Molecular Pharmacology
Heads: Drs. Susan George and Brian O'Dowd
In the past year, the Molecular Pharmacology Section continued work on
the biology of neurotransmitter receptors for dopamine, opioid peptides
and other novel receptors that we have identified. Many of these receptors
are highly expressed in brain, and are targeted by drugs used to treat
neuropsychiatric disorders. Understanding these receptors may lead to
the development of novel drugs. In the past year, our researchers published
20 peer-reviewed papers and three invited reviews. The research highlights
are summarized as follows.
Receptor Biology
Our investigation of the function of receptors has continued. Since we
originally cloned some of the opioid receptors, our work in this area
has helped to better define their individual pharmacological and biochemical
profiles. These opioid receptors are highly related to each other structurally,
so we examined whether the mu and delta opioid receptors complexed with
each other. We discovered that they interact to form novel signalling
receptor units. These mu-delta receptor complexes exhibit functional properties
and pharmacological characteristics that may provide a novel drug target
for opioid action in brain.
The functional role of D2 dopamine receptor complexes or oligomers have
been further studied to determine that receptors associate with each other
after they are synthesized in the cell. This association has a fundamental
role in how the receptors traffic to the surface of the cell to be available
for interaction with the neurotransmitter dopamine. Studies of the ability
of certain mutant receptors to prevent the normal receptors from properly
expressing at the cell surface have provided evidence regarding the structural
basis and the importance of receptor oligomerization. We recognized and
have made substantial progress into the nature of the three forces involved
in receptor oligomerization, and have used mutations at particular amino
acid residues to identify the sites involved within the receptors.
The D1 dopamine receptor exhibits rapid desensitization upon activation
by dopamine and is also internalized into the cell away from the cell
surface. We have identified the single specific amino acid residue involved
in the mechanism of receptor desensitization, and have identified a separate
group of three other residues that mediate receptor internalization.
Novel Receptors
Our search for novel receptors has discovered more than 40 receptor genes
thus far (representing over half of all novel receptors currently known).
Many of these receptors are highly expressed in brain, and because of
their discrete localization patterns, they have exciting potential to
mediate specific brain functions. Because they represent novel drug targets,
many of these receptors have become the focus of intense investigation
in pharmaceutical companies. Drugs targeting these receptors are predicted
to have beneficial effects on neuropsychiatric disorders.
In the past year, we discovered novel receptors for thyrotropin releasing
hormone, cysteinyl leukotriene, lysophosphatidic acid, sphingosine-1 phosphate
and histamine. In addition, we reported the cloning of 15 novel receptor
genes for which the endogenous ligands are not yet identified, and we
mapped their expression in brain.
Role of Receptors in Behaviour
We have continued our characterization of receptor-gene-deleted animals,
and now have colonies of D1, D3, D5 single-gene-knockout and D1"D3 double-knockout
animals. The D1 receptor-knockout mice have been further characterized
to have a spatial learning disability and an inability to discontinue
a previously learned task. Further studies showed the D1 receptor was
not important for acquiring or consolidating aversive learning, but had
an important role in extinguishing fear memory. We have shown that the
perception of reward in the D1-knockout mice was greatly attenuated, with
a reduction in working for sucrose and a reduction in preference for alcohol.
The preference for opioids and cocaine in these and other gene-deleted
animals is currently being investigated.
The D1"D3 double receptor-gene-deleted animals exhibited reduction of
exploratory behaviour and normalization of the reduced anxiety seen in
the D3-knockout animals, implicating an interaction between D1 and D3
receptor functions.
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