GPCR Signalling Complexes – Synthesis, Assembly, Trafficking and Specificity

298 Pages·2012·7.508 MB·English

by  Christian Nanoff, Michael Freissmuth (auth.), Denis J. Dupré, Terence E. Hébert, Ralf Jockers (eds.)

GPCR Signalling Complexes – Synthesis,
Assembly, Traf fi cking and Speci fi city
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Denis J. Dupré (cid:129) Terence E. Hébert (cid:129) Ralf Jockers
Editors
GPCR Signalling
Complexes – Synthesis,
Assembly, Traf fi cking
and Speci fi city
Editors
Denis J. Dupré Terence E. Hébert
Faculty of Medicine, Pharmacology Pharmacology and Therapeutics
Dalhousie University McGill University
Halifax , NS , Canada Montreal , QC , Canada
Ralf Jockers
Institut Cochin
Paris , France
ISSN 0306-0225
ISBN 978-94-007-4764-7 ISBN 978-94-007-4765-4 (eBook)
DOI 10.1007/978-94-007-4765-4
Springer Dordrecht Heidelberg New York London
Library of Congress Control Number: 2012953099
© Springer Science+Business Media Dordrecht 2012
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Contents
1 ER-Bound Steps in the Biosynthesis of G Protein-Coupled
Receptors ................................................................................................. 1
Christian Nanoff and Michael Freissmuth
2 Role of Chaperones in G Protein Coupled Receptor
Signaling Complex Assembly ................................................................. 23
Denis J. Dupré , Maha M. Hammad , Patrick Holland ,
and Jaime Wertman
3 GPCR Oligomerization: Contribution
to Receptor Biogenesis ............................................................................ 43
Kathleen Van Craenenbroeck
4 The Functional Size of GPCRs – Monomers,
Dimers or Tetramers? ............................................................................. 67
Darlaine Pétrin and Terence E. Hébert
5 Regulation of Post-Golgi Traf fi c
of G Protein-Coupled Receptors ............................................................ 83
Guangyu Wu
6 Regulated GPCR Traf fi cking to the Plasma Membrane:
General Issues and the CCR5 Chemokine
Receptor Example ................................................................................... 97
Hamasseh Shirvani , Gabriel Gätà , and Stefano Marullo
7 Regulatory Processes Governing the Cell Surface
Expression of LH and FSH Receptors .................................................. 113
Deborah L. Segaloff
8 Chaperone-Mediated Assembly of G Protein Complexes ................... 131
Barry M. Willardson and Christopher M. Tracy
v
vi Contents
9 Synthesis and Assembly of G Protein b g Dimers:
Comparison of In Vitro and In Vivo Studies ......................................... 155
Jane Dingus and John D. Hildebrandt
10 Preferential Assembly of G-a b g Complexes
Directed by the g Subunits ...................................................................... 181
Janet D. Robishaw
11 G Protein Traf fi cking .............................................................................. 193
Philip B. Wedegaertner
12 Differential Assembly of GPCR Signaling
Complexes Determines Signaling Speci fi city ........................................ 225
Pascal Maurice , Abla Benleulmi-Chaachoua , and Ralf Jockers
13 GPCR and Voltage-Gated Calcium Channels
(VGCC) Signaling Complexes ................................................................ 241
Christophe Altier
14 Pharmacological Chaperones Correct Misfolded GPCRs
and Rescue Function: Protein Traf fi cking
as a Therapeutic Target .......................................................................... 263
Guadalupe Maya-Núñez , Alfredo Ulloa-Aguirre ,
Jo Ann Janovick , and P. Michael Conn
Index ................................................................................................................. 291
Introduction
G protein-coupled receptors (GPCRs) constitute the largest family of cell surface
proteins involved in signal transduction. As such, a large proportion of currently
marketed drugs directly or indirectly target GPCRs. Our current lack of understanding
of the molecular basis of GPCR signalling complex assembly certainly plays into
the wide variety of side effects seen with these drugs. A thorough understanding of
the assembly of these receptors and their partners is needed to characterize and
maximize speci fi city of signal transduction for treating different diseases.
There is now signi fi cant evidence that GPCR signalling complexes (receptor,
G protein and effector) are stably assembled before expression at the plasma
membrane. Where these initial interactions occur remains misunderstood and a role
for the composition of a speci fi c signalling complex in determining its traf fi cking
pathway must be considered. When traf fi cking, dimerization, and addition of
signalling partners are considered, what was once de fi ned as a single receptor can
yield a highly heterogeneous population of signalling complexes leading to different
signalling outcomes even though they share the same receptor. Given the tight
regulation of signalling events in a cell, the maturation of receptors and their assembly
into signalling complexes must also be tightly regulated. It is noteworthy that several
molecular chaperones are involved in either the proper folding of receptors, or in the
assembly of signalling complexes. Therefore, one main question needs to be addressed:
since GPCRs are involved in highly ef fi cient and speci fic activation of signalling path-
ways, how are GPCR signalling complexes assembled to generate such speci fi city?
In order to answer this question, we need to understand how receptors and their
signalling partners are synthesized, folded, assembled and traf fi cked in order to
generate functional and unique signalling complexes. Next, we need to understand
how each partner in a given signalling complex is selected to join a complex, and
what makes this assembly possible. GPCRs are known to be able to function as
dimers or even oligomers, so what drives the assembly of individual receptors into
oligomers, and what will be the effects of such organization on speci fi city and
ef fi cacy of signal transduction? Once the receptor complexes are assembled, they
need to reach different locations in the cell; how is traf fi cking of GPCR signalling
complexes controlled? Finally, defects in synthesis, maturation or traf fi cking can
vii
viii Introduction
alter functionality of GPCRs signalling complexes; how can we manipulate these
systems to make them function normally again? Pharmacological chaperones may
just be part of the answer to this question.
These questions, and several other related issues, are addressed in this book by
experts in their respective fi elds. Each has gathered their thoughts on these different
questions, reviewed available literature and discussed their points of view in this
book.
Denis J. Dupré
Terence E. Hébert
Ralf Jockers
Chapter 1
ER-Bound Steps in the Biosynthesis
of G Protein-Coupled Receptors
Christian Nanoff and Michael Freissmuth
Contents
1.1 Membrane Insertion of the Receptor Polypeptide .......................................................... 2
1.1.1 Membrane Insertion in the Presence
or Absence of a Signal Peptide ............................................................................ 4
1.1.2 Additional Functions of Signal Peptides ............................................................. 5
1.1.3 Glycosylation ....................................................................................................... 6
1.2 Stability of the Receptor Structure ................................................................................. 7
1.3 The Transmembrane Domain ......................................................................................... 8
1.4 The Extracellular Domain ............................................................................................... 10
1.5 Helix Eight of the Cytoplasmic Domain ........................................................................ 11
1.5.1 ER Quality Control .............................................................................................. 12
1.6 ERAD (Endoplasmic Reticulum Associated Degradation) ............................................ 13
1.7 G Protein-Coupled Receptors Interacting with Chaperone Molecules ........................... 15
1.8 A Consideration Regarding the Experimental Assessment
of ER Quality Control in Mammalian Cells ................................................................... 17
References ................................................................................................................................ 18
Abstract The polypeptide of a G protein-coupled receptor is inserted into the
membrane of the endoplasmic reticulum while being translated and this process by
itself may be suf fi cient to establish the proper receptor fold. X-ray structures reveal
a common polypeptide topology with little variation in the alignment and orientation
of the seven transmembrane segments, the proximal carboxyl terminus (C-tail) and
parts of the extracellular loops. These de fi ne a structural core the stability of which
probably represents a major criterion for the receptor to pass endoplasmic reticulum
(ER) quality control; point mutations affecting the structure of the core have an
C. Nanoff (*) (cid:129) M. Freissmuth
Institute of Pharmacology, Centre for Physiology and Pharmacology,
Medizinische Universität Wien, Vienna , Austria
e-mail: [email protected] ; [email protected]
D.J. Dupré et al. (eds.), GPCR Signalling Complexes – Synthesis, Assembly, Traffi cking 1
and Specifi city, Subcellular Biochemistry 63, DOI 10.1007/978-94-007-4765-4_1,
© Springer Science+Business Media Dordrecht 2012