TY - JOUR
T1 - Gq/11-dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR
AU - White, Alex D.
AU - Jean-Alphonse, Frederic G.
AU - Fang, Fei
AU - Peña, Karina A.
AU - Liu, Shi
AU - König, Gabriele M.
AU - Inoue, Asuka
AU - Aslanoglou, Despoina
AU - Gellman, Samuel H.
AU - Kostenis, Evi
AU - Xiao, Kunhong
AU - Vilardaga, Jean Pierre
N1 - Funding Information:
ACKNOWLEDGMENTS. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Disease and the National Institute of General Medical Sciences of the National Institutes of Health under Grant Awards Numbers R01-DK111427, R01-DK116780, and R01-DK122259 (to J.-P.V.), and R01-GM056414 (to S.H.G.). J.-P.V. thanks Nevin Lambert (Augusta University) for providing the MasGRK3ct construct and Gerry Hammond (University of Pittsburgh) for providing the FKBP-PTEN and FRB-Lyn11 constructs.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/3/31
Y1 - 2020/3/31
N2 - cAMP production upon activation of Gs by G protein-coupled receptors has classically been considered to be plasma membranedelimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mechanisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11 signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gaq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cell surface Gβγ subunits, which, in turn, act in a phosphoinositide-3 kinase-dependent manner to promote the assembly of PTHR- βarrestin-Gβγ signaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal regulation of Gs-dependent cAMP signaling.
AB - cAMP production upon activation of Gs by G protein-coupled receptors has classically been considered to be plasma membranedelimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mechanisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11 signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gaq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cell surface Gβγ subunits, which, in turn, act in a phosphoinositide-3 kinase-dependent manner to promote the assembly of PTHR- βarrestin-Gβγ signaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal regulation of Gs-dependent cAMP signaling.
KW - CAMP
KW - Endosomal signaling
KW - G-proteins
KW - GPCR
KW - PTH
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U2 - 10.1073/pnas.1918158117
DO - 10.1073/pnas.1918158117
M3 - Article
C2 - 32184323
AN - SCOPUS:85082757475
SN - 0027-8424
VL - 117
SP - 7455
EP - 7460
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -