Outside-in signaling--a brief review of GPCR signaling with a focus on the Drosophila GPCR family

Abstract

G-protein-coupled receptors (GPCRs) are the largest family of receptors in many organisms, including worms, mice and humans. GPCRs are seven-transmembrane pass proteins that are activated by binding a stimulus (or ligand) in the extracellular space and then transduce that information to the inside of the cell through conformational changes. The conformational changes activate heterotrimeric G-proteins, which execute the downstream signaling pathways through the recruitment and activation of cellular enzymes. The highly specific ligand-GPCR interaction prompts an efficient cellular response, which is vital for the health of the cell and organism. In this Commentary, we review general features of GPCR signaling and then focus on the Drosophila GPCRs, which are not as well-characterized as their worm and mammalian counterparts. We discuss findings that the Drosophila odorant and gustatory receptors are not bona fide GPCRs as is the case for their mammalian counterparts. We also present here a phylogenetic analysis of the bona fide Drosophila GPCRs that suggest potential roles for several family members. Finally, we discuss recently discovered roles of GPCRs in Drosophila embryogenesis, a field we expect will uncover many previously unappreciated functions for GPCRs.

Keywords: AGS; G-proteins; GASP; GPCR; GPSM; GRK; RGS; Signaling; β-arrestin.

Fig. 1.

The GPCR cycle. The GPCR cycle starts on the top left of the figure. In its basal state, a GPCR is free of ligand (L). Gα binds to GDP and associates with Gβγ. The heterotrimeric protein complex might associate with the receptor at this point, or remain free in the membrane as pictured. Upon ligand binding the GPCR becomes activated and undergoes a conformational change. The activated GPCR acts as a GEF for Gα. The resulting GTP-bound Gα separates from βγ, and the heterotrimeric proteins are active (*). Activated Gα can then interact with an effector (E), such as PLC or adenylate cyclase, which results in effector activation (*) and initiation of a second-messenger cascade. The GTP in Gα is then hydrolyzed to GDP through the activity of Gα and RGS proteins (not shown), leading to Gα inactivation and reassociation of the heterotrimeric protein complex. Independently, GRKs bind to and phosphorylate the GPCR. This stimulates its binding by β-arrestin (βArr), which promotes internalization of the receptor. The GPCR can then be recycled back to the cell surface without ligand, restarting the cycle.

Fig. 2.

Rooted phylogenetic tree of classical Drosophila GPCRs. Full-length sequences of GPCRs obtained from Flybase (www.flybase.org) were used to construct the tree. The names correspond with the colored clades. Colors also correspond to those used in supplementary material Table S3.

Fig. 3.

GPCRs in Drosophila development. (A) The GPCR Mist binds to its ligand Fog in the early embryo; this activates the Gα Concertina (Cta) and its downstream effector Rho1 to mediate apical constriction of mesodermal cells during gastrulation. (B) Tre1 has two roles in the developing embryo. In germ cells (teal), Tre1 activates Gβ13f and Gγ1 to relocalize Rho1 and E-cadherin (ECad) to the rear of the migrating cells. In neuroblast stem cells (green), Tre1 interacts with Gα(o), which binds to Pins. Pins interacts with proteins that orient the mitotic spindle in such a way that correct cell fates are established. (C) Moody activates Gα(i), Gα(o), Gβ13f, and Gγ1 to alter the accumulation of actin in the surface glia, and affecting the organization of septate junction proteins. (D) An unknown GPCR is activated in cardial cells, which activates Gα(o), Gβ13f, and Gγ1. These proteins influence the localization of septate junction proteins in cardial cells, which interact in trans with septate junction proteins on pericardial cells, thereby facilitating adhesion between these two types of cells to ensure proper cardiogenesis. PNS, peripheral nervous system; CNS, central nervous system.