Biology Reference
In-Depth Information
AEA is believed to be made from N-arachidonyl phosphatidylethanolamine (N-ArPE),
which is believed to originate from the transfer of arachidonic acid (AA) from the sn-1
position of 1,2-sn-di-arachidonylphosphatidylcholine to phosphatidylethanolamine, catalyzed
by a calcium-dependent N-acyltransferase (NAT) (Fig. 2).
Figure 2. The potential pathways of anandamide biosynthesis. Stimulation of adenylate cyclase and
cAMP-dependent protein kinase potentiate the N-acyltransferase (Ca2+-dependent transacylase,
CDTA). A fatty arachidonic acid chain is transferred by CDTA from the sn-1 position of phospholipids
to the primary amine of phosphatidylethanolamine, in a Ca2+-dependent manner, forming an N-
arachidonyl phosphatidylethanolamine (N-ArPE). This N-ArPE intermediate is then hydrolyzed by a
phospholipase D (PLD)-like enzyme to yield the anandamide (AEA). Once synthesized, AEA can
transported to the outside of the cell through a process that has not yet been well characterized. AMT,
anandamide membrane transporter
N-ArPE is then cleaved by a N-acyl phosphatidylethanolamine (NAPE)-specific
phospholipase D (PLD) [61, 153, 176], which releases AEA and phosphatidic acid. It is not
clear whether the NAT or the NAPE-PLD controls the rate-limiting step of AEA synthesis
[59, 86, 186]. AEA biosynthesis was unaffected in NAPE-PLD knockout mice suggesting the
involvement of other enzymes [120]. Another pathway which involves the conversion of
NAPE into 2-lysol-NAPEs via the action of secretory PLA
2
has also been reported. 2-Lysol-
NAPEs are then converted into N-acyl-ethanolamides, including AEA, via a selective lyso
phospholipase D (lyso-PLD) [190]. A recent study proposed the existence in mouse brain and
RAW264.7 macrophages of a parallel pathway through which AEA is generated from NAPE
by a two-step process involving the PLC-catalyzed cleavage of NAPE to yield pAEA, which
is subsequently dephosphorylated by protein tyrosine phosphatases (PTPN22) [121]. Notably,
there is a strong evidence for calcium dependence in both of these synthesis steps, which may
underlie the requirement for postsynaptic Ca
2+
in certain forms of synaptic plasticity (see
below). As a putative neuromodulator, AEA that is released into the synaptic cleft is expected
