10.1021/acschemneuro.0c00199.s001
Cassandra
J. Hatzipantelis
Cassandra
J.
Hatzipantelis
Yao Lu
Yao
Lu
Daisy L. Spark
Daisy L.
Spark
Christopher J. Langmead
Christopher J.
Langmead
Gregory D. Stewart
Gregory D.
Stewart
β‑Arrestin-2-Dependent Mechanism of GPR52
Signaling in Frontal Cortical Neurons
American Chemical Society
2020
BTBZ
transfected HEK 293T cells
GPR 52 activation
GPR 52 Signaling
β- arrestin -2
HEK 293T cells
GPCR
GPR 52 agonist
neuron
Frontal Cortical Neurons
cAMP accumulation
β- arrestin -2-dependent mechanism
GPR 52 agonists
CREB
phosphorylation
ERK
3-
G αs receptor GPR 52
2020-07-07 13:42:22
Journal contribution
https://acs.figshare.com/articles/journal_contribution/_Arrestin-2-Dependent_Mechanism_of_GPR52_Signaling_in_Frontal_Cortical_Neurons/12619866
The
orphan Gαs-coupled receptor GPR52 is expressed exclusively
in the brain, predominantly in circuitry relating to symptoms of neuropsychiatric
and cognitive disorders such as schizophrenia. While GPR52 agonists
have displayed antipsychotic and procognitive efficacy in murine models,
there remains limited evidence delineating the molecular mechanisms
of these effects. Indeed, previous studies have solely reported canonical
cAMP signaling and CREB phosphorylation downstream of GPR52 activation.
In the present study, we demonstrated that the synthetic GPR52 agonist,
3-BTBZ, equipotently induces cAMP accumulation, ERK1/2 phosphorylation,
and β-arrestin-1 and -2 recruitment in transfected HEK293T cells.
In cultured frontal cortical neurons, however, 3-BTBZ-induced ERK1/2
phosphorylation was significantly more potent than cAMP signaling,
with a more prolonged signaling profile than that in HEK293T cells.
Furthermore, knock down of β-arrestin-2 in frontal cortical
neurons abolished 3-BTBZ-induced ERK1/2 phosphorylation, but not cAMP
accumulation. These results suggest a β-arrestin-2-dependent
mechanism for GPR52-mediated ERK1/2 signaling, which may link to cognitive
function <i>in vivo</i>. Finally, these findings highlight
the context-dependence of GPCR signaling in recombinant cells and
neurons, offering new insights into translationally relevant GPR52
signaling mechanisms.