G-protein-coupled receptor dimers

502 Pages·2017·12.963 MB·English

by  Di Giovanni, Giuseppe, Herrick-Davis, Katharine, Milligan, Graeme

The Receptors
Katharine Herrick-Davis
Graeme Milligan
Giuseppe Di Giovanni Editors
G-Protein-
Coupled
Receptor
Dimers
The Receptors
Volume 33
Series Editor
Giuseppe Di Giovanni
Department of Physiology & Biochemistry
Faculty of Medicine and Surgery
University of Malta
Msida, Malta
The Receptors book Series, founded in the 1980’s, is a broad-based and wellrespected
series on all aspects of receptor neurophysiology. The series presents published
volumes that comprehensively review neural receptors for a specific hormone or
neurotransmitter by invited leading specialists. Particular attention is paid to
in-depth studies of receptors’ role in health and neuropathological processes. Recent
volumes in the series cover chemical, physical, modeling, biological,
pharmacological, anatomical aspects and drug discovery regarding different
receptors. All books in this series have, with a rigorous editing, a strong reference
value and provide essential up-to-date resources for neuroscience researchers,
lecturers, students and pharmaceutical research.
More information about this series at http://www.springer.com/series/7668
Katharine Herrick-Davis • Graeme Milligan
Giuseppe Di Giovanni
Editors
G-Protein-Coupled Receptor
Dimers
Editors
Katharine Herrick-Davis Graeme Milligan
Department of Neuroscience and Centre for Translational Pharmacology
Experimental Therapeutics Institute of Molecular Cell and Systems
Albany Medical College Biology
Albany, NY, USA College of Medical, Veterinary and Life
Sciences
Giuseppe Di Giovanni University of Glasgow
Department of Physiology and Glasgow, Scotland, UK
Biochemistry
University of Malta
Msida, Malta
The Receptors
ISBN 978-3-319-60172-4 ISBN 978-3-319-60174-8 (eBook)
DOI 10.1007/978-3-319-60174-8
Library of Congress Control Number: 2017947899
© Springer International Publishing AG 2017
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This book is dedicated to all the researchers
in the GPCR field for their tireless efforts
and to future generations who will continue
the quest to solve the mysteries of this
important class of cell membrane signaling
proteins.
Foreword
On the Question of GPCR Oligomerization
Although evidence for the existence and role of G protein-coupled receptor (GPCR)
oligomerization goes back as far as the 1970s [1], even before the genes or proteins
forming their receptors were explicitly identified, the quaternary organization of
GPCRs and the role of homo- or hetero-oligomerization in their functions remain a
subject of intense debates [2–7] and vibrant research. The present book is a clear
illustration of the quantity and quality of ongoing research programs aiming at
probing the structural organization and physiological roles of GPCR oligomeric
assemblies.
The current interest in the notion that GPCRs form dimers and higher oligomeric
structures started in the late 1990s and early 2000s when biochemical, biophysical,
and functional data using well-defined engineered systems supported the existence
of family A receptor dimers [8, 9]. Soon after, the demonstration that the GABAb
receptor, a prototypical member of family C GPCRs, existed as an obligatory het-
erodimer [10] brought additional support to the notion that GPCRs may form oligo-
mers. These reports initiated a flurry of studies using a wide diversity of techniques
assessing various aspects of the oligomerization going from the dynamics of assem-
bly to the role of homo- and heterodimers in binding and signaling selectivity [11].
Despite this intense activity, healthy skepticism surrounding the notion of GPCR
oligomerization has certainly been a trademark of the field. The resistance to accept
family A GPCRs, which in contrast to family C do not require dimerization for
function in purified systems [12, 13], can be explained by the fact that many of the
data used to propose oligomerization stem from proximity-based assays such as
bioluminescence and fluorescence resonance energy transfer [14–18], protein com-
plementation [19–21], and imaging [22–25] that support the existence of oligomers
but do not prove direct protein-protein interactions. Even co-immunoprecipitation
and crystallographic evidence of dimers can be questioned as possible artifacts. At
the functional level, distinguishing between the direct impacts of heterodimeriza-
tion and downstream cross-talk regulation on binding and signaling properties of
proposed heterodimers often remains a challenge.
vii
viii Foreword
Despite these legitimate limitations in the interpretation of some aspects of
oligomerization studies, the abundance of evidence from multiple sources that are
based on many complementary approaches overwhelmingly supports the notion
that members of all GPCR subfamilies can form oligomers that have functional
roles. Given that GPCRs function as complex allosteric machines, it should not
come as a surprise that oligomerization among receptors and their signaling part-
ners represents an intrinsic part of their structural mode of action.
Yet many questions remain partially or completely unanswered, in particular
when considering family A and B receptors. Among these, whether ligands can
change the oligomeric state of GPCRs or merely promote conformational rear-
rangements of preexisting oligomers is still the object of active investigations. Early
evidence supported the notion that homodimerization occurred constitutively in the
endoplasmic reticulum and is required for proper targeting of receptors to the
plasma membrane [26–27]. This idea was reinforced by the observation that het-
erodimerization of GABABR1 and GABABR2 was required for the transport of an
active receptor at the surface of the cells [28]. More recent evidence supports the
notion that receptor assembly may be actively regulated by ligands once they have
reached the cell surface [22, 29]. More studies are clearly needed to clarify the role
of oligomerization in receptor trafficking and of the ligand-promoted regulation of
assembly dynamics in receptor function. A better understanding of the interfaces
involved in the oligomers’ architecture will certainly provide tools to directly assess
the regulation and the role of oligomerizaton in the various aspects of the receptor
life cycle. Despite some advances in identifying interfaces and/or specific residues
involved in the dimerization of specific receptors [30–33], no general rules have
emerged yet. This will be essential to understand the processes underlying the speci-
ficity of interactions among GPCRs. This question is intimately linked with that of
the stoichiometry of oligomerization. Although dimerization is often evoked as the
simplest arrangement explaining the data, increasing evidence indicates that higher-
order oligomers could be formed. In particular, the formation of tetramer has been
proposed for members of class C GPCRs [34].
One aspect of GPCR oligomerization that has attracted considerable attention is
the possibility that heterodimerization may lead to the formation of receptors with
binding and signaling properties that are unique and different from each of the
receptor protomers composing the complex [35]. This intriguing possibility takes a
particular twist when considering the phenomenon of ligand-biased signaling and
functional selectivity by which different ligands can direct the signaling of a given
receptor toward different subsets of signaling pathways [36, 37]. The role of het-
erodimerization in this phenomenon remains completely uncharted territory.
Ultimately, the most important question will be to determine the significance of
oligomerization in normal and pathological biology in vivo. Several studies have
started to address this question [38, 39], and tools are being developed to determine
whether or not the existence of family A or B homo- and heterodimers is required
for specific biological function and could represent targets for the development of
drugs with unique actions [40, 41]. Clearly, many questions remain open in the field
of GPCR oligomerization, and considerable efforts are still needed to fully under-
stand their structural organization and roles in biology. The present book offers a
Foreword ix
number of interesting paths that have been followed to give us the level of under-
standing that we now have and, more importantly, that need to be pursued to provide
an even clearer picture.
Department of Biochemistry and Molecular Medicine, Michel Bouvier
Institute for Research in Immunology and Cancer,
Université de Montréal, Montreal, QC, Canada
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