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The Journal of Neuroscience, January 30, 2008, 28(5):1058-1063; doi:10.1523/JNEUROSCI.5102-07.2008

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Brief Communications
Enzymatic Machinery for Endocannabinoid Biosynthesis Associated with Calcium Stores in Glutamatergic Axon Terminals

Rita Nyilas,¹ Barna Dudok,¹ Gabriella M. Urbán,¹ Ken Mackie,² Masahiko Watanabe,³ Benjamin F. Cravatt,⁴ Tamás F. Freund,¹ and István Katona¹

¹Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, ²Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, ³Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, and ⁴The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to Dr. István Katona, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony utca 43, Hungary. Email: katona{at}koki.hu

Endocannabinoids are regarded as retrograde signaling molecules at various types of synapses throughout the CNS. The lipid derivatives anandamide and 2-arachidonoylglycerol (2-AG) are generally thought to be the key molecular players in this process. Previous anatomical and electrophysiological studies provided compelling evidence that the biosynthetic enzyme of 2-AG is indeed localized in the postsynaptic plasma membrane, whereas its target, the CB₁ cannabinoid receptor, and the enzyme responsible for its inactivation are both found presynaptically. This molecular architecture of 2-AG signaling is a conserved feature of most synapses and supports the retrograde signaling role of 2-AG. Conversely, the molecular and neuroanatomical organization of synaptic anandamide signaling remains largely unknown. In contrast to its predicted role in retrograde signaling, here we show that N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), a biosynthetic enzyme of anandamide and its related bioactive congeners, the N-acylethanolamines (NAEs), is concentrated presynaptically in several types of hippocampal excitatory axon terminals. Furthermore, high-resolution quantitative immunogold labeling demonstrates that this calcium-sensitive enzyme is localized predominantly on the intracellular membrane cisternae of axonal calcium stores. Finally, the highest density of NAPE-PLD is found in mossy terminals of granule cells, which do not express CB₁ receptors. Together, these findings suggest that anandamide and related NAEs are also present at glutamatergic synapses, but the sites of their synthesis and action are remarkably different from 2-AG, indicating distinct physiological roles for given endocannabinoids in the regulation of synaptic neurotransmission and plasticity.

Key words: cannabinoid; NAPE-PLD; anandamide; glutamatergic synapse; calcium store; mossy terminal

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Received Nov. 16, 2007; revised Dec. 17, 2007; accepted Dec. 19, 2007.

Correspondence should be addressed to Dr. István Katona, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony utca 43, Hungary. Email: katona{at}koki.hu

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