Compartmentalized GPCR Signaling from Intracellular Membranes
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Compartmentalized GPCR Signaling from Intracellular Membranes Stephanie E. Crilly1 · Manojkumar A. Puthenveedu1,2 Received: 15 September 2020 / Accepted: 11 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Graphic Abstract
Keywords GPCR · Signaling · Trafficking · Endosomes · Golgi · Nuclear membrane
* Stephanie E. Crilly [email protected] 1
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2
Introduction G protein-coupled receptor (GPCR) signaling, which underlies complex processes ranging from smell and taste to immune responses to vision, learning, and memory, is being reconsidered in the context of the membranes from
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which GPCRs signal. GPCRs are the largest class of transmembrane signaling receptors and are activated by a wide array of inputs including light, ions, peptide and non-peptide hormones, and neurotransmitters. GPCRs transduce these inputs through conformational changes in their seven transmembrane domains. Conformational changes are driven and stabilized by interaction with classical heterotrimeric G protein effectors, which modulate diverse downstream signaling pathways and second messengers, including adenylyl cyclase and cAMP, ion channels, phospholipases, GTPases, and kinase cascades (Weis and Kobilka 2018; Wu et al. 2019). GPCRs were originally thought to activate these signaling pathways primarily from the plasma membrane. However, GPCRs also localize to other membranes in the cell and can signal from these membranes, suggesting an important spatial component of signaling. GPCRs signaling from intracellular membranes can occ
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