Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 133

Fig. 7.1 Predicted membrane topology of KISS1R. The typical G protein-coupled receptor topog-
raphy predicted for KISS1R is depicted with its seven transmembrane domains as well as the three
intracellular and three extracellular loops. The location of key genetic mutations identifi ed in
humans with reproductive disorders is shown

and the carboxyl-terminus is cytosolic (Fig. 7.1 ). In addition to the amino- and the
carboxyl-terminus, all GPCRs have three extracellular loops and three intracellu-
lar (or cytosolic) loops. The predicted seven-transmembrane structure for KISS1R
is represented in Fig. 7.1 . All GPCRs couple to G proteins, which in the case of
KISS1R is primarily G q/11 . Further analysis of KISS1R revealed the presence of
consensus sequences encoding residues typical of the Rhodopsin superfamily of
GPCRs and a signifi cant degree of identity with the galanin receptor-2. However,
no binding to KISS1R was detected for galanin receptor ligands [ 42 ]. Kisspeptin
(then named metastin) was identifi ed as the endogenous ligand for KISS1R in
2001 [ 44 , 45 ].
G proteins are composed of three subunits, , which form a trimeric

structure that binds to cytosolic domains of GPCRs. The trimeric structure is inac-
tive, as the inactive, GDP-bound G α subunit has high affi nity for the tightly bound
βγ

α , β , and γ

dimer. Activation of the cognate GPCR results in the release of GDP bound to
the G α -subunit, which then binds GTP. The GTP-bound G α subunit dissociates from
the G protein trimer, which thus dissociates from the cognate receptor to activate
downstream signaling cascades. Dissociated G protein subunits are active only
briefl y, as intrinsic GTPase activity within the G α subunit breaks down the GTP to