Journal article
An Amino Acid Residue in the Second Extracellular Loop Determines the Agonist-Dependent Tolerance Property of the Human D3 Dopamine Receptor
ACS chemical neuroscience, v 4(6), pp 940-951
11 Mar 2013
PMID: 23477444
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The D3 dopamine receptor
is a therapeutic target for treating various nervous system disorders
such as schizophrenia, Parkinson’s disease, depression, and
addictive behaviors. The crystal structure of the D3 receptor bound
to an
antagonist
was recently described; however,
the structural features that contribute to agonist-induced conformational
changes and signaling properties are not well understood. We have
previously described the conformation-dependent tolerance and slow
response termination (SRT) signaling properties of the D3 receptor
and identified the C147 residue in the second intracellular loop (IL2)
of the D3 receptor as important for the tolerance property. Interestingly,
while IL2 and the C147 residue, in particular, were important for
dopamine- and quinpirole-induced tolerance, this residue did not affect
the severe tolerance induced by the high affinity, D3 receptor-selective
agonist, PD128907. Here, we used D2/D3 receptor chimeras and site-specific
D3 receptor mutants to identify another residue, D187, in the second
extracellular loop (EC2) of the human D3 receptor that mediates the
tolerance property induced by PD128907, quinpirole, pramipexole, and
dopamine. Molecular dynamics simulations confirmed the distinct conformation
adopted by D3 receptor during tolerance and suggested that in the
tolerant D3 receptor the D187 residue in EC2 forms a salt bridge with
the H354 residue in EC3. Indeed, site-directed mutation of the H354
residue resulted in loss of PD1287907-induced tolerance. The mapping
of specific amino acid residues that contribute to agonist-dependent
conformation changes and D3 receptor signaling properties refines
the agonist-bound D3 receptor pharmacophore model which will help
develop novel D3 receptor agonists.
Metrics
Details
- Title
- An Amino Acid Residue in the Second Extracellular Loop Determines the Agonist-Dependent Tolerance Property of the Human D3 Dopamine Receptor
- Creators
- Sara Gil-Mast - Department of Pharmacology and PhysiologySandhya Kortagere - Department of Microbiology and ImmunologyKokila Kota - Department of Pharmacology and PhysiologyEldo V Kuzhikandathil - Department of Pharmacology and Physiology
- Publication Details
- ACS chemical neuroscience, v 4(6), pp 940-951
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000320899000006
- Scopus ID
- 2-s2.0-84879762668
- Other Identifier
- 991014877661904721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences