62
5
tract, skin, kidney, and brain. They are divided into α- and β-groups, whereby α1, α2, β1,
β2 and β3 subgroups are distinguished. Α1 receptors are coupled to Gq and α2 receptors
are coupled to Gi-proteins. In contrast, all subtypes of β-adrenergic receptors are coupled
to Gs, therefore stimulating the adenylyl cyclase activity and increasing the cellular cAMP
concentration.
Endogenous ligands of all adrenergic receptors include adrenaline (epinephrine) and
noradrenaline (norepinephrine), two hormones released by the adrenal gland in response
to acute stress. Both are also produced in certain neurons and function as neurotransmitters, whereby here noradrenaline has a more central position. Chemically they are catecholamines (see 7 Box 3.1). They are biogenic amines and are produced from tyrosine,
like serotonin and dopamine. One naturally occurring alkaloid that is present in lower
fungi is ergotamine. It binds to all catecholamine receptors with high affinity (Zajdel et al.
2015).
Both adrenaline and noradrenaline bind α-receptors with high affinity. At smooth
muscle synapses, α1-receptor activation leads to increase of Ca 2+ ions and therefore muscle contraction. Activation of presynaptic α2-receptors induces negative feedback via Giproteins and inhibits muscle contraction. Synthetic α1-receptor antagonists include
prazosin (Pfizer trade name Minipress), which is used to treat high blood pressure. The
indole alkaloid yohimbine from the West African jungle tree Corynanthe yohimbe is a
selective α2-receptor antagonist. Therefore, it enhances transmitter release from presynapses without affecting α1-receptors, thus acting as a sympathomimetic (Shannon and
Neuman 2000).
Β1-receptors are present in the heart where their activation increases power and frequency of heartbeat. Β1 signalling leads to increase in cAMP and activation of protein
kinase A, which phosphorylates Ca 2+ -channels of the L-type. This increases Ca 2+ -influx
and enhances release of Ca 2+ from ryanodine receptors of the sarcoplasmic reticulum
resulting in stronger muscle contraction. In addition, G s -activation by stimulating
β1-receptors leads to direct opening of Ca 2+ -channels in pacemaker cells and in this way
increases heart rate.
Β2-adrenergic receptors are expressed in smooth muscle cells of the blood and bronchial vessels. The latter are activated by adrenaline from the bloodstream; few are activated by synaptic noradrenaline. This leads to an increase in cAMP via Gs and adenylyl
cyclase stimulation. cAMP blocks myosin light chain kinase (MLCK). In contrast to
striatal muscle, where Ca 2+ -mediated release of troponin from actin-binding sites on the
myosin molecules induces contraction, in smooth muscle cells, MLCK phosphorylates
myosin light chains, and this allows myosin to contact actin fibres for contraction.
Therefore, β1-receptor activation, by inhibiting MLCK, leads to smooth muscle relaxation on vessels and vessel dilation as well as bronchodilation. The synthetic compound
propranolol blocks both types of β-receptors. It is used to treat hypertension; however, a
new generation of drugs is more selective for β1-receptors, and these include atenolol
and bisoprolol (Fergus et al. 2015; Ogrodowczyk et al. 2016). The natural compound
higenamine known for use in traditional Chinese medicine has partial agonistic activity
on β-receptors, its pharmacology has recently been reviewed and it seems that the
molecular basis for the effects of higenamine is still not completely understood (Zhang
et al. 2017). Since 2017, it is also on the list of forbidden substances of the World AntiDoping Agency.
The hormonal action of adrenaline and noradrenaline after release from the adrenal
gland in the presence of strong stress stimuli induces the so-called fight-or-flight response.
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs
5
tract, skin, kidney, and brain. They are divided into α- and β-groups, whereby α1, α2, β1,
β2 and β3 subgroups are distinguished. Α1 receptors are coupled to Gq and α2 receptors
are coupled to Gi-proteins. In contrast, all subtypes of β-adrenergic receptors are coupled
to Gs, therefore stimulating the adenylyl cyclase activity and increasing the cellular cAMP
concentration.
Endogenous ligands of all adrenergic receptors include adrenaline (epinephrine) and
noradrenaline (norepinephrine), two hormones released by the adrenal gland in response
to acute stress. Both are also produced in certain neurons and function as neurotransmitters, whereby here noradrenaline has a more central position. Chemically they are catecholamines (see 7 Box 3.1). They are biogenic amines and are produced from tyrosine,
like serotonin and dopamine. One naturally occurring alkaloid that is present in lower
fungi is ergotamine. It binds to all catecholamine receptors with high affinity (Zajdel et al.
2015).
Both adrenaline and noradrenaline bind α-receptors with high affinity. At smooth
muscle synapses, α1-receptor activation leads to increase of Ca 2+ ions and therefore muscle contraction. Activation of presynaptic α2-receptors induces negative feedback via Giproteins and inhibits muscle contraction. Synthetic α1-receptor antagonists include
prazosin (Pfizer trade name Minipress), which is used to treat high blood pressure. The
indole alkaloid yohimbine from the West African jungle tree Corynanthe yohimbe is a
selective α2-receptor antagonist. Therefore, it enhances transmitter release from presynapses without affecting α1-receptors, thus acting as a sympathomimetic (Shannon and
Neuman 2000).
Β1-receptors are present in the heart where their activation increases power and frequency of heartbeat. Β1 signalling leads to increase in cAMP and activation of protein
kinase A, which phosphorylates Ca 2+ -channels of the L-type. This increases Ca 2+ -influx
and enhances release of Ca 2+ from ryanodine receptors of the sarcoplasmic reticulum
resulting in stronger muscle contraction. In addition, G s -activation by stimulating
β1-receptors leads to direct opening of Ca 2+ -channels in pacemaker cells and in this way
increases heart rate.
Β2-adrenergic receptors are expressed in smooth muscle cells of the blood and bronchial vessels. The latter are activated by adrenaline from the bloodstream; few are activated by synaptic noradrenaline. This leads to an increase in cAMP via Gs and adenylyl
cyclase stimulation. cAMP blocks myosin light chain kinase (MLCK). In contrast to
striatal muscle, where Ca 2+ -mediated release of troponin from actin-binding sites on the
myosin molecules induces contraction, in smooth muscle cells, MLCK phosphorylates
myosin light chains, and this allows myosin to contact actin fibres for contraction.
Therefore, β1-receptor activation, by inhibiting MLCK, leads to smooth muscle relaxation on vessels and vessel dilation as well as bronchodilation. The synthetic compound
propranolol blocks both types of β-receptors. It is used to treat hypertension; however, a
new generation of drugs is more selective for β1-receptors, and these include atenolol
and bisoprolol (Fergus et al. 2015; Ogrodowczyk et al. 2016). The natural compound
higenamine known for use in traditional Chinese medicine has partial agonistic activity
on β-receptors, its pharmacology has recently been reviewed and it seems that the
molecular basis for the effects of higenamine is still not completely understood (Zhang
et al. 2017). Since 2017, it is also on the list of forbidden substances of the World AntiDoping Agency.
The hormonal action of adrenaline and noradrenaline after release from the adrenal
gland in the presence of strong stress stimuli induces the so-called fight-or-flight response.
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs