TY - JOUR
T1 - Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior
AU - Gross, Joshua D.
AU - Kaski, Shane W.
AU - Schmidt, Karl T.
AU - Cogan, Elizabeth S.
AU - Boyt, Kristen M.
AU - Wix, Kim
AU - Schroer, Adam B.
AU - McElligott, Zoe A.
AU - Siderovski, David P.
AU - Setola, Vincent
N1 - Funding Information:
These studies were supported in part by the WVU E.J. Van Liere Endowed Medicine Professorship (to DPS.) and K01 AA023555 (to ZAM.) JDG and SWK each acknowledge prior support from an NIH/ NIGMS Behavioral & Biomedical Sciences training grant (T32 GM081741) and current support from NIDA predoctoral NRSA fellowships (F31 DA043331 and F30 DA044711, respectively). KTS acknowledges support from P60 AA011605 and ESC acknowledges support from a postdoctoral training slot on T32 AA007573; KMB was supported by funding from U01 AA020911 and U24 AA025475. The authors declare no competing interests.
Publisher Copyright:
© 2019, American College of Neuropsychopharmacology.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KOR-dependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia—G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation.
AB - Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KOR-dependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia—G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation.
UR - http://www.scopus.com/inward/record.url?scp=85066938632&partnerID=8YFLogxK
U2 - 10.1038/s41386-019-0423-7
DO - 10.1038/s41386-019-0423-7
M3 - Article
C2 - 31141817
AN - SCOPUS:85066938632
SN - 0893-133X
VL - 44
SP - 1728
EP - 1741
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 10
ER -