Abstract
G protein-coupled receptors (GPCRs) are currently appreciated to be routed to diverse cellular platforms to generate both G protein-dependent and -independent signals. The latter has been best studied with respect to β-arrestin-associated receptor internalization and trafficking to signaling endosomes for extracellular signal-regulated kinase (ERK) activation. However, how GPCR structural and conformational variants regulate endosomal ERK signaling dynamics, which can be central in neural development, plasticity, and disease processes, is not well understood. Among class B GPCRs, the PACAP-selective PAC1 receptor is unique in the expression of variants that can contain intracellular loop 3 (ICL3) cassette inserts. The nervous system expresses preferentially the PAC1Null (no insert) and PAC1Hop (28-amino acid Hop insert) receptor variants. Our molecular modeling and signaling studies revealed that the PAC1Null and PAC1Hop receptor variants can associate with β-arrestin differentially, resulting in enhanced receptor internalization and ERK activation for the PAC1Hop variant. The study amplifies our understandings of GPCR intracellular loop structure/function relationships with the first example of how the duration of endosomal ERK activation can be guided by ICL3. The results provide a framework for how changes in GPCR variant expression can impact developmental and homeostatic processes and may be contributory to maladaptive neuroplasticity underlying chronic pain and stress-related disorders.
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Availability of Data and Material
All data generated are in the manuscript or supplemental information. Materials not available at repositories or commercial vendors will be made available upon reasonable request. Materials generated in the study are subject to material transfer agreements. Information and requests for resources and reagents should be directed to and will be fulfilled by the corresponding authors, Victor May (victor.may@med.uvm.edu) and Jianing Li (Jianing.li@uvm.edu).
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Acknowledgements
We thank Thomas Buttolph for technical assistance in the cellular studies.
Funding
The work was supported by grants GM129431 (JL) and MH097988 (VM) from the National Institutes of Health. Computational resources were provided to JL by VACC, PSC-ANTON, and XSEDE.
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VM, JL, and MB conceived of the project and wrote the manuscript. SS, CL, and JMR performed the simulations and analyzed the modeling data. VM and KMB performed the experiments and interpreted the experimental results with help from RLP. All authors participated in the editing of the manuscript, provided critical feedback, and helped shape the research, analysis, and manuscript.
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The animal study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Vermont and carried out with accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals. No human studies were performed in this article.
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Li, J., Remington, J.M., Liao, C. et al. GPCR Intracellular Loop Regulation of Beta-Arrestin-Mediated Endosomal Signaling Dynamics. J Mol Neurosci 72, 1358–1373 (2022). https://doi.org/10.1007/s12031-022-02016-8
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DOI: https://doi.org/10.1007/s12031-022-02016-8