91
6
causes neuronal cell death due to excess Ca 2+ -influx into neurons. This occurs during spinal cord injury, in Alzheimer and other neurodegenerative diseases, alcohol
withdrawal disease and also under conditions after over-rapid benzodiazepine withdrawal.
Glutamate-gated ion channels are primarily located in the brain. The AMPA and
kainite receptors are pure ligand-gated cation-channels with glutamate as the endogenous ligand. The third one, the NMDA receptor, is ligand and voltage gated. All glutamate receptors are formed from four subunits GluA1-GluA4. They are heterotetramers
with varying composition of these subunits. Each subunit has a large N-terminal extracellular domain responsible for receptor assembly and trafficking. This is followed by
the transmembrane helix M4 and a short intracellular loop, which leads to the M2-helix
that does not span the membrane completely but is rather buried into the inner membrane leaflet. It is followed by a loop half inside the membrane and half intracellular.
This loop connects to helix M3 spanning the membrane and is followed by another large
extracellular loop, which contains the ligand-binding site. Then helix M1 and a small
intracellular C-terminal domain follow. The glutamate receptors are additionally regulated by auxiliary subunits. Ibotenic acid is an agonist for all three glutamate receptors
and for metabotropic glutamate receptors. It causes excitation, agitation and neuronal
cell death.
AMPA is a synthetic glutamate derivative and binds AMPA receptors. Ethanol is an
antagonist on these receptors! Kainate is a product of seaweed. It is an antagonist of the
kainite receptor. It causes neuronal cell death and induces excitotoxic lesions. It is also
used as a remedy against parasitic worms. Similarly, the kainite analogon domoic acid,
which is produced by algae and causes amnesic shellfish poisoning, has been used as an
anthelmintic in Japan (Hanayanagi).
NMDA-receptors are activated by two processes. They need binding of ligands and the
release of a Mg 2 + -ion-block. Therefore, they only open after membrane depolarization,
usually caused by glutamate binding to co-expressed AMPA receptors. This change of
membrane charge releases the Mg 2+ -ion. NMDA receptors are therefore “silent” as long as
they are expressed alone on neuronal membranes and only become active when AMPA
receptors are co-expressed. Moreover, in addition to glutamate, they have obligatory coagonists, namely, glycine or D-serine. NMDA receptors play a role in synaptic plasticity,
learning and memory. In the cholinergic nervous system, NMDA receptor signalling
induces acetylcholine release (Traynelis et al. 2010).
The synthetic drug phenylcyclohexyl-piperidine (PCP or angels dust), originally used
as narcotic, is an open channel blocker of the NMDA receptor. Ketamine was synthesized
in order to obtain a general anaesthetic with less side effects than PCP. Ketamine turned
out to be a non-competitive antagonist of NMDA channels. As a hypnotic, it induces sleep
and dissociative anaesthesia, meaning that protective body reflexes are maintained.
Ketamine also has psychedelic potential and has been used as a street drug since the mid1970s. In small doses, it causes hallucinations, “out of body” experiences, euphoria and
others. Chronic administration causes loss of short- and long-term memory.
Notably, ketamine produces both positive and negative symptoms of schizophrenia
(see 7 Box 5.3). It is also used to induce a “schizophrenic condition in animals”. Therefore,
the original hypothesis of schizophrenia being caused by hyperactive dopamine transmission was amended. The “glutamate” hypothesis suggests that a hypofunction of NMDA
receptors on cortical and subcortical GABAergic interneurons is the underlying cause of
6.5 · Glutamate Receptors: Ibotenic Acid, Kainate and Ketamine
6
causes neuronal cell death due to excess Ca 2+ -influx into neurons. This occurs during spinal cord injury, in Alzheimer and other neurodegenerative diseases, alcohol
withdrawal disease and also under conditions after over-rapid benzodiazepine withdrawal.
Glutamate-gated ion channels are primarily located in the brain. The AMPA and
kainite receptors are pure ligand-gated cation-channels with glutamate as the endogenous ligand. The third one, the NMDA receptor, is ligand and voltage gated. All glutamate receptors are formed from four subunits GluA1-GluA4. They are heterotetramers
with varying composition of these subunits. Each subunit has a large N-terminal extracellular domain responsible for receptor assembly and trafficking. This is followed by
the transmembrane helix M4 and a short intracellular loop, which leads to the M2-helix
that does not span the membrane completely but is rather buried into the inner membrane leaflet. It is followed by a loop half inside the membrane and half intracellular.
This loop connects to helix M3 spanning the membrane and is followed by another large
extracellular loop, which contains the ligand-binding site. Then helix M1 and a small
intracellular C-terminal domain follow. The glutamate receptors are additionally regulated by auxiliary subunits. Ibotenic acid is an agonist for all three glutamate receptors
and for metabotropic glutamate receptors. It causes excitation, agitation and neuronal
cell death.
AMPA is a synthetic glutamate derivative and binds AMPA receptors. Ethanol is an
antagonist on these receptors! Kainate is a product of seaweed. It is an antagonist of the
kainite receptor. It causes neuronal cell death and induces excitotoxic lesions. It is also
used as a remedy against parasitic worms. Similarly, the kainite analogon domoic acid,
which is produced by algae and causes amnesic shellfish poisoning, has been used as an
anthelmintic in Japan (Hanayanagi).
NMDA-receptors are activated by two processes. They need binding of ligands and the
release of a Mg 2 + -ion-block. Therefore, they only open after membrane depolarization,
usually caused by glutamate binding to co-expressed AMPA receptors. This change of
membrane charge releases the Mg 2+ -ion. NMDA receptors are therefore “silent” as long as
they are expressed alone on neuronal membranes and only become active when AMPA
receptors are co-expressed. Moreover, in addition to glutamate, they have obligatory coagonists, namely, glycine or D-serine. NMDA receptors play a role in synaptic plasticity,
learning and memory. In the cholinergic nervous system, NMDA receptor signalling
induces acetylcholine release (Traynelis et al. 2010).
The synthetic drug phenylcyclohexyl-piperidine (PCP or angels dust), originally used
as narcotic, is an open channel blocker of the NMDA receptor. Ketamine was synthesized
in order to obtain a general anaesthetic with less side effects than PCP. Ketamine turned
out to be a non-competitive antagonist of NMDA channels. As a hypnotic, it induces sleep
and dissociative anaesthesia, meaning that protective body reflexes are maintained.
Ketamine also has psychedelic potential and has been used as a street drug since the mid1970s. In small doses, it causes hallucinations, “out of body” experiences, euphoria and
others. Chronic administration causes loss of short- and long-term memory.
Notably, ketamine produces both positive and negative symptoms of schizophrenia
(see 7 Box 5.3). It is also used to induce a “schizophrenic condition in animals”. Therefore,
the original hypothesis of schizophrenia being caused by hyperactive dopamine transmission was amended. The “glutamate” hypothesis suggests that a hypofunction of NMDA
receptors on cortical and subcortical GABAergic interneurons is the underlying cause of
6.5 · Glutamate Receptors: Ibotenic Acid, Kainate and Ketamine