302 Current Pharmaceutical Biotechnology, 2009, 10, 302-310

Roles of Calcium-Sensing Receptor (CaSR) in Renal Mineral Ion Trans-

port

Giuseppe Vezzoli1, Laura Soldati2 and Giovanni Gambaro3,*

1
Nephrology Unit, San Raffaele Scientific Institute, Milan, Italy; 2Department of Sciences and Biomedical Technologies,
Nephrology Section, University of Milan, Milan, Italy; 3 Nephrology Division, Columbus-Gemelli Hospital, Catholic
University, Rome, Italy

Abstract: Calcium-sensing receptor (CaSR), a member of family C of the G protein-coupled receptors, is expressed most
abundantly in the parathyroid glands and kidney. It plays key role in these two organs because it senses changes in ex-
tracellular calcium and regulates PTH secretion and calcium reabsorption to suit the extracellular calcium concentration.
In kidney, CaSR is expressed in all nephron segments. It has an inhibitory effect on the reabsorption of calcium, potas-
sium, sodium and water, depending on the particular function of the different tubular tracts. Among its inhibitory effects,
CaSR modulates the signaling pathways used by the tubulocytes to activate electrolyte or water reabsorption. The only
site where there is no such inhibitory effect is in the proximal tubule, where CaSR enhances phosphate reabsorption to
counteract the effect of PTH.
CaSR mutations and polymorphisms cause disorders characterized by alterations in renal excretion and serum calcium
concentrations. They also can cause sodium and potassium excretion disorders. CaSR also mediates the acute adverse re-
nal effects of hypercalcemia, which include a reduced sodium, potassium and water reabsorption.
From a teleological perspective, CaSR seems to protect human tissues against calcium excess in extracellular fluids.
Keywords: Gene, hypercalcemia, hypercalciuria, hypocalcemia, sodium handling, water reabsorption, renal stone.

INTRODUCTION (ERK) pathways [4,5]. It is via these signaling pathways that

Calcium-sensing receptor (CaSR) is a member of family
C of the G protein-coupled receptors (GPCR) (which also
includes the metabotropic glutamate receptor, gamma-
aminobutyric acid receptors, taste receptors and pheromone
receptors in the vomeronasal organ), expressed in a large
number of human tissues but most abundantly in the parathy-
roid glands and kidney [1-3]. CaSR has a key role in these
two organs because it senses changes in extracellular cal-
cium and regulates PTH secretion and calcium reabsorption
to suit the extracellular calcium concentration.
The CaSR molecule is a dimer located on the cell’s
plasma membrane. Each monomer consists of a wide ex-
tracellular domain (612 amino acids) capable of binding cal-
cium ions with its multiple negative charges, a transmem-
brane domain spanning 7 membranes (250 amino acids), and
a shorter intracellular tail (216 amino acids) enabling CaSR
to generate multiple intracellular transduction signals by
activating G protein family members (Gi, Gq, G11 or G12) [4].
Gi protein inhibits adenylyl cyclase, while Gq, G11 and G12
proteins stimulate phospholipase C, A2 or D [5]. The CaSR
intracellular domain may also interact with filamin A (a cy-
toskeletal scaffolding protein needed for Gq protein and Rho
signaling [6]) and activate mitogen-activated phosphorylase
kinase (MAPK) and extracellular signal-regulated kinase
*Address correspondence to this author at the Divisione di Nefrologia,
Dipartimento di Medicina Interna, Università Cattolica del Sacro Cuore,
Complesso Integrato Columbus-Policlinico Gemelli, Via Moscati, 00176
Roma, Italy; Tel: +39 045 8122521; Fax: +39 045 915176;
E-mail: giovanni.gambaro@univr.it
CaSR enables parathyroid glands and kidney to regulate
PTH secretion and calcium reabsorption as a function of
serum calcium concentration. CaSR thus has a key role in
calcium homeostasis with the specific task of maintaining
normal plasma calcium concentrations. CaSR is also ex-
pressed in bone and intestinal cells, where it may have a role
in calcium absorption and bone resorption, though this re-
mains uncertain [7,8].
In kidney, CaSR is expressed in all nephron segments
with the possible exception of the glomeruli, where its pres-
ence is debated. CaSR has an inhibitory effect on the reab-
sorption of calcium, potassium, sodium and water, depend-
ing on the particular function of the different tubular tracts.
Among its inhibitory effects, CaSR modulates the signaling
pathways used by the tubulocytes to activate electrolyte or
water reabsorption. The only site where there is no such in-
hibitory effect is in the proximal tubule, where CaSR en-
hances phosphate reabsorption to counteract the effect of
PTH.
GLOMERULI
No CaSR expression was detected in human and rat
glomeruli using immunohistochemical or immunofluorescent
methods, nor even when RT-PCR was applied to cDNA [9,
10].
These findings have been contradicted, however, by ob-
servations in cultured glomerular cells. Preliminary experi-
ments using the RT-PCR method revealed CaSR gene ex-

