Broad-spectrum amino acid-sensing class C G-protein coupled receptors

Pharmacology
& Therapeutics

Volume 127, Issue 3,
September 2010,
Pages 252-260
doi:10.1016/j.pharmthera.2010.04.007 | How to Cite or Link Using DOI
Copyright © 2010 Elsevier Inc. All rights reserved.
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Associate Editor: Peter Molenaar

Broad-spectrum amino acid-sensing
class C G-protein coupled receptors:
Molecular mechanisms, physiological significance and options for drug
development
Arthur D. Conigravea,
,
and David R. Hampsonb

a School of Molecular Bioscience (G08),
University of Sydney, NSW 2006, Australiab
Department of Pharmaceutical Sciences and Department of Pharmacology,
University of Toronto, 144 College St. Toronto, Ontario, Canada M5S 3M2

Available online 6 May 2010.
AbstractIn this article, we consider the
molecular mechanisms that underlie broad-spectrum amino acid sensing by a discrete subgroup
of class C G-protein-coupled receptors
that includes the calcium-sensing receptor,
GPRC6A and heterodimers composed of two closely related receptor
subunits, T1R1 and T1R3. We consider their
physiological significance highlighting their diverse spectrum of
cellular responses and the phenotypes of global and conditional knock-out mice. In addition, we consider
strategies for the development of new drugs that target these receptors.

Keywords: Allosteric modulators; Amino acid-sensing; Calcium-sensing receptor; Dimerisation;
GPRC6A; G-protein coupled receptor;
Molecular modelling; Taste receptors; Transgenic
mouse; Venus FlyTrap
Abbreviations: AMPA,
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid; CaSR, calcium-sensing receptor; CR,
Cysteine-rich; ERK, extracellular regulated kinase; GABA, Gamma-amino-butyric
acid; GABAB, GABA receptor Type B; GPCR, G-protein
coupled receptor; GPRC6A, G-protein
coupled receptor class C member 6A; HH, heptahelical; mGlu, metabotropic
glutamate receptor; NMDA,
N-methyl d-aspartate; T1R, Taste Receptor
Family-1; VFT domain, Venus Fly Trap
domain
Article Outline1. Introduction2.
Domain-based organization of class C G-protein coupled
receptors3. Dimers and higher order
oligomers4. Modes of signaling by class C
GPCRs4.1. Molecular basis of signal
transmission: a physical link between the VFT and CR domains5.
Ligand binding surfaces for class C GPCRs6.
A conserved amino acid binding site in class C GPCRs:
origins of promiscuity in broad-spectrum amino acid sensors7.
mGlu subgroup-selective compounds and design options
for agents that target the VFT domains of broad-spectrum amino
acid-sensing receptors7.1. Development
of agents that target the VFT domains of broad-spectrum amino
acid-sensing receptors8. Physiological
roles of broad-spectrum amino acid-sensing class C GPCRs8.1.
Tissue expression patterns and proposed roles of
broad-spectrum amino acid-sensing receptors8.1.1. CaSR8.1.2. C6A8.1.3.
T1R1/T1R38.2.
Insights from global and tissue-specific transgenic
mice8.2.1. CaSR8.2.2. C6A8.2.3. T1R1/T1R39.
ConclusionsAcknowledgementsReferences
1. IntroductionMammalian
class C G-protein coupled receptors
include metabotropic receptors for the amino
acid neurotransmitter glutamate (the so-called metabotropic glutamate receptors; mGlus); the α-carbon decarboxylated analog
of glutamate, GABA (the GABAB receptors); several
orphans; and a recently defined subgroup of broad-spectrum amino acid-sensing receptors including the
calcium-sensing receptor (CaSR) and GPRC6A (hereafter referred to as
C6A), both of which appear to
operate as homodimers, as well as T1R1/T1R3 taste
receptor heterodimers (Fig. 1). Receptors in this
latter subgroup are promiscuous in their amino
acid-sensing properties, being ‘tuned’ to respond to two or more
classes of amino acids. Collectively, they appear to operate as sensors
of protein nutrition and exhibit potencies for individual amino acids
that are appropriate for providing an integrated receptor response to
complex amino acid mixtures. In this
article we consider the molecular basis of broad-spectrum amino acid sensing by this subgroup of
class C G-protein-coupled receptors
together with their physiological significance along with potential
strategies for the design and development of new therapeutic agents that
target them.Full-size image
(22K)
High-quality image
(60K)Fig. 1. Schematic
representation of phylogenetic relationships between different members
of GPCR Class C. The analyses were
based on a protein sequence alignment that included both the VFT and HH domains but excluded the
receptors' C-termini. The red boxes indicate broad-spectrum amino acid-sensing receptors; the green
boxes indicate narrow-spectrum receptors. The ligand selectivities of
the putative pheromone receptors are currently unknown. The CaSR is most closely related to other
broad-spectrum amino acid-activated
receptors including GPRC6A, the 5.24 receptor and the T1R taste
receptors. The figure has been reproduced (Conigrave & Hampson, 2006). 2.
