Minireview: Role of Intracellular Scaffolding Proteins in the Regulation of Endocrine G Protein-Coupled Receptor Signaling

Abstract

The majority of hormones stimulates and mediates their signal transduction via G protein-coupled receptors (GPCRs). The signal is transmitted into the cell due to the association of the GPCRs with heterotrimeric G proteins, which in turn activates an extensive array of signaling pathways to regulate cell physiology. However, GPCRs also function as scaffolds for the recruitment of a variety of cytoplasmic protein-interacting proteins that bind to both the intracellular face and protein interaction motifs encoded by GPCRs. The structural scaffolding of these proteins allows GPCRs to recruit large functional complexes that serve to modulate both G protein-dependent and -independent cellular signaling pathways and modulate GPCR intracellular trafficking. This review focuses on GPCR interacting PSD95-disc large-zona occludens domain containing scaffolds in the regulation of endocrine receptor signaling as well as their potential role as therapeutic targets for the treatment of endocrinopathies.

Oligomerization of GPCRs involved in endocrine regulation

“…They may impact trafficking or act as allosteric modulators (Maurice et al 2011a). Furthermore, GPCRs also act as scaffolding proteins that link the receptor to downstream effectors (Walther & Ferguson 2015). Interacting proteins may interfere with the receptor either on the intracellular site or on the transmembrane spanning proteins and interact with the transmembrane helices (Kristiansen 2004).…”

“…Many interacting proteins exist, modifying the efficacy or mode of signaling and localization of the GPCRs (reviewed in Ritter & Hall 2009, Maurice et al 2011a, Walther & Ferguson 2015. Examples of intracellular proteins can be subdivided into arrestin, PDZ (postsynaptic density 95/disc large/zona occludens-1)-containing proteins, and non-PDZ-containing proteins (Walther & Ferguson 2015), which are a large group of scaffolding proteins modifying GPCR functions.…”

“…Examples of intracellular proteins can be subdivided into arrestin, PDZ (postsynaptic density 95/disc large/zona occludens-1)-containing proteins, and non-PDZ-containing proteins (Walther & Ferguson 2015), which are a large group of scaffolding proteins modifying GPCR functions. PDZ-containing proteins are a diverse group of proteins such as the Na+-H+ exchange regulatory factor (NHERF) (Dunn & Ferguson 2015), which changes signaling properties from Gs/adenylyl cyclase activation of the parathyroid hormone receptor (PTHR) to Gq/11 phospholipase C signaling (Ardura & Friedman 2011).…”

CRISPR-Mediated Protein Tagging with Nanoluciferase to Investigate Native Chemokine Receptor Function and Conformational Changes

“…G protein-coupled receptors (GPCRs) are a major class of membrane receptors that control numerous physiological responses via ligand-mediated signal transduction. The response elicited by a given GPCR is dependent on the cellular context, i.e., the cellular proteome and a cascade of factors including receptor compartmentalization (Ellisdon and Halls, 2016;Tsvetanova et al, 2015), association with interacting proteins (Bockaert et al, 2004), binding of a specific ligand and subsequent conformational rearrangement resulting in activation (Wang et al, 2018), coupling to specific intercellular effectors (e.g., G proteins) (Wang et al, 2018;Rankovic et al, 2016), or scaffolding proteins (e.g., GPCR kinases and arrestins) (Walther and Ferguson, 2015), as well as internalization, trafficking, and recycling of the receptor (Magalhaes et al, 2012). Many of these processes can be studied using genetically encoded luminescent and/or fluorescent fusion proteins that allow for investigation of receptor or protein function by sensitive microscopic or biophysical techniques such as resonance energy transfer.…”

Molecular Characterization of Gβ-Like Protein CpcB Involved in Antifungal Drug Susceptibility and Virulence in A. fumigatus

“…The heterotrimeric G protein complex comprises Gα, Gβ, and Gγ subunits and transduces signals to effectors in all eukaryotes ( Shukla et al, 2014 ; Dohlman, 2015 ; Walther and Ferguson, 2015 ). The circular β-bladed propeller structure of the Gβ protein confers interactions of Gβγ with a variety of proteins to perform diverse functions ( Chen et al, 2004 ).…”