland, E., de Lago, E., Fernandez-Ruiz, J., Chapman, V. & Kendall, D.A. (2006). Effects of inhibition of fatty acid amide hydrolase vs. the anandamide membrane transporter on TRPV1-mediated calcium responses in adult DRG neurons: The role of CB1 receptors. European Journal of Neuroscience 24, 34893495.
Ohno-Shosaku, T., Hashimotodani, Y., Maejima, T. & Kano, M. (2005). Calcium signaling and synaptic modulation: Regulation of endocannabinoid-mediated synaptic modulation by calcium. Cell Calcium 38, 369374.
Olah, Z., Szabo, T., Karai, L., Hough, C., Fields, R.D., Caudle, R.M., Blumberg, P.M. & Iadarola, M.J. (2001). Ligand-induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1. Journal of Biological Chemistry 276, 1102111030.
Opere, C.A., Zheng, W.D., Zhao, M., Lee, J.S., Kulkarni, K.H. & Ohia, S.E. (2006). Inhibition of potassium- and ischemia-evoked [3H] D-aspartate release from isolated bovine retina by cannabinoids. Current Eye Research 31, 645653.
Pertwee, R.G. (2005). The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS Journal 7, E625E654.
Price, T.J., Patwardhan, A.M., Flores, C.M. & Hargreaves, K.M. (2005). A role for the anandamide membrane transporter in TRPV-1 mediated neurosecretion from trigeminal sensory neurons. Neuropharmacology 49, 2539.
Rámon y Cajal, S. (1933). The Structure of the Retina (compiled and translated Thorpe, S.A. & M. Glickstein) 1972, Springfield, Illinois: Charles C. Thomas, Co.
Rosenbaum, T., Awaya, M. & Gordon, S.E. (2002). Subunit modification and association in VR1 ion Channels. BioMed Central Neuroscience 3, 4.
Ross, R.A. (2003). Anandamide and vanilloid TRPV1 receptors. British Journal of Pharmacology 140, 790801.
Ross, R.A., Gibson, T.M., Brockie, H.C., Leslie, M., Pashmi, G., Craib, S.J., DiMarzo, V. & Pertwee, R.G. (2001). Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. British Journal of Pharmacology 132, 631640.
Sagar, D.R., Smith, P.A., Millns, P.J., Smart, D., Kendall, D.A. & Chapman, V. (2004). TRPV1 and CB receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. European Journal of Neuroscience 20, 175184.
Sang, N., Zhang, J., Marcheselli, V., Bazan, N.G. & Chen, C. (2005). Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. Journal of Neuroscience 25, 98589870.
Schorderet, M., Hof, P. & Magistretti, P.J. (1984). The effects of VIP on cyclic AMP and glycogen levels in vertebrate retina. Peptides 5, 295298.
Slanina, K.A. & Schweitzer, P. (2005). Inhibition of cyclooxygenase-2 elicits a CB1-mediated decrease of excitatory transmission in rat CA1 hippocampus. Neuropharmacology 49, 653659.
Struik, M., Yazulla, S. & Kamermans, M. (2006). Cannabinoid agonist WIN 55212-2 speeds up the cone light offset response in goldfish. Visual Neuroscience 23, 285293.
Su, Y.Y.T., Fry, K.R., Lam, D.M.K. & Watt, C.B. (1986). Enkephalin in the goldfish retina. Cellular and Molecular Neurobiology 6, 331348.
Teranishi, T., Negishi, K. & Kato, S. (1985). Correlations between photoresponse and morphology of amacrine cells in the carp retina. Neuroscience Research—Supplement 2, S211S226.
Teranishi, T., Negishi, K. & Kato, S. (1987). Functional and morphological correlates of amacrine cells in carp retina. Neuroscience 29, 935950.
Tsou, K., Noguerón, I., Muthian, S., Sañudo-Peña, M.C., Hillard, C.J., Deutsch, D.G. & Walker, J.M. (1998). Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neuroscience Letters 254, 14.
Tucker, R.C., Kagaya, M., Page, C.P. & Spina, D. (2001). The endogenous cannabinoid agonist, anandamide stimulates sensory nerves in guinea-pig airways. British Journal of Pharmacology 132, 11271135.
van der Stelt, M. & Di Marzo, V. (2004). Endovanilloids. European Journal of Biochemistry 271, 18271834.
van der Stelt, M. & Di Marzo, V. (2005). Cannabinoid receptors and their role in neuroprotection. Neuromolecular Medicine 7, 3750.
Yamada, T., Marshak, D., Basinger, S., Walsh, J., Morley, J. & Stell, W.K. (1980). Somatostatin-like immunoreactivity in the retina. Proceedings of the National Academy of Sciences of the USA 77, 16911695.
Yazulla, S., Mosinger, J. & Zucker, C. (1984). Two types of pyriform Ab amacrine cells in the goldfish retina: An EM analysis of 3H-GABA uptake and somatostatin-like immunoreactivity. Brain Research 321, 352356.
Yazulla, S. & Studholme, K.M. (2001). Neurochemical anatomy of the zebrafish retina as determined by immunocytochemistry. Journal of Neurocytology 30, 551592.
Yazulla, S., Studholme, K.M., McIntosh, H.H. & Deutsch, D.G. (1999). Immunocytochemical localization of cannabinoid CB1 receptor and fatty acid amide hydrolase in rat retina. Journal of Comparative Neurology 415, 8090.
Yazulla, S., Studholme, K.M., McIntosh, H.H. & Fan, S.F. (2000). Cannabinoid receptors on goldfish retinal bipolar cells: Electron-microscope immunocytochemistry and whole-cell recordings. Visual Neuroscience 17, 391401.
Yazulla, S., Studholme, K.M. & Wu, J.-Y. (1986). Comparative distribution of 3H-GABA uptake and GAD immunoreactivity in goldfish retinal amacrine cells: A double-label analysis. Journal of Comparative Neurology 244, 149162.
Yazulla, S., Zucker, C.L., Mosinger, J.L. & Studholme, K.M. (1985). Pyriform Ab amacrine cells in the goldfish retina: An EM immunocytochemical/autoradiographical study. In Neurocircuitry in the Retina, A Cajal Memorial, eds. Gallego, A. & Gouras, P., pp. 161170. Amsterdam: Elsevier Press.
Yu, M., Ives, D. & Ramesha, C.S. (1997). Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. Journal of Biological Chemistry 272, 2118121186.
Zimov, S. & Yazulla, S. (2004). Localization of vanilloid receptor 1 (TRPV1/VR1)-like inmmunoreactivity in goldfish and zebrafish retinas: Restriction to photoreceptor synaptic ribbons. Journal of Neurocytology 33, 441452.
Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H., Sorgard, M., Di Marzo, V., Julius, D. & Hogestatt, E.D. (1999). Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452457.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed