| dc.description.abstract |
<p>The neuromodulator dopamine signals through the dopamine D2 receptor (D2R) to modulate
central nervous system functions through diverse signal transduction pathways. D2R
is a prominent target for drug treatments in disorders where dopamine function is
aberrant, such as schizophrenia. D2R signals through distinct G protein and β-arrestin
pathways and drugs that are functionally selective for these pathways could have improved
therapeutic potential. How D2R signals through the two pathways is still not well
defined, and efforts to elucidate these pathways have been hampered by the lack of
adequate tools for assessing the contribution of each pathway independently. To address
this, Evolutionary Trace was used to produce D2R mutants with strongly biased interactions
for either G protein or β-arrestin. Additionally, various permutations of these mutants
were used to identify critical determinants of D2R functional selectivity. D2R interactions
with the two major downstream signal transducers were effectively dissociated and
G protein signaling accounts for D2R canonical MAP kinase signaling cascade activation.
Nevertheless, when expressed in mice, the β-arrestin biased D2R caused a significant
potentiation of amphetamine-induced locomotion, while the G protein biased D2R had
minimal effects. The mutant receptors generated here provide a new molecular tool
set that enable a better definition of the individual roles of G protein and β-arrestin
signaling in D2R pharmacology, neurobiology and associated pathologies.</p>
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