Regulatory Processes Governing the Cell Surface Expression of LH and FSH Receptors - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 109

propensity for homodimerization is not affected by the activation status of the receptor.
However, within a receptor dimer, the activity of one protomer may allosterically
regulate the other protomer. Therefore, the dimerization of the gonadotropin receptors
appears to be an obligate process that is part of the normal itinerary for trafficking
to the cell surface and, once there, the dimerized receptors allow for additional
modulations of cell signaling.

Keywords Gonadotropin receptors ￿ Dimerization ￿ Molecular chaperone

￿ Pharmacological chaperone ￿ Signaling ￿ Traf fi cking

7.1 Introduction

The lutropin receptor (LHR) and follitropin receptor (FSHR) are structurally
related Family A GPCRs. Because their primary sites of expression are in the
gonads, they are referred to collectively as the gonadotropin receptors. In recent
years t,he LHR and FSHR have each been shown to also exhibit expression in other
reproductive and non-reproductive tissues, and the physiological roles of the receptors
in non-gonadal tissues is an area of active investigation (Blair and Zaidi 2006 ; Sun
et al. 2006 ; Radu et al. 2010 ; Berndt et al. 2006 ; Cameo et al. 2006 ; Apaja et al.
2004 ; Dos Santos et al. 2007 ; Banerjee and Fazleabas 2011 ; Zygmunt et al. 2002 ;
Reisinger et al. 2007 ). In the ovaries and testes, the LHR and FSHR are pivotal players
in reproductive physiology and are integral to normal fertility in both males and
females.
Cloning of the cDNAs for the receptors many years ago first revealed that the
receptors were each composed of a large extracellular domain containing multiple
leucine-rich repeats, which is attached to the prototypical GPCR serpentine domain
containing seven transmembrane helices (McFarland et al. 1989 ; Sprengel et al. 1990 ) .
The LHR and FSHR are most closely related to the thyrotropin receptor (TSHR) and
these three receptors, collectively termed the glycoprotein hormone receptors, are
now known to be also related to other leucine-rich repeat containing GPCRs (Hsu
et al. 2000 ). Earlier studies had determined that the extracellular domains of the LHR
and FSHR are responsible for high affinity binding of hormone (Xie et al. 1990 ;
Thomas et al. 1996 ; Davis et al. 1995 ; Braun et al. 1991 ). More recently, studies by
Fan and Hendrickson revealed the crystal structure of the hormone-binding region of
the extracellular domain of the human (h) FSHR complexed with FSH (Fan and
Hendrickson 2005, 2007 ), illuminating the precise intermolecular interactions between
the receptor's leucine-rich repeats and the hormone.
In response to the binding of hormone to the extracellular domain, the serpentine
domain is stabilized in an active conformation. However, the mechanisms by which
communication occurs between the hormone-extracellular domain complex and the
serpentine domain are not yet well understood. The gonadotropin receptors can also
be stabilized in active conformations by particular mutations that cause constitutive
activation of the receptor (Simoni et al. 1997 ; Latronico and Segaloff 1999 ; Ascoli