The Ilse & Helmut Wachter-Award 2001 goes to
Professor
HANNS MÖHLER, ETH Zürich
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H. Grunicke, M.D. (Dean), H. Möhler, Ph.D. |
P. Fritsch, M.D., H. Grunicke , M.D. (Dean), H. Möhler, Ph.D. |
SUMMARY OF ACHIEVEMENTS
The
regulation of brain function by a major group of psychoactive drugs,
the benzodiazepines, is the central theme of the scientific work of
Hanns Möhler. His studies are highly interdisciplinary, encompass
all levels of biological organisation from the genetic to the behavioural
level and excel by fundamental discoveries.
Mechanism
of action of benzodiazepines
Benzodiazepines are among the most widely used drugs worldwide. Unraveling
their mechanism of action is a landmark in the history of psychopharmacology,
pionieered to an essential part by Hanns Möhler. He not only co-authored
the original GABA hypothesis for the action of benzodiazepines but identified
their molecular target in the brain in a seminal paper which has become
a citation classic (1). The so-called benzodiazepine receptor was identified
by him not only as a radioligand binding site but also - by photoaffinity
labeling- as a protein (2). He succeeded in locating this receptor protein
in identified GABAergic synapses (3). The protein was the first identified
component of the GABAA-receptor.
A
new view of GABAergic transmission
Hanns Möhler changed our view of GABAergic transmission. Originally
considered to be a rather unified type of transmission he visualized
a genetic program in neurons permitting them to generate a wide variety
of GABAA-receptor subtypes based on different subunit complements. Using
highly advanced immunohistochemical techniques he identified the first
five GABAA-receptor subtypes in situ (4) and showed the distinctive
features of their channel function in recombinant receptor systems.
The newly discovered GABAA-receptor heterogeneity introduced a distinctive
synaptic marker into GABAergic neurotransmission.
Anxiety.
At the intersection of genes and environment
A deficit of GABAA-receptors is frequently seen by positron emission
tomography (PET) in patients with panic anxiety. In an animal model
Hanns Möhler was able to identify the molecular deficit of GABAA-receptor
as a contributor to anxiety behavior (5). The animal model was generated
by reducing the synaptic clustering of GABAA-receptors. This was achieved
in a mouse line heterozygous for the gamma 2-subunit which anchors the
GABAA-receptor to the postsynaptic cytoskeleton. Behaviorally, only
anxiety responses were enhanced including a cognitive bias for threat
cues which is a hallmark of anxiety symptoms in humans. Thus, by the
genetic alteration of GABAA-receptor clustering the brain was set to
operate in an anxiety mode (5). The underlying alterations in neuronal
circuits can now be studied as well as their mode of interaction with
the environment. Furthermore, the study points to potential candidate
genes for a genetic basis of anxiety disorders in humans.
A
new pharmacology
The contribution of Hanns Möhler to drug development was first
highlighted by the discovery of flumazenil, which is now in clinical
use as benzodiazepine antagonist (6). This compound is also the preferred
ligand for PET imaging of GABAA-receptors in various disease states.
Recently he opened up an entirely new realm for a rational drug development
ending a 30 year period of heuristic search for improved ligands acting
at the benzodiazepine site. GABAA-receptor subtypes have long been considered
as promising goals for drug development. However it was only recently
that the pharmacological function of GABAA-receptor subtypes was identified.
This was achieved with an ingenious point mutation methodology. By introducing
a single point mutation in the benzodiazepine binding site, specific
GABAA-receptor subtypes where rendered diazepam insensitive in vivo.
The drug action mediated by the corresponding receptor was expected
to be absent in the pharmacology of the point mutated mouse. This strategy
was implemented by generating mouse lines in which the a1-, a2- and
a3-GABAA-receptors were selectively point mutated by converting a conserved
histidine residue into arginine (7, 8). The genetic selection markers
(neomycin casette) were removed from the genome to avoid a potential
interference in the phenotype. Furthermore, it was demonstrated that
the point mutation did not interfere with the synthesis, assembly and
location of the GABAA-receptors. Finally, it was assured that the GABA-induced
gating of the channel in vivo was unimpaired by the point mutation.
In an outstanding series of publications Hanns Möhler identified the a1-GABAA-receptora as mediators of the sedative, anticonvulsant and anterograde amnesic actions of benzodiazepines (7). In addition the small population of a2-GABAA-receptors was found to mediate the anxiolytic activity of benzodiazepines (8). This result was in keeping with the location of a2-GABA-receptors in areas closely linked to the processing of emotional stimuli. a2-GABAA-receptors are highly expressed in the central nucleus of the amygdala and are densely packed on the axon initial segment of the principal cells in the cerebral cortex and hippocampus where they control their output activity. Thus, a new pharmacology for benzodiazepine site ligands is on the horizon. The classical spectrum of benzodiazepines and their side effects will be dissected by the development of ligands selective for GABAA-receptor subtypes. In addition, drug elicited at selective GABAA-receptors can be envisaged to go beyond those of the classical benzodiazepines.
