Many faces of the GPCR-arrestin interaction
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Online ISSN 1976-3786 Print ISSN 0253-6269
REVIEW
Many faces of the GPCR‑arrestin interaction Kiae Kim1 · Ka Young Chung1
Received: 17 July 2020 / Accepted: 11 August 2020 © The Pharmaceutical Society of Korea 2020
Abstract G protein-coupled receptors (GPCRs) belong to a major receptor family and regulate important physiological and pathological functions. Upon agonist activation, GPCRs couple to G proteins and induce the activation of G protein-dependent signaling pathways. The agonist-activated GPCRs are also phosphorylated by G protein-coupled receptor kinases (GRKs), which promote their interaction with arrestins. Arrestin binding induces desensitization (i.e., inability to couple to G proteins) and/or internalization of GPCRs. Arrestins not only desensitize and/or internalize GPCRs but also mediate other downstream signals such as mitogen-activated protein kinases. G protein-mediated signaling and arrestin-mediated signaling often result in different functional outcomes, and therefore, it has been suggested that signaling-selective regulation of GPCRs could lead to the development of more effective treatments with fewer side effects. Thus, studies have attempted to develop functionally biased (i.e., signaling-selective) GPCR-targeting drugs. To this end, it is important to elucidate the structural mechanism underlying functionally biased GPCR signaling, which includes understanding the structural mechanism underlying the GPCR-arrestin interaction. This review aims discuss the structural aspects of the GPCR-arrestin interaction, focusing on the differences between reported GPCR-arrestin complex structures. Keywords Arrestin · Structure · GPCR
* Ka Young Chung [email protected] 1
School of Pharmacy, Sungkyunkwan University, 2066 Seoburo, Jangan‑gu, Suwon 16419, Republic of Korea
Introduction G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors that mediate various physiological functions such as vision, smell, taste, cardiovascular regulation, neurological regulation, and immune responses (Sriram and Insel 2018). Owing to their roles in normal physiology and pathology, approximately one-third of the drugs currently prescribed target GPCRs (Sriram and Insel 2018). Extracellular signals, such as light, hormones, and neurotransmitters, bind to the extracellular part of the receptor, which induces conformational changes in the receptor, therefore enabling its interaction with downstream intracellular signaling molecules (Fig. 1). The most well-characterized downstream signaling molecule for GPCRs is the heterotrimeric G protein (hereafter referred to as the G protein) (Milligan and Kostenis 2006). Agonist-activated GPCRs interact with G proteins, and this interaction induces the release of guanidine diphosphate (GDP) (Fig. 1). The empty nucleotide-binding pocket of the G protein is then rapidly occupied by guanidine triphosphate (GTP), which results in the dissociation of the Gα subunit from the receptor and Gβγ subunits (Fig. 1). The dissociated Gα and βγ subunits
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