1389-2010/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Roles of Calcium-Sensing Receptor (CaSR)
pression in human glomerular resident progenitor cells (Sol-
dati, Zerbini et al unpublished finding). CaSR was also
found by immunocytochemical methods, RT-PCR and West-
ern blot analysis in a line of mouse mesangial cells. Func-
tional tests confirmed the presence of CaSR in mesangial
cells as they responded to increases in extracellular calcium
up to 20 mM, with a rise in intracellular calcium from 57±6
to 196±6 nM, and inositol-triphosphate production increas-
ing to 2.6 times the basal level. This cellular response was
proportional to the extracellular calcium concentration and
was inhibited by calcilytic drugs, which act as allosteric
CaSR antagonists (5
M NPS-2390 in cell culture medium).
Phospholipase C mediated this activity in that its inhibitor
U73122 prevented calcium-induced intracellular calcium
release [11].
Mesangial cells may directly influence physical forces
regulating glomerular filtration and permeability. They con-
trol relaxation of the glomerular capillary tuft and glomerular
hemodynamics responding to vasoactive agents such as an-
giotensin II, vasopressin, leukotrienes, and platelet-activating
factor [12,13]. Mesangial cell proliferation and matrix syn-
thesis by mesangial cells also take part in the physiopa-
thological events occurring in glomerular disorders, typically
in IgA nephropathy [13,14]. CaSR expression in mesangial
cells might thus contribute to regulating glomerular filtration
or to the onset of glomerular damage in glomerulonephritis.
This is merely a hypothesis, however, since no links have
been established between CaSR and mesangial alterations
with in vitro or in vivo experiments.
Together with their basement membrane, glomerular en-
dothelial cells and podocytes form the mechanical and elec-
trostatic barrier that determines the composition of glomeru-
lar filtrate [15]. Functional and immunocytochemical testing
of endothelial cells isolated from rat mesenteric arteries and
porcine coronary arteries have identified CaSR on their
membranes [16]. The pharmacological response of the endo-
thelium to calcimimetic drugs, acting as allosteric stimula-
tors of CaSR activity, indicated that CaSR triggered calcium-
activated potassium channels, resulting in outgoing potas-
sium flux, vascular smooth muscle cell hyperpolarization
and a vasorelaxant effect [16,17]. The presence of CaSR was
also confirmed in human aortic endothelium, where CaSR
activation by spermin (a polycationic protein that is an allos-
teric agonist of CaSR) led to the production of nitric oxide, a
locally vasodilating molecule [18,19]. These experiments
suggest that CaSR is involved in modulating vascular tone
and regulating blood pressure [16], an impression reinforced
by the observation of CaSR agonists altering blood pressure
values in uremic rats [20].
According to the published studies, glomerular endothe-
lium and mesangium are likely to express CaSR under par-
ticular conditions, though no studies have yet identified
CaSR in intact glomeruli under normal conditions. CaSR
activity may influence the state of contraction of pedicelli
and mesangial cells, modifying the glomerular filtration con-
ditions with a possible role in glomerulonephritis [21]. CaSR
expression has not been studied in isolated podocytes, how-
ever, and no data are currently available on this issue.
Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3 303
JUXTAGLOMERULAR APPARATUS
The presence of CaSR in the juxtaglomerular apparatus
has been documented in primary cultures of isolated mouse
juxtaglomerular cells by RT-PCR and Western blot. In addi-
tion, confocal microscopy and immunofluorescence methods
have identified CaSR in mouse juxtaglomerular cells and in
the basolateral membrane of tubular cells at the macula
densa [10]. Juxtaglomerular cells are located in the lamina
media of the afferent arteriole and they secrete renin. Acti-
vating CaSR in cultured juxtaglomerular cells by adding
CaSR agonists to the culture medium inhibited adenylyl cy-
clase activity and suppressed renin release [22,23]. This ob-
servation is consistent with previous findings of increased
calcium levels in the juxtaglomerular cells inhibiting cAMP
synthesis and renin secretion [24,25]. CaSR activation may
therefore inhibit renin secretion by reducing cAMP synthe-
sis. It might also reduce renin secretion in the juxtaglomeru-
lar apparatus via a paracrine mechanism [26]. As a conse-
