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Compartmentalized GPCR Signaling from Intracellular Membranes

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Abstract

G protein-coupled receptors (GPCRs) are integral membrane proteins that transduce a wide array of inputs including light, ions, hormones, and neurotransmitters into intracellular signaling responses which underlie complex processes ranging from vision to learning and memory. Although traditionally thought to signal primarily from the cell surface, GPCRs are increasingly being recognized as capable of signaling from intracellular membrane compartments, including endosomes, the Golgi apparatus, and nuclear membranes. Remarkably, GPCR signaling from these membranes produces functional effects that are distinct from signaling from the plasma membrane, even though often the same G protein effectors and second messengers are activated. In this review, we will discuss the emerging idea of a “spatial bias” in signaling. We will present the evidence for GPCR signaling through G protein effectors from intracellular membranes, and the ways in which this signaling differs from canonical plasma membrane signaling with important implications for physiology and pharmacology. We also highlight the potential mechanisms underlying spatial bias of GPCR signaling, including how intracellular membranes and their associated lipids and proteins affect GPCR activity and signaling.

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Acknowledgements

SEC and MAP would like to thank Ian Chronis, Josh Lott, Loyda Morales Rodriguez, Dr. Kasun Ratnayake, Dr. Prahatha Venkatraman, and Dr. Zara Weinberg for invaluable feedback and discussion on this manuscript. MAP was supported by National Institutes of Health GM117425 and National Science Foundation 1517776.

Funding

MAP was supported by NIH GM117425 and NSF 1517776.

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Authors and Affiliations

  1. Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, 48109, USA

    Stephanie E. Crilly & Manojkumar A. Puthenveedu

  2. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Manojkumar A. Puthenveedu

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  1. Stephanie E. Crilly
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  2. Manojkumar A. Puthenveedu
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Correspondence to Stephanie E. Crilly.

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Crilly, S.E., Puthenveedu, M.A. Compartmentalized GPCR Signaling from Intracellular Membranes. J Membrane Biol 254, 259–271 (2021). https://doi.org/10.1007/s00232-020-00158-7

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