Role of Chaperones in G Protein Coupled Receptor Signaling Complex Assembly - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 23

Keywords Assembly ￿ Molecular chaperone ￿ Oligomerization ￿ Signaling complex
￿ Traf fi cking

2.1 Introduction

G-Protein Coupled Receptors (GPCRs) are members of a large family of over 800
gene products characterized by a signature structure comprising seven a helical
domains spanning the cellular membranes, with an extracellular N- terminal domain
and an intracellular C- terminal domain. GPCRs can bind and be activated by a wide
range of ligands including, but not limited to, light, odorants, hormones, neurotrans-
mitters, chemokines, amino acids and Ca 2+ ions. GPCRs then mediate their effects
through the activation of a variety of heterotrimeric guanine nucleotide-binding
proteins (G proteins), which generally leads to the activation of several downstream
effectors such as adenylyl cyclases, various kinases and phospholipases. While
classical views suggest that G protein activation acts as the backbone for GPCR
signaling, further advances in the field of GPCRs have demonstrated a broadened
complexity of their activation and regulation. For example, the recognition of recep-
tor oligomerization, the discovery of regulators of G protein signaling and the
identification of multiple interaction partners such as scaffolds, adaptors and
chaperones are likely to contribute to the specificity of signaling by GPCR signaling
complexes. Also, the capacity of some GPCRs to signal via pathways independent
from the G protein has led to an alternative name for this family: the heptahelical
receptors or Seven Transmembrane Receptors (7TMRs). This classification increases
the range of physiological actions that this family of receptors trigger and/or regulate
(Woehler and Ponimaskin 2009 ) .
Given the number of GPCR effectors, regulators, adaptors and scaffolds that can
interact with a single GPCR to mediate various physiological processes, it is likely
that tight regulation of signaling complex assembly is necessary. Molecular chaper-
ones represent potential regulators of GPCR folding, maturation and assembly into
oligomers along with their signaling complex partners. This chapter will focus on the
functions of molecular chaperones in the regulation of GPCR assembly into oligo-
meric signaling complexes, particularly investigating the potential role of molecular
chaperones in the specific assembly of receptors into homo and heterodimers.

2.2 GPCR Dimerization

While other chapters of this topic cover GPCR oligomerization in more detail, some
basic critical points for understanding of the role of molecular chaperones in oligomer
maturation are provided here. GPCRs were initially believed to function as monomers;
however, this concept has evolved into one where the receptors cannot be considered
solely as single functional units, but rather as part of a multimolecular complex,
localized at the plasma membrane (Agnati et al. 2003, 2005 ; Franco et al. 2003 ) .