88
6
Some cyanobacteria produce the NAchR agonist anatoxin A. This is also called “very
fast death” factor because it kills animals within a few minutes. It has been made responsible for the death of 30,000 flamingos on lake Bogoria in Kenia in the autumn 1999
(Krienitz et al. 2003).
Acetylcholine receptors also have permeability for Ca 2+ -ions. This is important for
some additional functions of these receptors on non-neuronal cells. They are expressed on
immune cells, including macrophages. Stimulation then modulates inflammation. On Band T-cells, the activation process is inhibited by acetylcholine and also by nicotine, which
is responsible for immune suppression that can be observed in heavy smokers.
Finally, some prominent toxins acting on acetylcholine-dependent neurotransmission
do not work as agonists or antagonist at the receptor. They rather are inhibitors of acetylcholine esterase, the enzyme that degrades acetylcholine after its release into the synaptic cleft.
This leads to increased stimulation of the receptor. For example, physostigmine from
Physostigma venenosum is a reversible acetylcholinesterase inhibitor. It is toxic but is used
therapeutically as an antidote to poisoning with receptor antagonists (Proudfoot 2006).
Organophosphorus compounds have similar effects. These include the infamous nerve gas
Sarin and many insecticides that were used in the past. These have been banned in the 1970s.
6.3 GABA A Receptors: Muscimol, Valerenic Acid,
Thujone and Benzamidines
GABA A receptors are chloride channels, in contrast to GABA B , which is a GPCR (Bormann
2000). Their activation thus gates influx of negatively charged ions and therefore membrane hyperpolarization and neuronal inhibition. They also belong to the family of pentameric ligand-gated ion channels and have a similar structure as the previously discussed
NAchRs. However, there is one important difference. They are anion channels, and therefore their selectivity pores are positively charged. Thus, the electrostatic potential of the
pore is positive, and this provides conductivity for anions, in contrast to the negative electrostatic potential of cation channels in this class.
Chloride is the only halogen anion used in biological systems. Therefore, selectivity is
only required for exclusion of much larger anions like phosphate, sulphate, bicarbonate or
anionic peptides. Accordingly, the selectivity filter does not distinguish between chloride,
bromide and iodate.
GABA was discovered in 1960 as an inhibitory neurotransmitter. GABA A receptors are
prominent targets for psychoactive synthetic drugs including barbiturates and benzodiazepines. They are expressed in the brain, spinal cord, basal ganglia, cerebellum (Purkinje
cell, motor control) and in the thalamus (sleep control). A variety of drugs bind to different sites on the channels, and their activity is dependent on the precise subunit composition
of the pentameric receptors (Lynagh and Pless 2014). 19 different GABA A – subunits are
encoded in the human genome (Sigel and Steinmann 2012). Thus, GABA A receptor composition is highly diverse. This opens the possibility to design very specific compounds
that interfere only with certain subsets of these receptors and thereby to obtain more finely
tuned drugs (Sigel and Steinmann 2012). GABA A1 to GABA A6 -receptors, for instance, are
composed of α, β and γ-subunits. They are sensitive to benzodiazepines in contrast to
GABA A0 -receptors, which are composed of α, β and δ or ε-subunits and are insensitive to
these drugs. Benzodiazepines and barbiturates (derived from valerenic acid) bind the
GABA A receptor at two different positions, and both these sites are not physically overlapChapter 6 · Ion Channels as Targets for Plant-Derived Drugs
6
Some cyanobacteria produce the NAchR agonist anatoxin A. This is also called “very
fast death” factor because it kills animals within a few minutes. It has been made responsible for the death of 30,000 flamingos on lake Bogoria in Kenia in the autumn 1999
(Krienitz et al. 2003).
Acetylcholine receptors also have permeability for Ca 2+ -ions. This is important for
some additional functions of these receptors on non-neuronal cells. They are expressed on
immune cells, including macrophages. Stimulation then modulates inflammation. On Band T-cells, the activation process is inhibited by acetylcholine and also by nicotine, which
is responsible for immune suppression that can be observed in heavy smokers.
Finally, some prominent toxins acting on acetylcholine-dependent neurotransmission
do not work as agonists or antagonist at the receptor. They rather are inhibitors of acetylcholine esterase, the enzyme that degrades acetylcholine after its release into the synaptic cleft.
This leads to increased stimulation of the receptor. For example, physostigmine from
Physostigma venenosum is a reversible acetylcholinesterase inhibitor. It is toxic but is used
therapeutically as an antidote to poisoning with receptor antagonists (Proudfoot 2006).
Organophosphorus compounds have similar effects. These include the infamous nerve gas
Sarin and many insecticides that were used in the past. These have been banned in the 1970s.
6.3 GABA A Receptors: Muscimol, Valerenic Acid,
Thujone and Benzamidines
GABA A receptors are chloride channels, in contrast to GABA B , which is a GPCR (Bormann
2000). Their activation thus gates influx of negatively charged ions and therefore membrane hyperpolarization and neuronal inhibition. They also belong to the family of pentameric ligand-gated ion channels and have a similar structure as the previously discussed
NAchRs. However, there is one important difference. They are anion channels, and therefore their selectivity pores are positively charged. Thus, the electrostatic potential of the
pore is positive, and this provides conductivity for anions, in contrast to the negative electrostatic potential of cation channels in this class.
Chloride is the only halogen anion used in biological systems. Therefore, selectivity is
only required for exclusion of much larger anions like phosphate, sulphate, bicarbonate or
anionic peptides. Accordingly, the selectivity filter does not distinguish between chloride,
bromide and iodate.
GABA was discovered in 1960 as an inhibitory neurotransmitter. GABA A receptors are
prominent targets for psychoactive synthetic drugs including barbiturates and benzodiazepines. They are expressed in the brain, spinal cord, basal ganglia, cerebellum (Purkinje
cell, motor control) and in the thalamus (sleep control). A variety of drugs bind to different sites on the channels, and their activity is dependent on the precise subunit composition
of the pentameric receptors (Lynagh and Pless 2014). 19 different GABA A – subunits are
encoded in the human genome (Sigel and Steinmann 2012). Thus, GABA A receptor composition is highly diverse. This opens the possibility to design very specific compounds
that interfere only with certain subsets of these receptors and thereby to obtain more finely
tuned drugs (Sigel and Steinmann 2012). GABA A1 to GABA A6 -receptors, for instance, are
composed of α, β and γ-subunits. They are sensitive to benzodiazepines in contrast to
GABA A0 -receptors, which are composed of α, β and δ or ε-subunits and are insensitive to
these drugs. Benzodiazepines and barbiturates (derived from valerenic acid) bind the
GABA A receptor at two different positions, and both these sites are not physically overlapChapter 6 · Ion Channels as Targets for Plant-Derived Drugs