63
5
This involves increase of glucose release into the blood, degradation of glycogen in the
liver and in muscle cells, release of free fatty acids into the blood, increase in blood pressure and heart rate and partial dilation of smooth muscles, especially in the intestines
(Catterall 2015). For instance, β-receptor activation and concomitantly activated PKA
mediate phosphorylation of glycogen synthase. Phosphorylated glycogen synthase is inactive; therefore, glycogen synthesis is stopped. At the same time, PKA phosphorylates the
enzyme phosphorylase kinase, thereby activating it. This enzyme then phosphorylates
glycogen phosphorylase, which activates glycogen hydrolysis and glucose-1-phosphate is
released. In this way, the availability of glucose in the cell is increased in response to
adrenergic receptor activation. Dilation of vessels in skeletal muscles allows better blood
supply to muscles. This is also promoted by increased heart rates. In the brain, CREB can
be activated by PKA activation, and this is important for long-term potentiation (see
. Fig. 3.1). In summary, release of adrenaline and noradrenaline from the adrenal gland
induces a complex reaction of the organism to enable it to deal with acute stress.
Noradrenaline as a neurotransmitter is stored in neuronal granules prior to release
into the synaptic cleft. It is degraded after release by catechol-O-methyltransferases.
Moreover, a norepinephrine transporter (NET, SLC6A2) mediates reuptake of noradrenaline into neurons. This 12-transmembrane domain molecule is dependent on Na + and
Cl — ions and belongs to the large family of solute carrier proteins. NET is exclusively
expressed in noradrenergic neurons, but it can also transport dopamine back into the cell.
Its molecular function and structure are highly related to dopamine transporters (DAT,
see 7 Sect. 5.5). Such catecholamine transporters regulate the neurotransmitter concentration in the synaptic cleft and thus their availability for signal progression. Drugs targeting NET include the synthetic imipramine, which is used as an antidepressant. It increases
noradrenaline signalling in the brainstem in areas involved in regulating sleep-wake
rhythm, motivation and focusing attention and alertness.
Another natural compound with activity on adrenergic receptors is ephedrine. It was
shown that the four different isoforms of ephedrine (which are the result of the two chiral
centres in the molecule) bind to different isoforms of α- and β-adrenergic receptors (Ma
et al. 2007; Vansal and Feller 1999). However, pharmacological studies have also suggested
that their major targets are norepinephrine transporters (Kobayashi et al. 2003; Rothman
et al. 2003). In any case, ephedrines are considered to act as sympathomimetics.
Inside the cytoplasm, neurotransmitters have to be brought into neuronal granules
from where they are released into the synaptic cleft in response to excitation. Outside such
granules, they will be degraded via oxidation by monoaminooxidases (MAO). These
enzymes catalyse desamination of catecholamine neurotransmitters using H 2 O and oxygen. They are located at the outer mitochondrial membrane. Inhibitors of MAO A, which
is the main isoform implicated in neurotransmitter degradation, can have antidepressant
activity. The synthetic MAO inhibitors iproniazid and moclobemide are examples. The
indole alkaloid harmaline is a plant-derived MAO inhibitor. It is present in lianas, especially in the Amazonas Region, and is an ingredient of the hallucinogenic plant mixtures
from Banisteriopsis known as Ayahuasca (see 7 Sect. 5.6).
The indole alkaloid reserpine, which is found in certain species of Rauvolfia, on the
other hand, targets the “vesicular transporter for monoamine storage” (VMAT, SLC18a).
This is another solute carrier family member. It is a proton/neurotransmitter exchanger,
and the isoform VMAT2 mediates accumulation of norepinephrine, epinephrine,
dopamine, serotonin and histamine in neuronal granules. An ATP-driven proton pump
increases the proton concentration in storage granules resulting in a pH of ca. 5.5.
5.2 · Adrenergic Receptors: Reserpine and Ephedrine
5
This involves increase of glucose release into the blood, degradation of glycogen in the
liver and in muscle cells, release of free fatty acids into the blood, increase in blood pressure and heart rate and partial dilation of smooth muscles, especially in the intestines
(Catterall 2015). For instance, β-receptor activation and concomitantly activated PKA
mediate phosphorylation of glycogen synthase. Phosphorylated glycogen synthase is inactive; therefore, glycogen synthesis is stopped. At the same time, PKA phosphorylates the
enzyme phosphorylase kinase, thereby activating it. This enzyme then phosphorylates
glycogen phosphorylase, which activates glycogen hydrolysis and glucose-1-phosphate is
released. In this way, the availability of glucose in the cell is increased in response to
adrenergic receptor activation. Dilation of vessels in skeletal muscles allows better blood
supply to muscles. This is also promoted by increased heart rates. In the brain, CREB can
be activated by PKA activation, and this is important for long-term potentiation (see
. Fig. 3.1). In summary, release of adrenaline and noradrenaline from the adrenal gland
induces a complex reaction of the organism to enable it to deal with acute stress.
Noradrenaline as a neurotransmitter is stored in neuronal granules prior to release
into the synaptic cleft. It is degraded after release by catechol-O-methyltransferases.
Moreover, a norepinephrine transporter (NET, SLC6A2) mediates reuptake of noradrenaline into neurons. This 12-transmembrane domain molecule is dependent on Na + and
Cl — ions and belongs to the large family of solute carrier proteins. NET is exclusively
expressed in noradrenergic neurons, but it can also transport dopamine back into the cell.
Its molecular function and structure are highly related to dopamine transporters (DAT,
see 7 Sect. 5.5). Such catecholamine transporters regulate the neurotransmitter concentration in the synaptic cleft and thus their availability for signal progression. Drugs targeting NET include the synthetic imipramine, which is used as an antidepressant. It increases
noradrenaline signalling in the brainstem in areas involved in regulating sleep-wake
rhythm, motivation and focusing attention and alertness.
Another natural compound with activity on adrenergic receptors is ephedrine. It was
shown that the four different isoforms of ephedrine (which are the result of the two chiral
centres in the molecule) bind to different isoforms of α- and β-adrenergic receptors (Ma
et al. 2007; Vansal and Feller 1999). However, pharmacological studies have also suggested
that their major targets are norepinephrine transporters (Kobayashi et al. 2003; Rothman
et al. 2003). In any case, ephedrines are considered to act as sympathomimetics.
Inside the cytoplasm, neurotransmitters have to be brought into neuronal granules
from where they are released into the synaptic cleft in response to excitation. Outside such
granules, they will be degraded via oxidation by monoaminooxidases (MAO). These
enzymes catalyse desamination of catecholamine neurotransmitters using H 2 O and oxygen. They are located at the outer mitochondrial membrane. Inhibitors of MAO A, which
is the main isoform implicated in neurotransmitter degradation, can have antidepressant
activity. The synthetic MAO inhibitors iproniazid and moclobemide are examples. The
indole alkaloid harmaline is a plant-derived MAO inhibitor. It is present in lianas, especially in the Amazonas Region, and is an ingredient of the hallucinogenic plant mixtures
from Banisteriopsis known as Ayahuasca (see 7 Sect. 5.6).
The indole alkaloid reserpine, which is found in certain species of Rauvolfia, on the
other hand, targets the “vesicular transporter for monoamine storage” (VMAT, SLC18a).
This is another solute carrier family member. It is a proton/neurotransmitter exchanger,
and the isoform VMAT2 mediates accumulation of norepinephrine, epinephrine,
dopamine, serotonin and histamine in neuronal granules. An ATP-driven proton pump
increases the proton concentration in storage granules resulting in a pH of ca. 5.5.
5.2 · Adrenergic Receptors: Reserpine and Ephedrine