Domain-based organization of class C G-protein
coupled receptorsIn general, Class C GPCRs have a large extracellular region of around 500–600
amino acids that is organized into two separate sub-domains: a
neurotransmitter or nutrient-binding, N-terminal Venus FlyTrap (VFT) domain of around 450–500 amino acids
and a Cysteine-rich (CR) domain of around 60–70 amino acids (reviews: ([Blasi et al., 2001], [Conigrave & Hampson, 2006]
and [Wellendorph & Bräuner-Osborne,
2009])). Atypically, the CR domain is absent in GABAB receptors (Hu et al., 2000). In keeping with
all known members of the GPCR
superfamily, class C GPCRs exhibit a
heptahelical (HH) domain that is required for the docking and
activation of G-proteins ([Chang et al., 2000] and [Havlickova et al., 2003]) as well
as a large C-terminus (50–200 amino acids) that binds protein partners
to direct the receptors to specific cellular compartments for the
assembly of signaling networks, temporary storage or proteolysis. The four major domains of
class C GPCRs are organized in such a
way that the CR domain acts in series to couple the nutrient-sensing VFT domain to the HH domain-C-terminal
domain signaling unit (Fig. 2). The C-terminus of
the CR domain is connected to the first transmembrane helix of the HH
domain by a short peptide linker. In the CaSR
this peptide corresponds to residues 599–613 (Ray et al., 2007).Full-size image
(38K)
High-quality image
(367K)Fig. 2. Depiction of an mGlu-1 homodimer. The Venus FlyTrap (VFT), Cys-rich (CR) and heptahelical (HH)
domains are shown. The representation of the nutrient-binding VFT domain is based on the crystal
structure of mGlu-1 ([Kunishima et al., 2000] and [Tsuchiya et al., 2002]). The CR
and HH domains are homology models based on the crystal structures of
the extracellular domain of the type I tumor
necrosis factor receptor (Naismith et al., 1996) and bovine rhodopsin
(Palczewski et al., 2000)
respectively. With the exception of the relationships between the VFT domain and CR domains in mGlu-3 (Muto et al., 2007), the relative
orientations of the three domains are unknown. Several potential binding
surfaces are shown including the cavities of the bilobed VFT domains (a and a'), the
interprotomeric interface (b), the niches between the VFT domains and CR domains (c and c'), and
pockets within the HH domains that are recognized binding sites for
allosteric modulators (d and d'). Crystal structure analysis of the VFT domains of mGlu-1 ([Kunishima et al., 2000] and [Tsuchiya et al., 2002]), as well
as mGlu-3 and mGlu-7 (Muto et al., 2007) demonstrate
that the N-terminal VFT domain is
the site of glutamate binding in mGlus ([Kunishima et al., 2000], [Tsuchiya et al., 2002] and [Muto et al., 2007]) and analyses
of mutant and chimeric receptors indicates that it is also the site of l-amino acid binding
in the CaSR ([Zhang et al., 2002], [Mun et al., 2004] and [Mun et al., 2005]) and C6A ([Kuang et al., 2005] and [Wellendorph et al., 2005]).
Sequence alignments also suggest that the l-amino acid binding site is conserved in
the VFT domain(s) of T1R1/T1R3
heterodimers (review: (Conigrave & Hampson, 2006)).
Four primary structural states are recognized, irrespective of whether
the ligand is bound. These include an open–open (inactive) state,
closed–open and open–closed (partially active) states and a
closed–closed (fully active) state. Ligand binding stabilizes the closed
states and ligand binding can occur in both VFT domains simultaneously ([Kunishima et al., 2000] and [Tsuchiya et al., 2002]). The
closed–open/open–closed and closed–closed forms of the mGlus may define distinct G-protein
selectivities (Rondard et al., 2006).3. Dimers and higher order oligomersUnlike
GPCRs of Class A which, based on
recent crystal structure analyses, may be functionally active as
monomers ([Cherezov et al., 2007], [Rasmussen et al., 2007] and [Warne et al., 2008]) or Class B
which function as heterodimers with receptor
activity modifying proteins (RAMPs; review: (Hay et al., 2006)), class C GPCRs appear to be functionally active
only as homodimers (e.g., the CaSR, mGlus) or heterodimers with closely
related GPCR subunits (e.g., the T1R
and GABAB receptors).
