68
5
striatal neurons. A 1 and A 2A receptors can be tonically activated and are involved in signal transduction for sleep-wake regulation. In addition, pharmacological targeting of
these receptors has been implicated in neuroprotection, e.g. after spinal cord injury
(Rivera-Oliver and Diaz-Rios 2014).
In mice, A 2A receptors have been suggested to be the main target for caffeine. Outside
the nervous system, A 2A receptors are highly expressed in the spleen, thymus, blood platelets and leucocytes. A 2A receptors localized on arteriolar smooth muscle cells mediate
vasodilation. In recent years, the A 2A receptor has been in the centre of interest for drug
development. Adenosine itself is used in clinics to induce coronary artery vasodilation.
Regadenoson is the first synthetic A 2A receptor agonist approved by the FDA. It is also
approved in Switzerland and used as a vasodilator (7 www. pharmawiki. ch). Further therapeutic use for A 2A receptor agonists is implicated in inflammatory diseases, neuropathic
pain and wound healing (de Lera Ruiz et al. 2014). A 2A receptor antagonists, conversely,
are being tested for treating Parkinson’s disease. These are expected to increase motor
activity in striatal neurons where adenosine antagonizes dopamine D 2 receptors signalling
when they are co-localizing with A 2 receptors.
A 2B receptors are widely expressed, but with low abundance, they are the most
adenosine- insensitive receptors (only activated by mM concentrations). They are involved
in the regulation of hypoxia and inflammation.
A 3 receptors are coupled to G io and G q11 – they are expressed at low levels. They are
now also considered as a potential therapeutic target because they are up-regulated in
rheumatoid diseases and other inflammatory conditions as well as in cancer tissue.
Therefore, efforts are directed at designing A 3 receptor-selective drugs (Borea et al. 2015).
5.4 Cannabinoid Receptors: Cannabis and Cannabinoids
The endocannabinoid system comprises two cannabinoid receptors, CB1 and CB2, their
endogenous cannabinoid ligands and enzymes involved in synthesis, release, transport
and degradation of endogenous cannabinoids.
CB1 receptors are very abundant in the central nervous system. They are found in
basal ganglia and in the brain, especially in the cortex and hippocampus and in the cerebellum. They are localized at membranes of presynaptic nerve terminals (Mackie 2005;
Nyiri et al. 2005). CB1 is mainly coupled to inhibitory G-proteins (G i ). GTP-bound G i α
subunits inhibit the activity of adenylyl cyclase causing a decrease in cAMP and inactivation of PKA. Moreover, CB1 receptors mediate inhibition of neurotransmitter release
from the presynapse by blockage of several types of Ca 2+ channels (Brown et al. 2004) and
activation of G-protein-coupled inwardly rectifying K + channels (GIRK). GIRK channels
can be activated by the direct action of Gβ/γ subunits released from GTP-bound Gαi/o
proteins. Gβ/γ-subunits are known to stabilize the binding of GIRK channels to the phospholipid phosphatidylinositol-4,5-bisphosphate, PIP2. Another well-documented effect
of CB1 is the activation of the MAP kinase cascade (mitogen-activated protein kinase).
MAP kinases are activated in response to growth factor receptor signalling (e.g. the receptor tyrosine kinase EGF-R). The effect of CB1 receptors on MAP kinases probably involves
several mechanisms including a direct interaction of Gβ/γ-subunits with some MAP
kinase activators (Dalton et al. 2009). Activated MAP kinases may mediate changes in
gene expression as a long-term response to CB1 activation.
CB2, on the other hand, is predominantly localized outside the CNS, e.g. in the spleen.
It can be up-regulated during injury and inflammation in sensory neurons and in the
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs
5
striatal neurons. A 1 and A 2A receptors can be tonically activated and are involved in signal transduction for sleep-wake regulation. In addition, pharmacological targeting of
these receptors has been implicated in neuroprotection, e.g. after spinal cord injury
(Rivera-Oliver and Diaz-Rios 2014).
In mice, A 2A receptors have been suggested to be the main target for caffeine. Outside
the nervous system, A 2A receptors are highly expressed in the spleen, thymus, blood platelets and leucocytes. A 2A receptors localized on arteriolar smooth muscle cells mediate
vasodilation. In recent years, the A 2A receptor has been in the centre of interest for drug
development. Adenosine itself is used in clinics to induce coronary artery vasodilation.
Regadenoson is the first synthetic A 2A receptor agonist approved by the FDA. It is also
approved in Switzerland and used as a vasodilator (7 www. pharmawiki. ch). Further therapeutic use for A 2A receptor agonists is implicated in inflammatory diseases, neuropathic
pain and wound healing (de Lera Ruiz et al. 2014). A 2A receptor antagonists, conversely,
are being tested for treating Parkinson’s disease. These are expected to increase motor
activity in striatal neurons where adenosine antagonizes dopamine D 2 receptors signalling
when they are co-localizing with A 2 receptors.
A 2B receptors are widely expressed, but with low abundance, they are the most
adenosine- insensitive receptors (only activated by mM concentrations). They are involved
in the regulation of hypoxia and inflammation.
A 3 receptors are coupled to G io and G q11 – they are expressed at low levels. They are
now also considered as a potential therapeutic target because they are up-regulated in
rheumatoid diseases and other inflammatory conditions as well as in cancer tissue.
Therefore, efforts are directed at designing A 3 receptor-selective drugs (Borea et al. 2015).
5.4 Cannabinoid Receptors: Cannabis and Cannabinoids
The endocannabinoid system comprises two cannabinoid receptors, CB1 and CB2, their
endogenous cannabinoid ligands and enzymes involved in synthesis, release, transport
and degradation of endogenous cannabinoids.
CB1 receptors are very abundant in the central nervous system. They are found in
basal ganglia and in the brain, especially in the cortex and hippocampus and in the cerebellum. They are localized at membranes of presynaptic nerve terminals (Mackie 2005;
Nyiri et al. 2005). CB1 is mainly coupled to inhibitory G-proteins (G i ). GTP-bound G i α
subunits inhibit the activity of adenylyl cyclase causing a decrease in cAMP and inactivation of PKA. Moreover, CB1 receptors mediate inhibition of neurotransmitter release
from the presynapse by blockage of several types of Ca 2+ channels (Brown et al. 2004) and
activation of G-protein-coupled inwardly rectifying K + channels (GIRK). GIRK channels
can be activated by the direct action of Gβ/γ subunits released from GTP-bound Gαi/o
proteins. Gβ/γ-subunits are known to stabilize the binding of GIRK channels to the phospholipid phosphatidylinositol-4,5-bisphosphate, PIP2. Another well-documented effect
of CB1 is the activation of the MAP kinase cascade (mitogen-activated protein kinase).
MAP kinases are activated in response to growth factor receptor signalling (e.g. the receptor tyrosine kinase EGF-R). The effect of CB1 receptors on MAP kinases probably involves
several mechanisms including a direct interaction of Gβ/γ-subunits with some MAP
kinase activators (Dalton et al. 2009). Activated MAP kinases may mediate changes in
gene expression as a long-term response to CB1 activation.
CB2, on the other hand, is predominantly localized outside the CNS, e.g. in the spleen.
It can be up-regulated during injury and inflammation in sensory neurons and in the
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs