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Review
. 2012:63:193-223.
doi: 10.1007/978-94-007-4765-4_11.

G protein trafficking

Philip B Wedegaertner  1
Affiliations
Review

G protein trafficking

Philip B Wedegaertner. Subcell Biochem. 2012.

Abstract

The classical view of heterotrimeric G protein signaling places G -proteins at the cytoplasmic surface of the cell's plasma membrane where they are activated by an appropriate G protein-coupled receptor. Once activated, the GTP-bound Gα and the free Gβγ are able to regulate plasma membrane-localized effectors, such as adenylyl cyclase, phospholipase C-β, RhoGEFs and ion channels. Hydrolysis of GTP by the Gα subunit returns the G protein to the inactive Gαβγ heterotrimer. Although all of these events in the G protein cycle can be restricted to the cytoplasmic surface of the plasma membrane, G protein localization is dynamic. Thus, it has become increasingly clear that G proteins are able to move to diverse subcellular locations where they perform non-canonical signaling functions. This chapter will highlight our current understanding of trafficking pathways that target newly synthesized G proteins to the plasma membrane, activation-induced and reversible translocation of G proteins from the plasma membrane to intracellular locations, and constitutive trafficking of G proteins.

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Figures

Fig. 11.1
Fig. 11.1. Classical view of G protein signaling
In this view, heterotrimeric G proteins are restricted to the cytoplasmic surface of the PM. However, as discussed in this chapter, G proteins are found at a variety of subcellular locations and they can reversibly move between the PM and intracellular locations
Fig. 11.2
Fig. 11.2. Model of heterotrimeric G protein trafficking to the PM after synthesis
Discussed in detail in the text, the following key steps are known to be involved in trafficking newly synthesized G proteins to the PM. Chaperone proteins have been identified for each G protein subunit, and these chaperones are required for proper folding and/or initial delivery of the subunit to a membrane. After formation of the Gβγ in the cytoplasm, the C-terminal tail (CaaX motif) of Gγ is modified with a farnesyl or geranylgeranyl group, and then Gβγ is targeted to the ER. At the ER, C-terminal proteolysis and carboxymethylation of Gγ occurs. Gα initially binds to Gβγ at either the ER or Golgi and undergoes palmitoylation. The fully lipid modified G protein heterotrimer then trafficks to the PM via the Golgi-dependent secretory pathway or through an uncharacterized Golgi-independent process
Fig. 11.3
Fig. 11.3. Model of activation-induced G protein trafficking
Upon GPCR-mediated activation of an appropriate heterotrimeric G protein at the cytoplasmic surface of the PM, different, but not necessarily mutually exclusive, pathways of reversible translocation have been described. One series of studies has shown that after GPCR activation select Gβγ can undergo rapid (within seconds) movement from the PM to the Golgi. Then, Gβγ can return from the Golgi to the PM with similar rapidity. This cycle of Gβγ movement has been described as diffusion-mediated. Interestingly, the rapid activation-induced Gβγ PM-Golgi cycle depends upon palmitoylation, and likely by extension depalmitoylation. However, Gβγ appears to undergo this cycle while Gα remains on the PM; thus, Gα at the Golgi during activation-induced rapid translocation is indicated by the question mark. In another pathway, GPCR-mediated activation promotes depalmitoylation of Gα allowing Gα to translocate off of the PM. This pathway is slower (minutes) than the PM-Golgi pathway. Gβγ has also been observed to show such slower movement off of PM along with Gα. Gα may simply be released into the cytoplasm by virtue of its depalmitoylation, or it may follow a vesicle-mediated pathway involving recycling endosomes together with Gβγ. In this slower pathway, Gα and Gβγ would return to the PM even slower (0.5–1 h). The figure also indicates that Gα and Gβγ traffic independently of GPCR internalization. The models in this figure focus on translocation of G proteins in non-visual systems. See the text and accompanying references for more details regarding light-activated translocation of visual G proteins
Fig. 11.4
Fig. 11.4. Model of constitutive trafficking of G proteins
Two pathways of constitutive, i.e., in the absence of GPCR-mediated activation, trafficking of heterotrimeric G proteins have been described. In one pathway, the G protein heterotrimer is constantly moving between the PM and Golgi. This pathway utilizes the palmitoylation cycle, as described for other palmitoylated peripheral membrane proteins, such as H-Ras. In this pathway, Gα in the context of the inactive heterotrimer undergoes continual depalmitoylation at the PM. Next, the depalmitoylated heterotrimer will move by diffusion to the Golgi where palmitoyl acyltransferases can be located. After re-palmitoylation of Gα, the heterotrimer returns by diffusion to the PM. In another described constitutive pathway, inactive Gα internalizes along with a non-activated GPCR. It is likely that Gβγ also follows this pathway, since it would be expected to be bound to inactive Gα. Thus, a G protein heterotrimer would traffic together with a constitutively internalizing GPCR. It is not known whether cycles of Gα depalmitoylation and palmitoylation would regulate this slower GPCR constitutive internalization-dependent pathway. See the text for details of these pathways of constitutive G protein movement
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