The dimers are stabilized by disulfide bonds in the proximal VFT domain and by additional non-covalent
interactions ([Zhang et al., 2001] and [Hampson et al., 2008]). In the CaSR, for example, intermolecular
disulfides act to asymmetrically crosslink residues C129 and C131 (Ray et al., 1999) and non-covalent
interactions involving residues L112 and L156 also participate in dimer
formation (Jiang et al., 2004b). In addition,
the crystal structure of the entire mGlu-3
extracellular domain demonstrates that intramolecular disulfides are
required for normal receptor function. Four intramolecular disulfides
stabilize the CR domain into a rigid structure to permit the application
of rotational forces from the VFT
to the HH domains. An additional intramolecular disulfide appears to
provide a lever between lobe-2 of the VFT
domain (Cys-240) and the Cys-rich domain (Cys-527; (Muto et al., 2007)). A model of
the dimer arrangements between mGlu
subunits is provided in Fig. 2.Analyses of
heterodimers, including the GABAB
and T1R1/T1R3 receptors, demonstrate that one
subunit is specialized for ligand binding in its VFT domain (e.g., T1R1 and GABAB1) whereas the other
subunit (e.g., T1R3 and GABAB2)
is required for expression and intracellular signaling responses ([Jones et al., 1998], [Kaupmann et al., 1998], [White et al., 1998], [Jiang et al., 2004a] and [Zhang et al., 2008]). Whether
subunit specialization might operate in a cyclical manner in class C
homodimers (e.g., involving mGlus, CaSR or C6A)
under certain conditions is currently unclear. In one cyclical scheme,
the VFT domain of subunit A might
mediate nutrient binding to induce signaling via the HH domain of its
protomeric partner subunit A' followed by nutrient binding in subunit A'
and attendant signaling via subunit A. Recent evidence suggesting that
only one active HH domain is required for mGlu-1
signaling (Hlavackova et al., 2005) is
consistent with such a possibility.Recent analyses in HEK293
cells and COS7 cells indicate that
RAMPs 1 and/or 3 are required for CaSR
trafficking to the plasma membrane
in certain cell contexts ([Bouschet et al., 2005] and [Bouschet et al., 2008]) raising
the possibility that the CaSR might
form heterodimers or higher order oligomers with non GPCR chaperones. Whether RAMPs are
required for CaSR trafficking in
endogenous cells or facilitate plasma
membrane targeting in cells in which the CaSR is over-expressed heterologously is
currently uncertain. If RAMPs are indeed required for normal endogenous
expression, it seems possible that they may also be required for the
expression of other members of GPCR
class C.Why are dimers formed from closely related subunits
required for the function of class C receptors and not other GPCR classes? As noted above, class C
receptors are unusual in binding nutrient ligands in their extended
extracellular VFT domains.
Therefore, a mechanism is required to transmit the molecular signal
associated with VFT domain closure
to the transmembrane domains where
intracellular signaling is initiated, requiring the transmission of
turning moments from the raised FlyTraps
to the HH domain signaling units (review: (Pin et al., 2004)). Consistent
with this notion, receptor activation appears to arise from the
approximation of neighbouring lobes 2 in receptor dimers and associated
adjustment of the spatial relationship between adjacent HH domains
(review: (Pin et al., 2009)). In one
scenario the heptahelical partners exchange domains to generate an
active G-protein binding site (Brock et al., 2007).4. Modes of signaling by class C GPCRsSeveral subclasses of metabotropic glutamate receptors are
recognized based on sequence homologies, signaling properties and
pharmacological behaviour (review: (Conn, 2003)). Upon receptor
activation, Group 1 mGlus (mGlu-1 and mGlu-5)
elicit Gq/11 dependent activation of PI-PLC associated with intracellular Ca2+
mobilization. mGlus belonging to
Groups II (mGlu-2 and -3) and III (mGlu-4, -6, -7 and -8), on the other
hand, elicit Gi/G0 dependent inhibition of adenylyl cyclase (Ferraguti & Shigemoto, 2006).
Among the broad-spectrum amino acid-sensing
subgroup of class C GPCRs, the CaSR elicits both Gq/11-dependent
activation of PI-PLC (review: (Hofer & Brown, 2003)) and
intracellular Ca2+ mobilization as well as Gi/0-dependent
inhibition of adenylyl cyclase (Gerbino et al., 2005), thereby
combining properties of both group I and group II/III receptors (Table 1). In addition, both C6A ([Kuang et al., 2005], [Wellendorph et al., 2005] and [Wellendorph et al., 2007]) and
the T1R1/T1R3 heterodimeric receptors (Nelson et al., 2002) activate PI-PLC, although their impacts on adenylyl cyclase activity are less
certain. It is not currently known whether the CaSR recruits G-proteins of both classes
simultaneously to separate G-protein docking sites, switches
repetitively between different classes of G-proteins, or is specialized
for G-protein binding according to
its protein binding partners and
membrane localization.Table 1. G-protein
selectivities of class C GPCRs.
Well-characterized members of GPCR
class C are shown. The mGlus have
been organized according to their three main groups. The broad-spectrum amino acid-sensing receptors (CaSR, C6A
and T1R1/T1R3 heterodimers) are collected
together as a subgroup at the bottom of the table. The CaSR appears to be unusual in its high
degree of promiscuity for different G-proteins.
ReceptorG-protein selectivities
mGlu Group I (1, 5)Gq/11
mGlu Group II (2, 3)Gi/o
mGlu Group III (4, 6, 7, 8)Gi/o
GABABGi/o
CaSRGq/11; Gi/o; G12/13
C6AGq/11
T1R1/T1R3α-gustducin
T1R2/T1R3α-gustducin; α-transducin
4.1.
