Abstract
Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney. Accessory proteins are being identified as direct binding partners for heterotrimeric G-protein α or βγ subunits to promote more diverse mechanisms by which G-protein signaling is controlled. In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors. Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell. In this review, we will highlight the expression profile, localization and functional importance of these newly identified accessory proteins to control the function of select G-protein subunits under normal and various disease conditions observed in the kidney.
Highlights
The kidney plays a fundamentally important role in controlling a wide array of physiological processes, including fluid and electrolyte balance, hormone production, acid-base balance, and blood pressure regulation (Alpern et al, 2013). In many of these biological functions, heterotrimeric G-proteins play a crucial role through the stimulation of cell surface G-protein coupled receptors (GPCRs) to activate diverse signaling networks depending upon their association with distinct G-protein subunits (Wettschureck and Offermanns, 2005; Insel et al, 2007)
This study provides evidence that Regulator of G-protein Signaling 2 (RGS2) attenuated the onset of renal fibrosis in part by accelerating the deactivation of the angiotensin type 1 receptor (AT1R)-mediated signaling of the pro-fibrogenic and inflammatory systems (Jang et al, 2014)
The kidney has a well-documented history of canonical GPCR-dependent signaling in the renal vascular, glomerular and tubular system, the role of accessory proteins on G-protein function has only begun to emerge within the last few years
Summary
The kidney plays a fundamentally important role in controlling a wide array of physiological processes, including fluid and electrolyte balance, hormone production, acid-base balance, and blood pressure regulation (Alpern et al, 2013). GTPase-Activating Proteins (GAP) Upon activation of Gα subunits following its binding with GTP, Gα subunits have an intrinsic rate in which GTP can be hydrolyzed back to GDP (Figure 1A) This leads to the reassociation with its native Gβγ partners, which inactivates the G-protein signaling output back to control levels (Siderovski and Willard, 2005). GRK2/3 isoforms possess weak GAP function to desensitize GPCR signaling by selective interaction with Gαq/11subunits (Carman et al, 1999b); whereas GRK4 was unable to bind to active Gαq or alter Gαq-dependent signaling (Picascia et al, 2004) Another important domain in the Cterminal region of GRK2/3 is the pleckstrin homology (PH) region that can interact directly with Gβγ dimers.
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