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A Rab10–ACAP1–Arf6 GTPases cascade modulates M4 muscarinic acetylcholine receptor trafficking and signaling

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Abstract

Membrane trafficking processes regulate the G protein-coupled receptor activity. The muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, but the cellular machineries that control the trafficking of these receptors remain largely elusive. Here, we revealed the role of the small GTPase Rab10 as a negative regulator for the post-activation trafficking of M4 mAChR and the underlying mechanism. We show that constitutively active Rab10 arrests the receptor within Rab5-positive early endosomes and significantly hinders the resensitization of M4-mediated Ca2+ signaling. Mechanistically, M4 binds to Rab10-GTP, which requires the motif 386RKKRQMAA393 (R386-A393) within the third intracellular loop. Moreover, Rab10-GTP inactivates Arf6 by recruiting the Arf6 GTPase-activating protein, ACAP1. Strikingly, deletion of the motif R386-A393 causes M4 to bypass the control by Rab10 and switch to the Rab4-facilitated fast recycling pathway, thus reusing the receptor. Therefore, Rab10 couples the cargo sorting and membrane trafficking regulation through cycle between GTP-bound and GDP-bound state. Our findings suggest a model that Rab10 binds to the M4 like a molecular brake and controls the receptor’s transport through endosomes, thus modulating the signaling, and this regulation is specific among the mAChR subtypes.

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All plasmids and data generated in this study will be freely provided upon request to the corresponding author.

Abbreviations

AD:

Alzheimer’s disease

A568-Tf:

Alexa568-labeled Transferrin

Arf6:

ADP-ribosylation factor 6

β1AR:

β1 Adrenoceptor

CCh:

Carbachol

CDE:

Clathrin-dependent endocytic

CHC:

Clathrin heavy chain

CHX:

Cycloheximide

CIE:

Clathrin-independent endocytic

Co-IP:

Co-immunoprecipitation

DOPr:

δ-Opioid receptor

EE:

Early endosome

EHBP-1:

Effector EH domain binding protein 1

ER:

Endoplasmic reticulum

FI:

Fluorescence intensity

GGA3:

Golgi-associated, gamma adaptin ear-containing, Arf-binding protein 3

GIPC:

Gαi-interacting protein C terminus

GPCR:

G protein-coupled receptor

GST:

Glutathione S-transferase

GST-GGA3-PBD:

Protein 3 binding domain (PBD) of GGA3 fused to glutathione S-transferase

mAChRs:

Muscarinic acetylcholine receptors

LHR:

Luteinizing hormone receptor

PBD:

Protein 3 binding domain

PDZ:

Postsynaptic density-95/Discs large/Zonula occludens 1

PM:

Plasma membrane

PTX:

Pertussis toxin

RE:

Recycling endosome

SNX27:

Sorting nexin 27

TAC:

IL-2 receptor α-chain

TfR:

Transferrin receptor

TLR4:

Toll-like receptor 4

WT:

Wild type

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Acknowledgements

We thank Dr. Victor Hsu (Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA), Dr. Emmanuel Boucrot (Institute of Structural and Molecular Biology, University College London, London, UK), and Dr. Eli Song(Institute of Biophysics, Chinese Academy of Sciences, Beijing, China) for kindly donating material. This work was supported by the Major Research Plan of the National Natural Science Foundation of China (91954107), and the National Natural Science Foundation of China (32270739, 31571468) to RZ.

Funding

This work was supported by the Major Research Plan of the National Natural Science Foundation of China (91954107), and the National Natural Science Foundation of China (32270739, 31571468) to RZ.

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Author notes

  1. Min Wan

    Present address: Department of Molecular Biology and Genetics, Cornell University, Ithaca, USA

  2. Xuemeng Shi

    Present address: College of Life Science, Henan Agricultural University, Zhengzhou, Henan, China

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  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Rongmei Xu, Min Wan, Xuemeng Shi, Shumin Ma, Lina Zhang, Ping Yi & Rongying Zhang

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Conceptualization, RZ; Investigation, RX, MW, XS, SM, and LZ; Methodology, RX, PY, MW, XS, and RZ; Formal analysis, RX, and MW; Funding acquisition, RZ; Project administration, PY, RZ; Original draft, RZ; Writing and review and editing, RX, PY, MW, and RZ.

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Correspondence to Ping Yi or Rongying Zhang.

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Xu, R., Wan, M., Shi, X. et al. A Rab10–ACAP1–Arf6 GTPases cascade modulates M4 muscarinic acetylcholine receptor trafficking and signaling. Cell. Mol. Life Sci. 80, 87 (2023). https://doi.org/10.1007/s00018-023-04722-x

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