Molecular basis of signal transmission: a physical link between the VFT and CR domainsThe mechanism
by which ligand binding in the VFT
domain induces the transmission of signals from the VFT domain to the HH domain and, in turn,
controls coupling to one or more G-proteins is critical to an
understanding of the mechanism of receptor activation. Noting the
presence of nine cysteines in the CaSR
CR domains Hu et al. investigated the possibility of a disulfide link
between the CaSR VFT and CR domains by introducing a
selective tobacco etch virus protease cleavage site (NLYFQG) between residue
E536, the last residue encoded by exon-5 at the C-terminus of the VFT domain and V537, the first residue
encoded by exon-6 (Hu et al., 2001). Following proteolytic cleavage, the VFT domains were released as C129–C131
disulfide-linked dimers from the remainder of the dimeric protein,
apparently disproving the hypothesis that a disulfide directly links the
VFT and CR domains (Hu et al., 2001).Surprisingly,
evidence for a disulfide link between the VFT
and CR domains was subsequently identified for rat mGlu-2
raising the possibility of a class-wide mode of operation (Rondard et al., 2006).
Particularly compelling was the observation that mutations of mGlu-2 Cys-234 disabled receptor function
without impairing surface expression and abolished the positive impact
of the HH domain-binding positive allosteric modulator 4-MPPTS on glutamate binding (Rondard et al., 2006). Tight
conservation of mGlu-2 Cys-234 and
its CR domain partner Cys-518, together with the demonstration of an
interdomain disulfide in the crystal structure of the entire
extracellular domain of mGlu-3 (Muto et al., 2007), strengthen the
case that a highly conserved disulfide between the VFT and CR domains is critical for signal
transmission in all class C GPCRs.
As noted recently by Hu and Spiegel (2007), the failure
to demonstrate an intramolecular disulfide between the CaSR's VFT
and CR domains in their earlier study (Hu et al., 2001) may have arisen
from its relative instability under the conditions used to process and
separate the protein bands.5.
Ligand binding surfaces for class C GPCRsSeveral
ligand binding surfaces are recognized for class C GPCRs. Given that all these receptors
appear to operate as dimers formed from closely related subunits,
potential binding surfaces include both VFT
interlobar fissures ([Kunishima et al., 2000] and [Tsuchiya et al., 2002]), the
interprotomeric interface between VFT
domains ([Tsuchiya et al., 2002] and [Abe et al., 2003]), the niches
between the VFT domains and CR
domains, and pockets within the HH domains (Miedlich et al., 2004). The
locations of these sites are shown schematically in Fig. 2. It is not yet
certain, however, whether all these potential sites are used
physiologically. The best recognized binding site in the broad-spectrum amino acid-sensing subgroup is the
conserved VFT interlobar crevice for
amino acid binding. Based on the
crystal structure of the mGlu-1 VFT domain, there is also a multivalent cation binding site in the
interprotomeric interface, which supports the agonist activity of Gd3+
(Tsuchiya et al., 2002). It seems
doubtful, however, that this site supports multivalent cation sensing in
the CaSR since the negatively
charged interface is interrupted by local positive charge. Instead the CaSR appears to provide Ca2+
binding sites within the interlobar crevice of the VFT domain ([Huang et al., 2007] and [Huang et al., 2009]) and
associated with the extracellular surface of the HH domains ([Hauache et al., 2000], [Ray & Northup, 2002] and [Mun et al., 2004]).The VFT domain interlobar crevice and HH
domain-binding pockets have proven to be suitable target sites for drug
development. In general, whereas activators that bind in the VFT domains are agonists, activators that
bind in the HH domains are positive allosteric modulators (PAMs).
Similarly whereas, in general, inhibitors that bind in the VFT domains are antagonists, inhibitors
that bind in the HH domains are negative allosteric modulators. The VFT domain-associated amino acid binding site of the CaSR appears to be an exception since it
operates as a PAM with respect to intracellular Ca2+
mobilization ([Conigrave et al., 2000a], [Conigrave et al., 2000b] and [Conigrave & Hampson, 2006]).
Successful development of high potency, high efficacy, positive and
negative allosteric modulators of class C GPCRs
including mGlus and the CaSR offer new approaches to drug
development (review: (Conn et al., 2009)).6. A conserved amino acid binding site in class C GPCRs: origins of promiscuity in
broad-spectrum amino acid sensorsIn
addition to allosteric sites in the HH domains, all deorphanized
members of Class C GPCRs possess an amino acid-, or modified amino acid binding pocket in their VFT domains. In the mGlus, the glutamate-binding
pocket occupies a relatively small cavity within the crevice of the VFT domain compared to other Class C
receptors ([Wang & Hampson, 2006] and [Wang et al., 2006]) and is highly
selective for l-glutamate ([Frauli et al., 2006] and [Kuang et al., 2006]). From the
crystal structures it appears that as many as 12 residues establish
H-bonds or salt bridges with the bound glutamate ([Kunishima et al., 2000], [Tsuchiya et al., 2002] and [Muto et al., 2007]) and
additional bonding interactions occur with more complex ligands, thereby
increasing affinity, potency and subgroup selectivity (reviews: ([Conigrave & Hampson, 2006]
and [Wellendorph & Bräuner-Osborne,
2009])). In rat mGlu-1, five residues support normal
binding of the α-amino and αcarboxylatemoieties of glutamate: S165,
T188, D208, Y236, and D318 (Kunishima et al., 2000) and these
residues are highly conserved across the class (review: (Conigrave & Hampson, 2006)).In
contrast, residues that ligate the amino
acid side chains are not conserved across class C receptors and
variation in the side-chain binding pockets is responsible for the
diversity and promiscuity of l-amino acid sensing in the CaSR, C6A
and T1R1/T1R3 heterodimers ([Wang & Hampson, 2006] and [Wang et al., 2006]). In mGlu-1, R78 and K409 ligate the
γ-carboxylate side-chain of the bound glutamate, and R78 is tightly
conserved across all three mGlu
subgroups ([Hampson et al., 1999] and [Kuang et al., 2006]). The
side-chain binding pockets of other Class C receptors are less well
defined and mediate broad-spectrum amino
acid selectivities for basic and aliphatic amino acids in 5.24
and C6A (([Speca et al., 1999], [Kuang et al., 2005] and [Wellendorph et al., 2005]) as
well as aromatic, aliphatic and polar amino acids in the CaSR (([Conigrave et al., 2000b] and [Conigrave & Hampson, 2006]);
see Fig. 3).Full-size image
(89K)
High-quality image
(1273K)Fig. 3. Comparisons of
the binding pockets of mGlu-1 C6A, 5.24 and the CaSR. The Connolly surfaces that define
the binding pockets were constructed in the absence of ligand using the
MOLCAD module in Sybyl software. Ligands are displayed as ball and stick
representations (glutamate in the case of mGlu-1;
arginine in the cases of C6A and
5.24 and l-Phe in the case of the CaSR). The figure has been adapted from
Ref. (Wang & Hampson, 2006). 7. mGlu subgroup-selective compounds and
design options for agents that target the VFT
domains of broad-spectrum amino acid-sensing
receptorsConsiderable effort has gone into the development of
high potency agonists and antagonists of the orthosteric sites in the mGlu VFT
domains. In general, these compounds exhibit either: (i) broad-spectrum
activity across all eight mGlu
subtypes or (ii) selectivity for an mGlu
subgroup (review: (Conn, 2003)) although some
receptor specific agents are also recognized. Examples of
group-selective compounds include the potent Group I-selective agonist quisqualate which binds to either mGlu-1 or mGlu-5
in an orientation that permits the formation of additional H-bonds (Sato et al., 2003), the Group
II-selective agonist DCG-IV, in
which an additional side-chain carboxylate interacts with a
group-specific Tyr residue (Y150 in mGlu-2;
([Muto et al., 2007] and [Yao et al., 2003])) and Group
III-selective agonists (e.g., l-amino-4-phosphonobutyric
acid and l-serine-O-phosphate) in which negatively charged
phosphonate side-chains bind in a positively charged microenvironment ([Hermit et al., 2004] and [Rosemond et al., 2004]).7.1. Development of agents that target
the VFT domains of broad-spectrum amino acid-sensing receptorsAlthough
potent and selective positive and negative allosteric modulators of the
CaSR's HH domains, known
respectively as calcimimetics and calcilytics, have been developed
successfully ([Nemeth, 2006] and [Marquis et al., 2009]), the
design and/or development of compounds that target the VFT domain ligand binding sites of
broad-spectrum amino acid-sensing
receptors is in its infancy. Recent molecular modelling, successfully
predicting that the VFT ligand
binding domains of the CaSR, C6A and 5.24 receptors can accommodate the
peptide glutathione (Wang et al., 2006), however,
suggests an approach to the design of novel activators and inhibitors of
all members of broad-spectrum amino acid-sensing
receptors based on γ-glutamyl or β-aspartyl nuclei. Consistent with this
notion, γ-glutamyl peptides have been reported recently to
act as CaSR-mediated taste-enhancing
agents (Ohsu et al., 2010).8. Physiological roles of
broad-spectrum amino acid-sensing
class C GPCRsThe
physiological significance of class C GPCRs
can be assessed by a consideration of tissue expression patterns and
the impact of receptor activation on cell and tissue responses.
