Opioid and Cannabinoid Receptors - Drug Design and Discovery - page 323

endoplasmic reticulum. However, a transporter protein has not been characterized and the concept
of an uptake transporter for a lipophilic molecule is disputed.
2-AG is formed primarily from diacylglycerol, e.g., 1-stearoyl-2-arachidonoyl-glycerol, cata-
lyzed by a Sn -1 specii c diacylglycerol lipase and it is degraded by a monoacylglycerol lipase. The
precursor, diacylglycerol, is known to be formed during receptor-stimulated turnover of inositol
phospholipids where inositol-1,4,5-trisphosphate is also formed. Thus, this diacylglycerol forma-
tion occurs in the cell membrane where the diacylglycerol lipase also is located. It is generally
accepted that 2-AG is formed in postsynaptic neurons upon activation of neuronal inositol phospho-
lipids whose turnover depends on phospholipase Cb, whereupon it activates, in a retrograde fashion,
the presynaptic CB 1 -receptor that subsequently results in the inhibition of neurotransmitter release
(Figure 19.10). It is not exactly known how 2-AG travels through the aqueous l uid to reach the
presynaptic neuron. This retrograde signaling can decrease the release of glutamate, GABA, acetyl-
choline and other neurotransmitters. 2-AG is degraded by a monoacylglycerol lipase that is located
in the presynaptic neuron. In this way 2-AG and the CB 1 -receptors may contribute to homosynaptic
plasticity of excitatory synapses and heterosynaptic plasticity between excitatory and inhibitory
contacts that is part of the basic mechanism in learning and memory. This retrograde control is also
called as the depolarisation-induced suppression of inhibition (DSI) and depolarisation-induced
suppression of excitation (DSE) for GABAergic and glutamatergic synapses, respectively.

Presynaptic
neuron

CB1

Neurotransmitters

2-AG

PLC

DAGL

DAG 2-AG

Postsynaptic neuron

FIGURE 19.10 Synaptic endocannabinoid formation during neurotransmitter release. PLC, phospholipase C;
DAG, diacylglycerol; DAGL, diacylglycerol lipase; 2-AG, 2-arachidonoyl glycerol; CB 1 , cannabinoid receptor-1.

19.2.2 C ANNABINOID R ECEPTOR 1
CB 1 -receptor belongs to the Class A rhodopsin-like family of GPCRs and it couples through G i/o pro-
teins negatively to adenylate cyclase and positively to mitogen-activated protein kinase. In addition,
CB 1 -receptor can also couple to ion channels through the same G-proteins, positively to A-type and
inwardly rectifying K + -channels and negatively to N-type and P/Q type Ca 2+ -channels. CB 1 -receptor
is primarily localized in the brain where it is particularly abundant in cortex, hippocampus, amygdale,
basal ganglia, cerebellum, and the emetic centers of the brain stem. CB 1 -receptor can also be found in
lower abundance in spleen, tonsils, white blood cells, gastrointestinal tissue, urinary bladder, adrenal