Fine-tuning of GPCR activity by receptor-interacting proteins

Abstract

G protein-coupled receptors (GPCRs) mediate physiological responses to various ligands, such as hormones, neurotransmitters and sensory stimuli. The signalling and trafficking properties of GPCRs are often highly malleable depending on the cellular context. Such fine-tuning of GPCR function can be attributed in many cases to receptor-interacting proteins that are differentially expressed in distinct cell types. In some cases these GPCR-interacting partners directly mediate receptor signalling, whereas in other cases they act mainly as scaffolds to modulate G protein-mediated signalling. Furthermore, GPCR-interacting proteins can have a big impact on the regulation of GPCR trafficking, localization and/or pharmacological properties.

Figure 1

GPCR signaling can be mediated by receptor-interacting proteins. A) Certain GPCR-interacting proteins can act as mediators of agonist-induced receptor signaling, independent of G protein- or arrestin-mediated signaling pathways. An example of this phenomenon is the interaction of the non-receptor tyrosine kinase Jak2 with the angiotensin AT1 receptor. Association of Jak2 with the phosphatase SHP-2 and stimulation of AT1 with angiotensin II together promote Jak2 association with the AT1 receptor and initiation of Jak2-dependent signaling. Activated Jak2 can phosphorylate members of the STAT family of transcription factors, leading to STAT dimerization, translocation into the nucleus, and regulation of genes controlling cell growth. B) In other cases, the agonist-dependent dissociation of an interacting protein from a GPCR can alter the activity of an intracellular signaling pathway. For example, the interaction between the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) and the somatostatin type II receptor (SSTR2) is disrupted by agonist stimulation, leading to reduced PI3K-mediated Akt signaling and suppression of cell survival pathways.

Figure 2

GPCR-interacting proteins can modulate G protein-mediated signaling. In the example shown in panel A, interaction between the NHERF scaffold proteins and the parathyroid hormone receptor (PTH1R) leads to a preferential enhancement of the downstream Gαq-mediated signaling by PTH1R. Through its various protein-protein interaction domains, NHERF not only binds to PTH1R, but also tethers multiple downstream signaling effectors in close proximity to the PTH1R, thereby creating an efficient complex for Gαq-mediated signaling. However, when PTH1R is in a different cell type or separate cellular compartment in which NHERF proteins are absent, PTH1R instead preferentially signals through Gαs to activate adenylyl cyclase. A contrasting example is shown in panel B. Periplakin can associate with the μ opioid receptor (μOPR) to attenuate G protein-mediated signaling. However, in cell types or cellular compartments where periplakin is not found, μOPR ligands can more robustly activate the receptor to stimulate signaling by G proteins.

Figure 3

GPCR-interacting proteins can regulate the post-endocytic trafficking of GPCRs. Following agonist-induced receptor endocytosis, some GPCRs are targeted for proteolytic and/or lysosomal degradation, while other GPCRs rapidly recycle back to the plasma membrane. As shown in panel A, the interaction between the GPCR-interacting protein GASP1 and the δ-opioid receptor (δOPR) promotes the endocytic targeting of agonist-internalized δ-opioid receptors to lysosomes, where the receptors are degraded. In contrast, as shown in panel B, the interaction between the GPCR-interacting protein NHERF-1 and the β2-adrenergic receptor (β2-AR) promotes the rapid recycling of receptors following agonist-promoted internalization.

Figure 3

GPCR-interacting proteins can regulate the post-endocytic trafficking of GPCRs. Following agonist-induced receptor endocytosis, some GPCRs are targeted for proteolytic and/or lysosomal degradation, while other GPCRs rapidly recycle back to the plasma membrane. As shown in panel A, the interaction between the GPCR-interacting protein GASP1 and the δ-opioid receptor (δOPR) promotes the endocytic targeting of agonist-internalized δ-opioid receptors to lysosomes, where the receptors are degraded. In contrast, as shown in panel B, the interaction between the GPCR-interacting protein NHERF-1 and the β2-adrenergic receptor (β2-AR) promotes the rapid recycling of receptors following agonist-promoted internalization.