Alternatively, their significance can be assessed in transgenic mice derived, for example, by
global or conditional deletion strategies. In the subsequent sections,
the physiological significance of the broad-spectrum amino acid-sensing class C GPCRs is considered from both these
perspectives.8.1. Tissue
expression patterns and proposed roles of broad-spectrum amino acid-sensing receptors8.1.1. CaSRThe
CaSR is widely expressed in
mammalian tissues (Brown & MacLeod, 2001). In endocrine cells including parathyroid chief cells and thyroid C-cells, it respectively inhibits
the secretion of parathyroid hormone
and promotes the secretion of calcitonin,
thereby reciprocally modulating two opposing regulators of whole body
calcium metabolism (Brown, 2007). In renal tubular
segments it modulates calcium, phosphate,
salt and water transport ([Ward & Riccardi, 2002] and [Vezzoli et al., 2009]). In the gastrointestinal tract, it is expressed
in epithelial cells of the stomach, small and large intestine, thereby promoting
digestion along with the absorption of macronutrients, micronutrients
and water (reviews: ([Conigrave & Brown, 2006] and [Geibel & Hebert, 2009])). It
is also expressed in enteroendocrine cells
in which it promotes the secretion of gut hormones including gastrin (Buchan et al., 2001) and possibly cholecystokinin (Hira et al., 2008), as well as neurones of the enteric nervous system (Chattopadhyay et al., 1998), thus
contributing to the control of intestinal motility (Geibel & Hebert, 2009). In
addition, the CaSR is expressed in
mesenchymal tissues and recent evidence suggests that it plays a key
role in the development of cartilage
and in bone homeostasis (Chang et al., 2008) (see below).The
CaSR is also expressed in the central nervous system (CNS) ([Ruat et al., 1995] and [Rogers et al., 1997]). Although
its roles in the CNS are not
well-defined, its expression is developmentally regulated and it
contributes to: (i) the central control of salt and water metabolism via
its expression in the subfornical organ
(Rogers et al., 1997); (ii) the
modulation of neurotransmission via adjustments in the activity of
non-selective cation channels (Phillips et al., 2008); and (iii)
normal CNS development including myelination ([Ferry et al., 2000] and [Chattopadhyay et al., 2008]) and
the generation of sympathetic nerves
(Vizard et al., 2008). During brain development and prior to the
formation of the blood brain barrier,
activation of the CaSR by
physiological levels of Ca2+, amino acids and/or other
activators may suppress excitatory postsynaptic currents to promote
neuronal growth and neurite
arborization.8.1.2. C6AThe recently cloned basic amino acid-sensing receptor C6A responds to arginine, lysine,
ornithine and various aliphatic amino acids as well as divalent cations
(reviews: ([Conigrave & Hampson, 2006]
and [Wellendorph et al., 2009a]). Like
the CaSR, C6A mRNA and protein are widely expressed
in tissues including the lung, kidney, liver,
spleen, heart, skeletal
muscle, brain and taste buds ([Kuang et al., 2005] and [Wellendorph et al., 2007]). In
consequence, its proposed roles are diverse and include regulation of
nutrient disposition and/or amino acid
metabolism (Wellendorph et al., 2005),
nutrient-dependent control of neurotransmission ([Kuang et al., 2005] and [Wellendorph et al., 2007]),
regulation of mesenteric blood flow (Harno et al., 2008), specialized
calcium- and amino acid-sensing in bone ([Pi et al., 2005] and [Pi et al., 2006]), and even the
detection of cell death (Civelli, 2005). C6A may also mediate some of the
long-recognized effects of basic amino acids on hormone secretion. Surprisingly, it has
proven difficult to express C6A
heterologously in cultured cells ([Kuang et al., 2005] and [Wellendorph et al., 2005])
raising the possibility that it forms heterodimers with a currently
unidentified partner(s).8.1.3.
T1R1/T1R3Three T1R taste receptors (T1R1,
T1R2, and T1R3) represent a well-defined subset
of receptors within the broad-spectrum amino
acid-sensing group. They form heterodimers in which T1R3
specializes as the signaling subunit to activate, respectively, PI-PLC and adenylyl
cyclase via the heterotrimeric
G-proteins α-gustducin and
α-transducin (reviews: ([Chandrashekar et al., 2006] and [Palmer, 2007]). T1R1
combines with T1R3 to form broad-spectrum l-amino acid
sensors, and T1R2 combines with T1R3 to form
sweet-taste sensors for simple sugars and d-amino
acids. T1R1/T1R3 amino
acid-sensing heterodimers contribute to the perception of
savoury taste (umami) in combination with purine
nucleotide enhancers including IMP
and GMP ([Li et al., 2002] and [Nelson et al., 2002]) and recent
mutational analysis and molecular modelling indicates that amino acids
and IMP bind at different sites in the extracellular domain of T1R1
(Zhang et al., 2008).Studies
of cellular expression in mouse
taste tissue indicate that T1R1 is expressed alone (i.e.,
without T1R3) in a significant number of cells in both
circumvallate and fungiform papillae (Kim et al., 2003) suggesting that
in some cell contexts it may operate either as homodimers or in
heterodimers with other members of GPCR
class C (e.g., with one or more mGlus).
