92
6
excessive dopaminergic and glutaminergic signalling in the cortex. This leads to the positive and negative symptoms of schizophrenia (see 7 Box 5.3) (Cioffi 2013). Moreover, a
polymorphism in the NMDA receptor subunit gene GRIN2B was found in association
with the disease (Li and He 2007).
6.6 TRPV and TRPM8: Heat and Cold, Capsaicin and Menthol
TRPV receptors can be subdivided into several subfamilies, of which TRPV1 and TRPV2
are chemo- and thermosensors, TRPV4 is functioning as thermo- and osmosensor and
TRPV5 and TRPV6 are Ca 2+ channels in epithelial cells.
TRPV1 channels are localized on peripheral sensory nerve endings, in the brain and
in the spinal cord. They are pain receptors because they detect noxious stimuli and, in
response, activate afferent sensory neurons. Therefore, they have been extensively studied
as novel targets for the development of analgetics. As non-specific cation channels, they
conduct Ca 2+ , K + and Na + -ions. TRPV1 channels mediate signals of higher temperatures,
acids and chemicals that we associate with heat and pain (see hot chillies), as well as
inflammatory responses that we also experience as heat and pain. Small molecule chemicals interacting with TRPV1 include capsaicin, the active compound of hot chilli peppers.
Interestingly, capsaicin is also used as part of creams to reduce pain, for instance, in
arthritic disease conditions. This is supposed to be due to its ability to desensitize TRPV1
(Zhang et al. 2008a, b). Further chemicals binding TRPV1 channels are vanillotoxins from
tarantula venom. Endogenous TRPV1 agonists are referred to as endovanilloids, and they
include the endocannabinoids anandamide and N-arachidonoyl dopamine, and endogenous lipids like N-acetylethanolamines and polyunsaturated fatty acids. As previously
described, endocannabinoids are released from cells in an activity-dependent manner.
This also counts for derivatives of arachidonic acid, including eicosanoids, which are
released after stimulation of nerve endings with mediators of inflammation, such as bradykinin and prostaglandins (Brito et al. 2014).
TRPV1 channels are part of our temperature-sensing system in the body. Temperature
sensitive neurons are present in trigeminal ganglia and dorsal root ganglia and convey
signals received from peripheral terminals to the CNS. TRPV1 channels respond to
increased temperature (>43 °C), which constitutes a moderate heat. Some of the chemical
activators of TRPV1 work by shifting down the threshold temperature for channel opening thus inducing pain sensations already at normal body temperature. TRPV2, also found
on sensory neurons and in the brain, is activated at ca. 50 °C, a noxious heat. TRPV3,
especially found in the skin and tongue, responds to pleasant warmth of 34–40 °C and
TRPV4 to 27–40 °C. The latter is expressed in the airway, liver, heart and brain and in the
skin. It is also activated by the endocannabinoid anandamide.
In contrast, TRPM8 channels, members of the melastatin-related TRP family, are
modulated by temperatures below 25 °C. They are voltage-dependent cold-sensing Ca 2+
channels. Menthol and eucalyptol work as allosteric regulators on TRPM8 channels.
Binding of these compounds shifts the activation temperature for the channel up; therefore the receptor is activated at higher temperatures. Moreover, these compounds also
shift the voltage-dependence of TRPM8 to more negative membrane potentials. Together
Chapter 6 · Ion Channels as Targets for Plant-Derived Drugs
6
excessive dopaminergic and glutaminergic signalling in the cortex. This leads to the positive and negative symptoms of schizophrenia (see 7 Box 5.3) (Cioffi 2013). Moreover, a
polymorphism in the NMDA receptor subunit gene GRIN2B was found in association
with the disease (Li and He 2007).
6.6 TRPV and TRPM8: Heat and Cold, Capsaicin and Menthol
TRPV receptors can be subdivided into several subfamilies, of which TRPV1 and TRPV2
are chemo- and thermosensors, TRPV4 is functioning as thermo- and osmosensor and
TRPV5 and TRPV6 are Ca 2+ channels in epithelial cells.
TRPV1 channels are localized on peripheral sensory nerve endings, in the brain and
in the spinal cord. They are pain receptors because they detect noxious stimuli and, in
response, activate afferent sensory neurons. Therefore, they have been extensively studied
as novel targets for the development of analgetics. As non-specific cation channels, they
conduct Ca 2+ , K + and Na + -ions. TRPV1 channels mediate signals of higher temperatures,
acids and chemicals that we associate with heat and pain (see hot chillies), as well as
inflammatory responses that we also experience as heat and pain. Small molecule chemicals interacting with TRPV1 include capsaicin, the active compound of hot chilli peppers.
Interestingly, capsaicin is also used as part of creams to reduce pain, for instance, in
arthritic disease conditions. This is supposed to be due to its ability to desensitize TRPV1
(Zhang et al. 2008a, b). Further chemicals binding TRPV1 channels are vanillotoxins from
tarantula venom. Endogenous TRPV1 agonists are referred to as endovanilloids, and they
include the endocannabinoids anandamide and N-arachidonoyl dopamine, and endogenous lipids like N-acetylethanolamines and polyunsaturated fatty acids. As previously
described, endocannabinoids are released from cells in an activity-dependent manner.
This also counts for derivatives of arachidonic acid, including eicosanoids, which are
released after stimulation of nerve endings with mediators of inflammation, such as bradykinin and prostaglandins (Brito et al. 2014).
TRPV1 channels are part of our temperature-sensing system in the body. Temperature
sensitive neurons are present in trigeminal ganglia and dorsal root ganglia and convey
signals received from peripheral terminals to the CNS. TRPV1 channels respond to
increased temperature (>43 °C), which constitutes a moderate heat. Some of the chemical
activators of TRPV1 work by shifting down the threshold temperature for channel opening thus inducing pain sensations already at normal body temperature. TRPV2, also found
on sensory neurons and in the brain, is activated at ca. 50 °C, a noxious heat. TRPV3,
especially found in the skin and tongue, responds to pleasant warmth of 34–40 °C and
TRPV4 to 27–40 °C. The latter is expressed in the airway, liver, heart and brain and in the
skin. It is also activated by the endocannabinoid anandamide.
In contrast, TRPM8 channels, members of the melastatin-related TRP family, are
modulated by temperatures below 25 °C. They are voltage-dependent cold-sensing Ca 2+
channels. Menthol and eucalyptol work as allosteric regulators on TRPM8 channels.
Binding of these compounds shifts the activation temperature for the channel up; therefore the receptor is activated at higher temperatures. Moreover, these compounds also
shift the voltage-dependence of TRPM8 to more negative membrane potentials. Together
Chapter 6 · Ion Channels as Targets for Plant-Derived Drugs