69
5
spinal cord. CB2 is coupled to G i , inactivating adenylyl cyclase. Moreover, it activates
MAP kinase signalling in a PKC-dependent manner. It is probably not involved in inactivation of Ca 2+ -channels or activation of GIRKs (Pertwee 1997).
The endogenous ligands for both receptors, CB1 and CB2, are derivatives of arachidonic
acid. The two major endocannabinoids are arachidonoylglycerol (2AG) and arachidonoylethanolamine (AEA, anandamide). 2AG is thought to be responsible for a fast direct CB1
activation. This results in inhibition of presynaptic neurotransmitter release. Anandamide
apparently modulates neurotransmission on a slower time scale and may therefore mediate
a more tonic signal and long-term depression in this system. It binds to CB1 receptors, but
in addition, it was shown that it also activates the TRP channel TRPV1 – also known as
vanilloid receptor. In recent years, ion channel regulation, especially involving TRP channels (discussed later), has been identified as an important function of endocannabinoids in
addition to their function as CB-receptor ligands (De Petrocellis et al. 2017).
The endocannabinoid system is a thoroughly investigated retrograde signalling system
for neurotransmission in the nervous system. Cannabinoid receptors on presynapses are
activated by signals from their respective postsynapses, and in response they block secretion of neurotransmitters from the presynapse. The signal that is received by the CB1
receptor is essentially produced in response to postsynaptic activity (Wilson and Nicoll
2001). While neurotransmitters are usually stored in secretory granules and released after
membrane depolarization, endocannabinoids are not visibly stored but made “on demand”.
Thus, they deliver information about postsynaptic activity back to the presynapse. This
function of the endocannabinoid system is seen as a paradigm for retrograde signalling of
neurons (Ulugol 2014); see . Fig. 5.6. The ligands for cannabinoid receptors, the endocannabinoids, are in fact the most ubiquitous endogenous signalling molecules. The change
in neurotransmitter release caused by cannabinoid receptor activation is potent, fast and
long-lasting.
The cannabinoid receptor ligand 2AG is formed mainly from diacylglycerol (DAG) by
the enzyme diacylglycerol lipase (DAGL) (. Fig. 5.7a). The stimuli that initiate its production and release include an increase in intracellular Ca 2+ -concentration, causing the socalled Ca 2+ -driven endocannabinoid release, and activation of G q -coupled receptors,
causing the so-called basal receptor-driven endocannabinoid release. It is also possible
that the postsynaptic cell experiences a combination of both types of stimuli, and this is
called Ca 2+ -assisted receptor-driven endocannabinoid release. Ca 2+ -signals are a response
to depolarization of the postsynaptic membrane as a result of neurotransmitter signalling
from the presynapse. Voltage-gated Ca 2+ -channels are activated and this leads to the production of DAG due to an unknown mechanism. DAG is, as discussed above, also produced by PLC, which can be activated in response to GPCR signalling via activation of G q .
Metabotropic glutamate receptors in the postsynaptic membrane are activated by glutamate neurotransmission from the presynapse. Activation of the MAchR and some others
also increases DAG in the membrane.
For degradation, 2AG is oxidized by the enzyme COX-2 (cyclooxygenase) in a twostep reaction leading to prostaglandin E2 glyceryl ester (therefore the enzyme is also
called prostaglandin synthase 2). Monoacylglycerol lipase (MAGL) and α,β-hydrolase
domain containing ABHD6 and ABHD12 degrade 2AG to arachidonic acid and glycerol. Fatty acid amide hydrolase (FAAH) degrades anandamide to arachidonic acid and
ethanolamine. The sap of the fire tree (Euphorbia tirucalli), which is used to make latex
and oil, contains the MAGL-inhibitor euphol – an anti-inflammatory drug. An overview over further 2AG degradation pathways is shown in . Fig. 5.7b, (Ohno-Shosaku
et al. 2012).