T1R receptors also contribute to the coordination of nutrient digestion
and absorption in the small intestine,
operating in networks with other nutrient-sensing receptors as well as
transporters for peptides, amino
acids and monosaccharides (Mace et al., 2009). T1R2/T1R3
heterodimers, for example, promote the secretion of the
glucose-regulating hormone GLP-1
from enteroendocrine L-cells (Jang et al., 2007).8.2. Insights from global and
tissue-specific transgenic miceGlobal
and conditional null mice have been
described for several members of the broad-spectrum amino acid-sensing subgroup within GPCR class C. These mice are providing important insights into
the physiological significance of the receptors. However, mouse models need to be approached with
caution. In addition to differences between the mouse and other mammals, so-called ‘background’ genetic
differences between strains of M. musculus can modify phenotypic
outcomes. Furthermore, phenotypic differences can arise from the
strategy chosen to disrupt gene function. It is now apparent, for
example, that partial gene deletion strategies based on the targeting of
individual exons can lead to substantial diversity in the resulting
phenotype depending on the exon selected. This appears to be especially
true for the CaSR and, possibly, C6A (see below). Interestingly, the gene
structures of the cluster of broad-spectrum amino
acid-sensing receptors are strikingly similar (Fig. 4).Full-size image
(45K)
High-quality image
(336K)Fig. 4. Structural
similarities between the genes encoding the CaSR,
C6A, and T1R1 taste
receptors. The number of residues encoded by each exon is indicated
above the corresponding rectangles. Introns are depicted as lines
(sequence lengths shown in kilobases). Isoform 1 of C6A is shown together with transcript
variant 2 of T1R1. The exons that define the specific forms
of C6A and T1R1 shown are
depicted as grey boxes. 8.2.1.
CaSRMice homozygous for global disruption of
exon-5 of the CaSR gene, which
encodes residues 460–536 in the C-terminus of the human VFT
domain (www.casrdb.mcgill.ca), exhibit a phenotype
characterized by growth retardation, skeletal abnormalities, parathyroid hyperplasia,
markedly elevated serum Ca2+
and parathyroid hormone
concentrations as well as early death — features typical of untreated
neonatal severe hyperparathyroidism
in humans (Ho et al., 1995). Thus, the first
global CaSR-null mouse to be described, exhibited a
phenotype consistent with the effect of disabling a gene with a key,
non-redundant role in parathyroid Ca2+-sensing
and appeared to exclude other non-redundant roles for the CaSR. Consistent with this notion,
heterozygous CaSR-ex5+/− mice exhibited features consistent with familial hypocalciuric hypercalcemia in humans, which arises from the impact of
inactivating CaSR mutations on
calcium-sensing in the parathyroid
and kidney (Ho et al., 1995).More
recent work has led to a re-evaluation of CaSR
exon-5 as a target in transgenic mouse
studies. As a result of alternative splicing that induces in-frame
deletion of exon-5, various tissues express a shortened form of the CaSR with a modified glycosylation pattern ([Oda et al., 1998] and [Oda et al., 2000]). The exon-5
minus CaSR traffics normally to the cell membrane in growth plate chondrocytes
prepared from CaSR-ex5−/− mice and retains receptor function as
revealed by high extracellular Ca2+-stimulated inositol phosphate turnover (Rodriguez et al., 2005). These
surprising findings indicate that the exon-5 null mouse is an “incomplete knock-out”, which
retains significant residual CaSR
function, providing a theoretical basis for the development and
investigation of alternative CaSR-null
mice in which other exons are
targeted. These include exons required for the formation of the
nutrient-binding, bilobed VFT domain
(exons 2–4), the Cys-rich domain (exon-6) or the entire HH domain and
C-terminal domain (exon-7). In response to this need, several new transgenic mouse strains have been
developed from tissue-selective ablation of exon-7 in the following
tissues (promoter in parentheses): parathyroid
(PTH), osteoblasts
(Col(I) α1-subunit or Osterix) and growth plate chondrocytes
(Col(II) α1-subunit) (Chang et al., 2008). These new transgenic mice have transformed our
understanding of the physiological breadth of the non-redundant roles
played by the CaSR.As
expected, parathyroid-specific
ablation of CaSR exon-7 resulted in a
phenotype consistent with neonatal primary
hyperparathyroidism with no effect on birth length or weight but
marked postnatal growth retardation associated with skeletal
under-mineralization and hypercalcemia
(Chang et al., 2008). The phenotype
observed in these mice resembled
that of the global exon-5 null mouse
(Ho et al., 1995). Surprisingly, mice homozygous for growth plate chondrocyte-specific
ablation of CaSR exon-7, exhibited a
much more severe phenotype in which all progeny died in utero,
typically prior to embryonic day 12 (Chang et al., 2008). In addition, osteoblast-specific ablation resulted in a
major skeletal phenotype exhibiting postnatal growth retardation and
under-mineralization of the skull
and long bones. On micro-CT analysis
these mice exhibited markedly
reduced femoral trabecular number and volume and analysis of gene
expression revealed impaired expression of early and late markers of osteoblast differentiation, as well as
marked alterations in the expression of key growth and survival factors (Chang et al., 2008). In
particular, in osteoblast-specific, CaSR exon-7 null mice there was impaired expression of insulin-like growth factor-1 (IGF-1) and prosurvival factors including Bcl2.The phenotype of the osteoblast-specific CaSR-null mouse
is at variance with predictions based on previous studies of Gcm2/CaSR-ex5
(Tu et al., 2003) and PTH/CaSR-ex5
(Kos et al., 2003) double null mice in which the skeletal effects of
global exon-5 ablation were found to depend on PTH gene expression and associated primary hyperparathyroidism secondary to
defective Ca2+o-mediated feedback. These
discrepancies underscore the incomplete nature of the exon-5 knock-out
strategy. The results from the Col (I) and Osterix-directed
exon-7 null mice suggest that the CaSR plays a key role in skeletal development by up-regulating the osteoblast-dependent expression of
autocrine and paracrine growth and survival factors (Chang et al., 2008) and, together
with the findings for the Col (II)-directed exon-7 null mouse, demonstrate the existence of
physiologically critical, PTH-independent
roles for the CaSR in the
development and homeostasis of cartilage and bone.Are the multi-metabolic
sensing functions of the CaSR
including sensitivities to amino acids, ionic strength, pH and
temperature ([Conigrave et al., 2000a] and [Breitwieser et al., 2004]) or the
demonstrations of roles for the CaSR
in neurotransmission and neuronal development ([Phillips et al., 2008] and [Vizard et al., 2008])
physiologically significant or redundant i.e., largely supported by
other mechanisms? Evaluation of the wider physiological significance of CaSR expression in the kidney, gastrointestinal
tract, brain and other sites
awaits the generation of new tissue-selective CaSR-null mice.
