G Protein Trafficking - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 186

Keywords Assembly ￿ G protein ￿ Isoprenylation ￿ Miristoylation ￿ Palmitoylation ￿
Traf fi cking

11.1 Introduction

A major role of heterotrimeric G proteins is to couple activated G protein-coupled
receptors at the cell surface to appropriate intracellular signaling pathways
(Preininger and Hamm 2004 ; Dorsam and Gutkind 2007 ). As the name implies,
heterotrimeric G proteins are composed of three subunits, Ga , G b and Gg , encoded
by 16, 5 and 12 genes, respectively, in mammals. Based on sequence identity and
functional similarity, Ga are typically grouped into four sub-families, termed Ga s ,
Ga i , G a q and Ga 12/13 . G b and Gg form an irreversible Gb g dimer, with the exception
of the Gb 5 subunit (Sondek and Siderovski 2001 ) , and functional differences
between different Gb g combinations are not well-defined.
G proteins function as molecular switches by cycling between guanine-nucleotide
bound states. The G protein cycle is characterized by Ga binding to either GDP or
GTP and by dissociation and association of Ga and Gb g. In the inactive state, the G
protein exists as a heterotrimer in which Ga binds GDP. When a cell-surface GPCR
is activated by binding an extracellular agonist, it interacts with its cognate het-
erotrimeric G protein at the cytoplasmic surface of the plasma membrane and cata-
lyzes the release of GDP from Ga. Next, GTP replaces GDP by binding to Ga . GTP
binding to Ga induces a conformational change that decreases its affinity for Gb g
and increases its affinity for effector proteins. Consequently, Ga and Gb g dissociate,
at least partially (Lambert 2008 ), and both GTP-bound Ga and free Gb g are able to
interact with and regulate numerous effector proteins, such as ion channels, adeny-
lyl cyclases and phospholipases, to name a few classical examples. The intrinsic
GTP hydrolysis activity of Ga, which is often greatly accelerated through binding
to RGS (regulator of G protein signaling) proteins, returns Ga to the GDP-bound
state and allows it to interact again with Gb g, thereby re-forming an inactive
heterotrimer.
The classical view of heterotrimeric G protein signaling focuses on G proteins
being associated with the cytoplasmic surface of the plasma membrane (Fig. 11.1 ).
In this view, G proteins remain tethered to the PM while traversing through the G
protein cycle and carrying out their cellular signaling functions. However, it has
become clear that G proteins are not always localized at the cytoplasmic surface of
the PM. Instead, G proteins dynamically localize to diverse subcellular locations and
transit specific trafficking pathways. Thus, superimposed upon the classical view of
G protein function, we must consider how trafficking of G proteins provides novel
mechanisms for regulating G protein signaling. This chapter will discuss our current
knowledge of G protein trafficking to the PM after synthesis, activation-dependent
and constitutive internalization and recycling of G proteins, and how trafficking to
unique subcellular locations provides novel G protein signaling functions.