5.4 · Cannabinoid Receptors: Cannabis and Cannabinoids
5
spinal cord. CB2 is coupled to G i , inactivating adenylyl cyclase. Moreover, it activates
MAP kinase signalling in a PKC-dependent manner. It is probably not involved in inactivation of Ca 2+ -channels or activation of GIRKs (Pertwee 1997).
The endogenous ligands for both receptors, CB1 and CB2, are derivatives of arachidonic
acid. The two major endocannabinoids are arachidonoylglycerol (2AG) and arachidonoylethanolamine (AEA, anandamide). 2AG is thought to be responsible for a fast direct CB1
activation. This results in inhibition of presynaptic neurotransmitter release. Anandamide
apparently modulates neurotransmission on a slower time scale and may therefore mediate
a more tonic signal and long-term depression in this system. It binds to CB1 receptors, but
in addition, it was shown that it also activates the TRP channel TRPV1 – also known as
vanilloid receptor. In recent years, ion channel regulation, especially involving TRP channels (discussed later), has been identified as an important function of endocannabinoids in
addition to their function as CB-receptor ligands (De Petrocellis et al. 2017).
The endocannabinoid system is a thoroughly investigated retrograde signalling system
for neurotransmission in the nervous system. Cannabinoid receptors on presynapses are
activated by signals from their respective postsynapses, and in response they block secretion of neurotransmitters from the presynapse. The signal that is received by the CB1
receptor is essentially produced in response to postsynaptic activity (Wilson and Nicoll
2001). While neurotransmitters are usually stored in secretory granules and released after
membrane depolarization, endocannabinoids are not visibly stored but made “on demand”.
Thus, they deliver information about postsynaptic activity back to the presynapse. This
function of the endocannabinoid system is seen as a paradigm for retrograde signalling of
neurons (Ulugol 2014); see . Fig. 5.6. The ligands for cannabinoid receptors, the endocannabinoids, are in fact the most ubiquitous endogenous signalling molecules. The change
in neurotransmitter release caused by cannabinoid receptor activation is potent, fast and
long-lasting.
The cannabinoid receptor ligand 2AG is formed mainly from diacylglycerol (DAG) by
the enzyme diacylglycerol lipase (DAGL) (. Fig. 5.7a). The stimuli that initiate its production and release include an increase in intracellular Ca 2+ -concentration, causing the socalled Ca 2+ -driven endocannabinoid release, and activation of G q -coupled receptors,
causing the so-called basal receptor-driven endocannabinoid release. It is also possible
that the postsynaptic cell experiences a combination of both types of stimuli, and this is
called Ca 2+ -assisted receptor-driven endocannabinoid release. Ca 2+ -signals are a response
to depolarization of the postsynaptic membrane as a result of neurotransmitter signalling
from the presynapse. Voltage-gated Ca 2+ -channels are activated and this leads to the production of DAG due to an unknown mechanism. DAG is, as discussed above, also produced by PLC, which can be activated in response to GPCR signalling via activation of G q .
Metabotropic glutamate receptors in the postsynaptic membrane are activated by glutamate neurotransmission from the presynapse. Activation of the MAchR and some others
also increases DAG in the membrane.
For degradation, 2AG is oxidized by the enzyme COX-2 (cyclooxygenase) in a twostep reaction leading to prostaglandin E2 glyceryl ester (therefore the enzyme is also
called prostaglandin synthase 2). Monoacylglycerol lipase (MAGL) and α,β-hydrolase
domain containing ABHD6 and ABHD12 degrade 2AG to arachidonic acid and glycerol. Fatty acid amide hydrolase (FAAH) degrades anandamide to arachidonic acid and
ethanolamine. The sap of the fire tree (Euphorbia tirucalli), which is used to make latex
and oil, contains the MAGL-inhibitor euphol – an anti-inflammatory drug. An overview over further 2AG degradation pathways is shown in . Fig. 5.7b, (Ohno-Shosaku
et al. 2012).
5.4 · Cannabinoid Receptors: Cannabis and Cannabinoids