Furthermore, recent work suggesting that the CaSR suppresses branching morphogenesis in
the lung prior to the later stages
of fetal development (Finney et al., 2008) indicates a
need for transgenic mice in which
there is developmental as well as tissue-specific manipulation of CaSR expression.8.2.2. C6AThe
recent generation of global exon-2 and exon-6 null mice in two separate studies has provided
opportunities to evaluate the non-redundant functions of C6A ([Pi et al., 2008], [Wellendorph et al., 2009b] and [Wellendorph et al., 2009a]).
Exon-2 encodes residues 66–167 of the mouse
ortholog of C6A (Kuang et al., 2005) and should
disable nutrient sensing by the VFT
domain. Exon-6, on the other hand, encodes the entire HH domain and
C-terminal domain and should eliminate the receptor's signaling function
([Kuang et al., 2005] and [Wellendorph et al., 2007]).
Surprisingly, two very different outcomes have been reported ([Pi et al., 2008] and [Wellendorph et al., 2009b]). In
the case of the exon-2 null mouse, a
multi-system phenotype was reported featuring normal body weight but
increased fat mass, decreased lean body mass, hyperglycemia and insulin resistance, proteinuria, renal calcium and phosphate wasting, impaired bone mineral density and defective
testicular function resulting in low serum
testosterone levels (Pi et al., 2008). Remarkably, in
the case of the C6A exon-6 null mouse, however, no phenotypic disturbance
was observed (Wellendorph et al., 2009b). If the
disparity is real, the results suggest that the nutrient-sensing
function of exon-2 is critical to the processing of normal metabolic
signals arising from basic amino acids and/or divalent cations but the
signaling function of exon-6 is redundant. Such a situation might arise
if, as suggested above, C6A normally
operates in heterodimers with an, as yet unidentified, signaling
partner. If this is the case, the cloned C6A
subunit might be analogous to the T1R1 and GABAB1 subunits whose
heterodimeric partners are T1R3 and GABAB2 respectively.8.2.3. T1R1/T1R3Studies
on T1R1 global null mice
generated by targeted deletion of the HH and C-terminal domains (Zhao et al., 2003), or T1R3
global null mice generated by
deletion of the N-terminal extracellular domain (Zhao et al., 2003) or entire gene
locus (Damak et al., 2003) support the
hypothesis that T1R1/T1R3 heterodimers form
broad-spectrum l-amino acid receptors, which contribute to
umami taste. Importantly, responses to l-glutamate
and other amino acids were impaired in both the absence and presence of
the umami enhancing agents IMP and GMP
([Damak et al., 2003] and [Zhao et al., 2003]). On the other
hand, evidence for residual glutamate sensing in T1R3 null mice (Damak et al., 2003), points to
roles for additional receptors (e.g., mGlu-4)
in umami sensing (Maruyama et al., 2006). The
potential physiological significance of T1Rs in coordinating intestinal
responses to nutrients has not yet been addressed in transgenic mouse models.9. ConclusionsAs we get to know
them better, Class C GPCRs are
presenting no shortage of surprises. For these receptors, multi-ligand
sensing and multi-modal signaling is the norm. Nutrient molecules, once
the preserve of biochemists and nutrition scientists, are also now of
great interest to molecular pharmacologists as well as cell and systems
physiologists. The design of the receptors is deceptively simple and
highly conserved but, depending on the cell in which they are expressed,
their preferences for nutrients, binding partners, modes of operation
and physiological roles are impressively plastic. The subgroup of
broad-spectrum amino acid sensors
including the CaSR, C6A and T1R1/T1R3
receptors have roles in nutrient sensing that contribute to taste,
control of appetite and satiety, as well as coordination of intestinal
digestion, absorption and nutrient disposition. These receptors are also
potentially important drug targets with strategies now defined for
their development. Stay tuned!
AcknowledgmentsThe authors
thank Mr Sujeenthar Tharmalingam for his assistance in preparing the
diagrams and also wish to thank the National Health and Medical Research
Council of Australia (ADC and DRH) and the Canadian Institutes for
Health Research and the Canadian Natural Sciences and Engineering
Research Council (DRH) for research support.
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