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Review
. 2023 Aug;28(8):103641.
doi: 10.1016/j.drudis.2023.103641. Epub 2023 May 24.

Modulating GPCR and 14-3-3 protein interactions: Prospects for CNS drug discovery

Sathapana Kongsamut  1 , Haifeng Eishingdrelo  2
Affiliations
Review

Modulating GPCR and 14-3-3 protein interactions: Prospects for CNS drug discovery

Sathapana Kongsamut et al. Drug Discov Today. 2023 Aug.

Abstract

The activation of G-protein-coupled receptors (GPCRs) triggers a series of protein-protein interaction events that subsequently induce a chain of reactions, including alteration of receptor structures, phosphorylation, recruitment of associated proteins, protein trafficking and gene expression. Multiple GPCR signaling transduction pathways are evident - two well-studied pathways are the GPCR-mediated G-protein and β-arrestin pathways. Recently, ligand-induced interactions between GPCRs and 14-3-3 proteins have been demonstrated. This linking of GPCRs to 14-3-3 protein signal hubs opens up a whole new realm of signal transduction possibilities. 14-3-3 proteins play a key part in GPCR trafficking and signal transduction. GPCR-mediated 14-3-3 protein signaling can be harnessed for the study of GPCR function and therapeutics.

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Conflict of interest statement

Conflicts of interest

H.E. is an inventor of the patented LinkLight™ technology. S.K. declares no competing interests.

Figures

Figure 1.
Figure 1.
The world of 14-3-3 protein interaction complexes. A large number of very diverse proteins is known to interact with 14-3-3 proteins. These proteins are located from the membrane to the nucleus. 14-3-3 protein binding changes target protein conformation, facilitating or disrupting binding with other proteins, activating or inhibiting target protein activity and transporting or distributing the target proteins to different subcellular compartments. Almost all cellular processes such as cell proliferation, differentiation, mobility, apoptosis, neurogenesis, synaptogenesis, neuroplasticity, among others, are regulated by these 14-3-3 protein interaction signaling complexes. Thus, malfunction of 14-3-3-signaling pathways can change cell physiology and result in disease.
Figure 2.
Figure 2.
Participation of 14-3-3 proteins in G-protein-coupled receptor (GPCR) signaling and trafficking. 14-3-3 proteins participate in GPCR signaling and trafficking by interacting with many different proteins and in multiple locations. At the membrane, 14-3-3 proteins can bind to regulators of G-protein signaling (RGS) proteins to regulate G-protein signaling; and 14-3-3 protein binding to GPCRs can regulate trafficking. In the cytoplasm, 14-3-3 proteins can bind to kinases, phosphatases and other enzymes in response to GPCR activation to transduce signals. In Golgi and ER, 14-3-3 binding to GPCRs can facilitate cell-surface trafficking. In addition, 14-3-3 protein binding to transcription factors can facilitate their transport into and out of the nucleus.
Figure 3.
Figure 3.
Opioid receptor signaling pathway diversity and its impact on cellular processes and cell physiology. At least three different signaling pathways (G-protein, β-arrestin and 14-3-3) are involved in opioid receptor activation. Activation of the G-protein-signaling pathway mediates ion channel activity and inhibits adenylyl cyclase (AC) activity, resulting in the acute analgesic effect of opioids. β-arrestin promotes receptor endocytosis and disrupts G-protein signaling and its signaling was initially suggested to associate with side effects of opioid tolerance. However, emerging evidence indicates that the G-protein pathway, not the β-arrestin pathway, contributes to the development of opioid side effects and enhances respiratory depression. G-protein-coupled receptor (GPCR) β-arrestin-2 engagement reduces, rather than exacerbates, the development of analgesic tolerance. Opioid-induced antinociceptive tolerance can develop in the absence of β-arrestin-2 activation. The involvement of β-arrestin signaling in the development of constipation and respiratory depression is in question. 14-3-3 proteins participate in GPCR trafficking. Modulating opioid receptor trafficking can reduce the development of addiction-like behavior. Receptor endocytosis and recycling decrease opioid tolerance and dependence. 14-3-3 proteins interact with ion channels and some RGS proteins to regulate G-protein signaling activity. Activation of GPCRs mediates interactions of 14-3-3 proteins with various kinases, regulates kinase activity and influences diverse biological effects. 14-3-3 proteins have important roles in synaptic plasticity.
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