Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain.
Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid 2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders.
Bisogno
Tiziana
T
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, 80078 Pozzuoli, Italy.
Howell
Fiona
F
Williams
Gareth
G
Minassi
Alberto
A
Cascio
Maria Grazia
MG
Ligresti
Alessia
A
Matias
Isabel
I
Schiano-Moriello
Aniello
A
Paul
Praveen
P
Williams
Emma-Jane
EJ
Gangadharan
Uma
U
Hobbs
Carl
C
Di Marzo
Vincenzo
V
Doherty
Patrick
P
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis*; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D019556:COS Cells; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D003712:Dendrites / Q000201:enzymology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000096:biosynthesis*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics / Q000302:isolation & purification*; D051379:Mice; D008969:Molecular Sequence Data; D016501:Neurites / Q000187:drug effects / Q000201:enzymology; D017729:Presynaptic Terminals / Q000201:enzymology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D013570:Synaptic Membranes / Q000201:enzymology; D013997:Time Factors
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D018076:DNA, Complementary; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D006133:Growth Substances; C094503:glyceryl 2-arachidonate; C480280:DAGLA protein, human; C480281:DAGLB protein, human; D008071:Lipoprotein Lipase