G protein-regulated endocytic trafficking of adenylyl cyclase type 9

André M. Lazar; Roshanak Irannejad; Tanya A. Baldwin; Aparna B. Sundaram; J. Silvio Gutkind; Asuka Inoue; Carmen W. Dessauer; Mark Von Zastrow

doi:10.7554/eLife.58039

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

André M. Lazar, Roshanak Irannejad, Tanya A. Baldwin, Aparna B. Sundaram, J. Silvio Gutkind, Asuka Inoue, Carmen W. Dessauer, Mark Von Zastrow

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires b-arrestin but not Gs, AC9 traffic control requires Gs but not b-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector.

Original language	English
Article number	e58039
Pages (from-to)	1-24
Number of pages	24
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.58039
Publication status	Published - 2020 Jun
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.7554/eLife.58039

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@article{5b1108fb99d649e79353b5cc4085a71c,

title = "G protein-regulated endocytic trafficking of adenylyl cyclase type 9",

abstract = "GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires b-arrestin but not Gs, AC9 traffic control requires Gs but not b-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector.",

author = "Lazar, {Andr{\'e} M.} and Roshanak Irannejad and Baldwin, {Tanya A.} and Sundaram, {Aparna B.} and Gutkind, {J. Silvio} and Asuka Inoue and Dessauer, {Carmen W.} and Zastrow, {Mark Von}",

note = "Funding Information: We thank B Lobingier, G Peng, L Ripoll, M Stoeber and other current and past members of the von Zastrow laboratory for advice and critical discussions. We thank R D Mullins, R Sunahara and J Taun-ton for valuable discussion and suggestions. We thank M Soto-Velasquez and V Watts for valuable discussion and the generous gift of AC3/6 knockout cells. We thank the E Roth group for their generous support and lab equipment, and K Kurtz for assistance. This work was supported by grants from the US National Institutes of Health (DA010711 and DA012864 to MvZ; GM60419 to CWD; HL124049 to AAS; CA209891 to JSG). AL is an ARCS scholar. Publisher Copyright: {\textcopyright} Lazar et al.",

year = "2020",

month = jun,

doi = "10.7554/eLife.58039",

language = "English",

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AU - Lazar, André M.

AU - Irannejad, Roshanak

AU - Baldwin, Tanya A.

AU - Sundaram, Aparna B.

AU - Gutkind, J. Silvio

AU - Inoue, Asuka

AU - Dessauer, Carmen W.

AU - Zastrow, Mark Von

N1 - Funding Information: We thank B Lobingier, G Peng, L Ripoll, M Stoeber and other current and past members of the von Zastrow laboratory for advice and critical discussions. We thank R D Mullins, R Sunahara and J Taun-ton for valuable discussion and suggestions. We thank M Soto-Velasquez and V Watts for valuable discussion and the generous gift of AC3/6 knockout cells. We thank the E Roth group for their generous support and lab equipment, and K Kurtz for assistance. This work was supported by grants from the US National Institutes of Health (DA010711 and DA012864 to MvZ; GM60419 to CWD; HL124049 to AAS; CA209891 to JSG). AL is an ARCS scholar. Publisher Copyright: © Lazar et al.

PY - 2020/6

Y1 - 2020/6

N2 - GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires b-arrestin but not Gs, AC9 traffic control requires Gs but not b-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector.

AB - GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires b-arrestin but not Gs, AC9 traffic control requires Gs but not b-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector.

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G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Abstract

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