84
6
What You Will Learn in This Chapter
In this chapter we will describe the physiological and psychological actions of prominent
plant derived and synthetic compounds that target ion channel signalling. These include
neurotoxins binding to voltage gated ion channels as well as drugs and toxins like nicotine,
thujone, muscimol and strychnine interacting with neurotransmitter gated ion channels.
Synthetic compounds such as benzamidine, ketamine and PCP will be discussed. Finally we
will briefly explain the interactions of capsaicin and menthol with specific TRP-channels.
6.1 Neurotoxin Binding Sites on Voltage-Gated Ion Channels
Many neurotoxins exhibit their effect through binding to voltage-gated cation channels.
These include a number of animal venoms that are produced by frogs, snails, snakes and
spiders.
Pharmacological studies have identified several sites of action for neurotoxins on
voltage- gated sodium channels. At extracellular sites (site 1, . Fig. 4.2b), the water-soluble
heterocyclic guanidines tetrodotoxin (TTX), a tarantula toxin and saxitoxin (STX) from
dinoflagellates and snail-derived peptides, like μ-conotoxin, can dock. This blocks ion
conductance. These toxins have been used to identify regions of the channels that are
involved in pore opening and to distinguish between different sodium channel isoforms
(Cestele and Catterall 2000). It was suggested that bacteria of the genus Vibrio, which
produce tetrodotoxin and are found in some marine animals, e.g. Fugu vermicularis,
might be the source of the poison (Noguchi et al. 1986). Saxitoxin is enriched in some
mussels and the source of paralytic shellfish poisoning. It is produced by dinoflagellates,
which in some conditions grow abundantly in marine regions and cause “red tides”.
Conotoxins are produced by snails of the genus Conus. They comprise a large variety of
short peptides of 10–30 amino acids. These are stabilized by disulphide bonds and due to
their small size easily penetrate the skin of prey animals.
Some toxins bind especially to the activated state of Na + -channels and keep it open.
This causes persistent activation. They bind to a site on helix S6 of the first and the fourth
subdomain of the α-subunits of the channel (site 2) (. Fig. 4.2b). Aconitine from plants of
the Aconitum genus is the most famous toxin in this group. Due to persistent channel
activation, aconitine at first works excitatoric on central and peripheral nerves and causes
arrhythmia of the heart. Later it leads to paralysis and eventually it causes death.
Pyrethrins, which are found in several plants from the Asteraceae family, also target
voltage-gated Na + -channels (Soderlund et al. 2002). Specifically, they change the kinetics
of activation and inactivation of the neuronal voltage-dependent Na + -channel in some
arthropodes. However, by exposing large populations of house flies to these compounds
for a long time, the so-called knockdown-resistant flies appear, which have amino acid
substitutions in the linker sequence between helix S4 and helix S5 of the second subdomain of this channel protein. Interestingly, these sites also differ in their amino acid
sequence between mammals and insects. Mammalian Na + -channels are much less sensitive to pyrethrins counting for the low mammalian toxicity of these compounds. This
makes pyrethrins sought after insecticides (Vais et al. 2000).
Chapter 6 · Ion Channels as Targets for Plant-Derived Drugs
6
What You Will Learn in This Chapter
In this chapter we will describe the physiological and psychological actions of prominent
plant derived and synthetic compounds that target ion channel signalling. These include
neurotoxins binding to voltage gated ion channels as well as drugs and toxins like nicotine,
thujone, muscimol and strychnine interacting with neurotransmitter gated ion channels.
Synthetic compounds such as benzamidine, ketamine and PCP will be discussed. Finally we
will briefly explain the interactions of capsaicin and menthol with specific TRP-channels.
6.1 Neurotoxin Binding Sites on Voltage-Gated Ion Channels
Many neurotoxins exhibit their effect through binding to voltage-gated cation channels.
These include a number of animal venoms that are produced by frogs, snails, snakes and
spiders.
Pharmacological studies have identified several sites of action for neurotoxins on
voltage- gated sodium channels. At extracellular sites (site 1, . Fig. 4.2b), the water-soluble
heterocyclic guanidines tetrodotoxin (TTX), a tarantula toxin and saxitoxin (STX) from
dinoflagellates and snail-derived peptides, like μ-conotoxin, can dock. This blocks ion
conductance. These toxins have been used to identify regions of the channels that are
involved in pore opening and to distinguish between different sodium channel isoforms
(Cestele and Catterall 2000). It was suggested that bacteria of the genus Vibrio, which
produce tetrodotoxin and are found in some marine animals, e.g. Fugu vermicularis,
might be the source of the poison (Noguchi et al. 1986). Saxitoxin is enriched in some
mussels and the source of paralytic shellfish poisoning. It is produced by dinoflagellates,
which in some conditions grow abundantly in marine regions and cause “red tides”.
Conotoxins are produced by snails of the genus Conus. They comprise a large variety of
short peptides of 10–30 amino acids. These are stabilized by disulphide bonds and due to
their small size easily penetrate the skin of prey animals.
Some toxins bind especially to the activated state of Na + -channels and keep it open.
This causes persistent activation. They bind to a site on helix S6 of the first and the fourth
subdomain of the α-subunits of the channel (site 2) (. Fig. 4.2b). Aconitine from plants of
the Aconitum genus is the most famous toxin in this group. Due to persistent channel
activation, aconitine at first works excitatoric on central and peripheral nerves and causes
arrhythmia of the heart. Later it leads to paralysis and eventually it causes death.
Pyrethrins, which are found in several plants from the Asteraceae family, also target
voltage-gated Na + -channels (Soderlund et al. 2002). Specifically, they change the kinetics
of activation and inactivation of the neuronal voltage-dependent Na + -channel in some
arthropodes. However, by exposing large populations of house flies to these compounds
for a long time, the so-called knockdown-resistant flies appear, which have amino acid
substitutions in the linker sequence between helix S4 and helix S5 of the second subdomain of this channel protein. Interestingly, these sites also differ in their amino acid
sequence between mammals and insects. Mammalian Na + -channels are much less sensitive to pyrethrins counting for the low mammalian toxicity of these compounds. This
makes pyrethrins sought after insecticides (Vais et al. 2000).
Chapter 6 · Ion Channels as Targets for Plant-Derived Drugs