New Concepts in Dopamine D2Receptor Biased Signaling and Implications for Schizophrenia Therapy.
The dopamine D2receptor (D2R) is a G protein-coupled receptor that is a common target for antipsychotic drugs. Antagonism of D2R signaling in the striatum is thought to be the primary mode of action of antipsychotic drugs in alleviating psychotic symptoms. However, antipsychotic drugs are not clinically effective at reversing cortical-related symptoms, such as cognitive deficits in schizophrenia. While the exact mechanistic underpinnings of these cognitive deficits are largely unknown, deficits in cortical dopamine function likely play a contributing role. It is now recognized that similar to most G protein-coupled receptors, D2Rs signal not only through canonical G protein pathways but also through noncanonical beta-arrestin2-dependent pathways. We review the current mechanistic bases for this dual signaling mode of D2Rs and how these new concepts might be leveraged for therapeutic gain to target both cortical and striatal dysfunction in dopamine neurotransmission and hence have the potential to correct both positive and cognitive symptoms of schizophrenia.
Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina.
Nikhil M
NM
Urs
Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina.
Sean M
SM
Peterson
Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina; Medicine, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina. Electronic address: marc.caron@dm.duke.edu.
Marc G
MG
Caron
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018491:Dopamine Agonists / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins / Q000378:metabolism
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins
Antipsychotics; Arrestin; Dopamine; Functional selectivity; Schizophrenia; System bias