87
6
channel is negatively charged. Point mutations in the second helices of the five receptor
subdomains change the conductivity of the channel (Lynagh and Pless 2014; Nys et al.
2013).
NAchRs are involved in excitation-secretion coupling at neuronal synapses in the central and peripheral nervous system. For instance, in the carotid body, acetylcholine is
released from afferent nerve endings that report oxygen tension. Moreover, acetylcholine
is used as a neurotransmitter in the parasympathetic autonomous nervous system (this
takes care of the “rest and digest and breed and feed” regulation of the body). In the sympathetic nervous system, acetylcholine is used at preganglionic short nerve endings where
it helps to depolarize postganglionic fibres, resulting in adrenalin and noradrenaline
receptor activation (taking care of our “fight or flight” response); see . Fig. 4.7.
Presynaptic facilitatory NAchRs modulate neurotransmitter release, e.g. of acetylcholine, glutamate, noradrenalin, dopamine and GABA. Decreased expression of NAchRs has
been observed in several disorders including schizophrenia, epilepsy and drug addiction.
Myasthenia gravis, a usage-dependent muscle weakness, is caused by autoantibodies
against the NAchR. There are numerous drugs that target the NAchR (Daly 2005). Some
are produced by animals, e.g. bungarotoxin, a snake venom. These compounds antagonise
acetylcholine, probably by preventing the twisting of the helices. Bungarotoxin is an 8 kDa
peptide with a so-called three-finger fold. By forming intramolecular cysteine bridges, this
molecule is extremely stable.
Plant-derived drugs interfering with the NAchR include curare alkaloids from the
plant Strychnos toxifera. They are competitive antagonists of the receptor and used as an
arrow poison. By antagonizing acetylcholine, they cause muscle paralysis. When the diaphragm gets paralysed, the result is a fatal breathing arrest. Poison Hemlock, a common
plant found on meadows and fields in Europe and North Africa, contains, amongst other
poisonous alkaloids, coniin, a competitive NAchR antagonist. Apparently, this was used to
make the “Cup of Hemlock” (Schierlingsbecher) to execute the death penalty on Sokrates.
Nicotine is a competitive agonist for the NAchR, and it has given the receptor its
name. Nicotine crosses the blood-brain barrier and reaches the brain cells in 10–20 s. Its
elimination half-life is 2 h. Nicotine acts on α3β4 receptors that are present on autonomic
ganglia and in the adrenal medulla. By binding to these receptors, it increases their permeability for Na + ions and thus increases the excitability of neurons in the brain. At high
doses nicotine is toxic for humans, because it then also targets the neuromuscular junction and induces muscle contractions. However, at lower doses it increases neurotransmitter release in the brain, for instance, at dopaminergic neurons, and this explains
feelings of euphoria and relaxation that can be experienced through tobacco smoking.
Interestingly, tobacco also contains monoamine oxidase inhibitors (enzymes that break
down serine, dopamine and norepinephrine, see 7 Sect. 5.4). This fact possibly contributes to tobacco addiction.
In the sympathetic nervous system, nicotine stimulates the release of adrenalin.
Therefore, an additional stimulator effect on the sympathicus is observed, including
increased heart rate, blood pressure and facilitation of memory and attention. The golden
chain tree produces the alkaloid cytisine, which has similar effects as nicotine. It has been
used in tobacco replacement therapy because it does not appear to be addictive (produced
in Bulgaria under the trade name Tabex) (Walker et al. 2014). However, cytisine at appropriate doses stimulates the acetylcholine receptor and desensitizes it for acetylcholine.
Therefore, this compound is toxic, and in Germany, the golden chain tree was the “poisonous plant of the year” in 2012 (7 https://de. wikipedia. org/wiki/Giftpflanze_des_Jahres).
6.2 · Nicotinic Acetylcholine Receptor (NAchR): Nicotine
6
channel is negatively charged. Point mutations in the second helices of the five receptor
subdomains change the conductivity of the channel (Lynagh and Pless 2014; Nys et al.
2013).
NAchRs are involved in excitation-secretion coupling at neuronal synapses in the central and peripheral nervous system. For instance, in the carotid body, acetylcholine is
released from afferent nerve endings that report oxygen tension. Moreover, acetylcholine
is used as a neurotransmitter in the parasympathetic autonomous nervous system (this
takes care of the “rest and digest and breed and feed” regulation of the body). In the sympathetic nervous system, acetylcholine is used at preganglionic short nerve endings where
it helps to depolarize postganglionic fibres, resulting in adrenalin and noradrenaline
receptor activation (taking care of our “fight or flight” response); see . Fig. 4.7.
Presynaptic facilitatory NAchRs modulate neurotransmitter release, e.g. of acetylcholine, glutamate, noradrenalin, dopamine and GABA. Decreased expression of NAchRs has
been observed in several disorders including schizophrenia, epilepsy and drug addiction.
Myasthenia gravis, a usage-dependent muscle weakness, is caused by autoantibodies
against the NAchR. There are numerous drugs that target the NAchR (Daly 2005). Some
are produced by animals, e.g. bungarotoxin, a snake venom. These compounds antagonise
acetylcholine, probably by preventing the twisting of the helices. Bungarotoxin is an 8 kDa
peptide with a so-called three-finger fold. By forming intramolecular cysteine bridges, this
molecule is extremely stable.
Plant-derived drugs interfering with the NAchR include curare alkaloids from the
plant Strychnos toxifera. They are competitive antagonists of the receptor and used as an
arrow poison. By antagonizing acetylcholine, they cause muscle paralysis. When the diaphragm gets paralysed, the result is a fatal breathing arrest. Poison Hemlock, a common
plant found on meadows and fields in Europe and North Africa, contains, amongst other
poisonous alkaloids, coniin, a competitive NAchR antagonist. Apparently, this was used to
make the “Cup of Hemlock” (Schierlingsbecher) to execute the death penalty on Sokrates.
Nicotine is a competitive agonist for the NAchR, and it has given the receptor its
name. Nicotine crosses the blood-brain barrier and reaches the brain cells in 10–20 s. Its
elimination half-life is 2 h. Nicotine acts on α3β4 receptors that are present on autonomic
ganglia and in the adrenal medulla. By binding to these receptors, it increases their permeability for Na + ions and thus increases the excitability of neurons in the brain. At high
doses nicotine is toxic for humans, because it then also targets the neuromuscular junction and induces muscle contractions. However, at lower doses it increases neurotransmitter release in the brain, for instance, at dopaminergic neurons, and this explains
feelings of euphoria and relaxation that can be experienced through tobacco smoking.
Interestingly, tobacco also contains monoamine oxidase inhibitors (enzymes that break
down serine, dopamine and norepinephrine, see 7 Sect. 5.4). This fact possibly contributes to tobacco addiction.
In the sympathetic nervous system, nicotine stimulates the release of adrenalin.
Therefore, an additional stimulator effect on the sympathicus is observed, including
increased heart rate, blood pressure and facilitation of memory and attention. The golden
chain tree produces the alkaloid cytisine, which has similar effects as nicotine. It has been
used in tobacco replacement therapy because it does not appear to be addictive (produced
in Bulgaria under the trade name Tabex) (Walker et al. 2014). However, cytisine at appropriate doses stimulates the acetylcholine receptor and desensitizes it for acetylcholine.
Therefore, this compound is toxic, and in Germany, the golden chain tree was the “poisonous plant of the year” in 2012 (7 https://de. wikipedia. org/wiki/Giftpflanze_des_Jahres).
6.2 · Nicotinic Acetylcholine Receptor (NAchR): Nicotine