76
5
single cell can receive thousands of inputs, both excitatory (majority) and inhibitory.
Pyramidal neurons in the prefrontal cortex, for instance receive input from areas that
process sensory information. Stimulation of 5HT 2A receptors in the thalamus and neocortex makes these pyramidal cells hyperexcitable which can override the sensory input. In
this way, a sensory and cognitive information overload is perceived, and this might contribute to the symptoms that are experienced with psychedelic drugs.
To add another level of complexity, serotonin and metabotropic glutamate receptors
(mGlu), both GPCRs, interact with each other and form hetero-dimers or heterooligomers. This affects ligand binding and signal transduction. LSD, for instance, binds to
dimers of mGlu2/3 and 5HT 2A . Dysregulation of such receptor complexes has been found
in some patients with schizophrenia (Fribourg et al. 2011).
5.7 Opioid Receptors: Morphine, Heroin and Salvinorin A
Opiates are a class of different alkaloids that are present in the opium poppy. These
include morphine and codeine. Furthermore, in lower concentrations, noscapine and
thebaine are found. There are other substances, including synthetic- and plant-derived
drugs that produce morphine-like effects in humans. These substances are referred to as
opioids. Accordingly, the receptors that all of these compounds activate are opioid
receptors. There are three subtypes of opioid receptors: μ, δ and κ. All are coupled to
G-proteins.
The endogenous ligands for opioid receptors are peptides, including the pentapeptides
Met-enkephalin and Leu-enkephalin (Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu)
(. Fig. 5.10). These are synthesized in cells from precursor proteins, e.g. the 35 kDa
protein proenkephalin A. Prohormone processing enzymes, such as PC1, PC2 and furin,
specifically hydrolyse peptide bonds at basic amino acids and release four Met-enkephalin
peptides and one Leu-enkephalin peptide from each proenkephalin A molecule.
Proenkephalin B, also called prodynorphin, is a 26 kDa protein and, when cleaved by
prohormone processing enzymes, releases Leu-enkephalin peptides and dynorphins,
which are extended Leu-enkephalins with 17, 13 or 8 amino acids beginning with an
N-terminal Leu-enkephalin sequence. β-Endorphins are extended Met-enkephalins. The
precursor is proopiomelanocortin, the C-terminus of which constitutes the 90 amino acid
long β-lipotropin. From β-lipotropin, β-endorphin, melanocyte-stimulating hormone
(MSH) and γ-lipotropin can be released by proteolytic processing. All opioid peptides are
referred to as endorphins. This term is derived from “endogenous” and “morphine”
(Pasternak and Pan 2013).
Opioid peptides, like other neuropeptides, are stored in large dense-core vesicles
(diameter ca. 20–250 nm). Usually, these coexist in neurons with small clear-core
synaptic vesicles (ca. 40–60 nm diameter) containing small-molecule “classical” neurotransmitters (including acetylcholine). Whereas the vesicles with small-molecule
neurotransmitters are stored close to the synapse, many of them already tethered to
the synaptic membrane to be readily releasable, dense-core vesicles with neuropeptides
are also found at extrasynaptic sites. In addition, very often neuropeptides coexist in
dense-core vesicles together with biogenic amine transmitters, including catecholamines, serotonin and histamine (Hokfelt 2010). After release, the latter enable fast
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs
5
single cell can receive thousands of inputs, both excitatory (majority) and inhibitory.
Pyramidal neurons in the prefrontal cortex, for instance receive input from areas that
process sensory information. Stimulation of 5HT 2A receptors in the thalamus and neocortex makes these pyramidal cells hyperexcitable which can override the sensory input. In
this way, a sensory and cognitive information overload is perceived, and this might contribute to the symptoms that are experienced with psychedelic drugs.
To add another level of complexity, serotonin and metabotropic glutamate receptors
(mGlu), both GPCRs, interact with each other and form hetero-dimers or heterooligomers. This affects ligand binding and signal transduction. LSD, for instance, binds to
dimers of mGlu2/3 and 5HT 2A . Dysregulation of such receptor complexes has been found
in some patients with schizophrenia (Fribourg et al. 2011).
5.7 Opioid Receptors: Morphine, Heroin and Salvinorin A
Opiates are a class of different alkaloids that are present in the opium poppy. These
include morphine and codeine. Furthermore, in lower concentrations, noscapine and
thebaine are found. There are other substances, including synthetic- and plant-derived
drugs that produce morphine-like effects in humans. These substances are referred to as
opioids. Accordingly, the receptors that all of these compounds activate are opioid
receptors. There are three subtypes of opioid receptors: μ, δ and κ. All are coupled to
G-proteins.
The endogenous ligands for opioid receptors are peptides, including the pentapeptides
Met-enkephalin and Leu-enkephalin (Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu)
(. Fig. 5.10). These are synthesized in cells from precursor proteins, e.g. the 35 kDa
protein proenkephalin A. Prohormone processing enzymes, such as PC1, PC2 and furin,
specifically hydrolyse peptide bonds at basic amino acids and release four Met-enkephalin
peptides and one Leu-enkephalin peptide from each proenkephalin A molecule.
Proenkephalin B, also called prodynorphin, is a 26 kDa protein and, when cleaved by
prohormone processing enzymes, releases Leu-enkephalin peptides and dynorphins,
which are extended Leu-enkephalins with 17, 13 or 8 amino acids beginning with an
N-terminal Leu-enkephalin sequence. β-Endorphins are extended Met-enkephalins. The
precursor is proopiomelanocortin, the C-terminus of which constitutes the 90 amino acid
long β-lipotropin. From β-lipotropin, β-endorphin, melanocyte-stimulating hormone
(MSH) and γ-lipotropin can be released by proteolytic processing. All opioid peptides are
referred to as endorphins. This term is derived from “endogenous” and “morphine”
(Pasternak and Pan 2013).
Opioid peptides, like other neuropeptides, are stored in large dense-core vesicles
(diameter ca. 20–250 nm). Usually, these coexist in neurons with small clear-core
synaptic vesicles (ca. 40–60 nm diameter) containing small-molecule “classical” neurotransmitters (including acetylcholine). Whereas the vesicles with small-molecule
neurotransmitters are stored close to the synapse, many of them already tethered to
the synaptic membrane to be readily releasable, dense-core vesicles with neuropeptides
are also found at extrasynaptic sites. In addition, very often neuropeptides coexist in
dense-core vesicles together with biogenic amine transmitters, including catecholamines, serotonin and histamine (Hokfelt 2010). After release, the latter enable fast
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs