A beta-arrestin 2 signaling complex mediates lithium action on behavior.
Besides their role in desensitization, beta-arrestin 1 and 2 promote the formation of signaling complexes allowing G protein-coupled receptors (GPCR) to signal independently from G proteins. Here we show that lithium, a pharmacological agent used for the management of psychiatric disorders such as bipolar disorder, schizophrenia, and depression, regulates Akt/glycogen synthase kinase 3 (GSK3) signaling and related behaviors in mice by disrupting a signaling complex composed of Akt, beta-arrestin 2, and protein phosphatase 2A. When administered to beta-arrestin 2 knockout mice, lithium fails to affect Akt/GSK3 signaling and induce behavioral changes associated with GSK3 inhibition as it does in normal animals. These results point toward a pharmacological approach to modulating GPCR function that affects the formation of beta-arrestin-mediated signaling complexes.
Beaulieu
Jean-Martin
JM
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Marion
Sébastien
S
Rodriguiz
Ramona M
RM
Medvedev
Ivan O
IO
Sotnikova
Tatyana D
TD
Ghisi
Valentina
V
Wetsel
William C
WC
Lefkowitz
Robert J
RJ
Gainetdinov
Raul R
RR
Caron
Marc G
MG
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D019390:Arrestins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D019964:Mood Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; D018692:Antimanic Agents; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D018021:Lithium Chloride