quence, CaSR activation may reduce the stimulating effect of
renin on sodium reabsorption and arteriolar tone.
PROXIMAL TUBULE
Using immunofluorescent methods, CaSR was found in
the rat proximal tubule where it was located at the base of
the brush border in the apical cell membrane [10, 27]. The
intensity of the fluorescent CaSR signal faded from the more
proximal to the more distant segments of the proximal tu-
bule. No CaSR expression was found, however, in other
studies using the RT-PCR method in rat proximal tubule
[28].
The proximal tubule reabsorbs around 75% of filtered
sodium, calcium and phosphate. It also has an endocrine
activity, synthesizing 1,25(OH)2D by 1
-hydroxylation of
25(OH)D. The majority of calcium reabsorption in the
proximal tubule proceeds via a passive paracellular pathway
and is secondary to iso-osmotic sodium reabsorption. Only a
small amount of calcium may be actively reabsorbed in the
proximal tubule [29]. Proximal phosphate reabsorption oc-
curs mainly in the convoluted segment, which is the princi-
pal determinant of serum phosphate concentrations that cor-
relate closely with the phosphate excretion threshold [30]. In
humans, phosphate is reabsorbed in the proximal tubule by
different sodium-phosphate cotransporters located on the
apical membrane of the tubulocytes; the most active is
NPT2c, accounting for 85% of the phosphate reabsorbed
[31]. NPT2c activity is sustained by the electrochemical gra-
dient across the apical plasma membrane, maintained by the
basolateral sodium-potassium pump continuously driving
sodium out of the cells. Other proximal phosphate carriers
are NPT1, accounting for less than 15% of the ion’s reab-
sorption, and NPT3 (Glvr1 and Ram1), which are responsi-
ble for a marginal phosphate reabsorption not responding to
PTH [32]. A small amount of phosphate is reabsorbed in the
distal tubule. NPT2c activity is inhibited by FGF23, PTH
and dietary phosphate intake. PTH and phosphate intake
make the NPT2c carriers become incorporated in subapical
vesicles derived from the brush border, where they are de-
graded into lysosomes [31]. This mechanism reduces the
number of NPT2c copies in the plasma membrane and limits
304 Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3
phosphate reabsorption by the proximal tubulocytes [33]. A
transcriptional effect of dietary phosphate has also been sug-
gested because a phosphate-response element has been de-
scribed in the NPT2 gene promoter [34]. FGF23 is a fibro-
blast growth factor that is mainly synthesized in the liver and
is activated by the endoprotease Phex [35,36]. It regulates
serum phosphate concentration by reducing NPT2c expres-
sion in the kidney’s proximal tubulocytes. The phosphate
reabsorption impairment caused by FGF23 is probably due
to NPT2c incorporation [37,38].
Experiments in mouse proximal tubules perfused in the
presence of PTH showed that, activated by the increased
calcium in the tubular fluid, CaSR inhibited the ability of
PTH to reduce phosphate reabsorption: this occurred when
PTH interacted with either its luminal or its basolateral tubu-
locyte membrane receptor PTHr1 [39]. As the mechanism by
which PTH internalizes NPT2c is cAMP-mediated, this is
probably the pathway inhibited by CaSR in order to counter-
act the PTH-mediated NPT2c incorporation and consequent
phosphaturic effect of PTH in the proximal tubules (Fig. 1).
Accordingly, divalent cations were seen to inhibit PTH-
induced cAMP production in the proximal cells, probably
due to CaSR activation [40]. The antiphosphaturic effect of
CaSR also antagonizes the PTH-induced sodium excretion
and may mitigate the overall sodium loss caused by CaSR
[39]. The influence of CaSR activation in inhibiting the
NPT2c membrane expression mediated by FGF23 and diet
has not been studied specifically, though dietary phosphate
was found to reduce both CaSR and NPT2 expression in rat
proximal tubule [41]. Taken together, these findings suggest
that the higher calcium concentration in the proximal tubular
fluid enhances phosphate reabsorption, thereby reducing the
phosphate concentration in the proximal lumen and prevent-
ing the potential complications of calcium-phosphate salts
precipitating in the kidney.
Fig. (1). CaSR in proximal tubular cells: it is located in the apical
membrane and its activation by higher luminal calcium concentra-
tions inhibits the internalization of NPT2 phosphate carriers in en-
dosomes and their degradation into lysosomes by PTH, and possi-
bly also by FGF23. CaSR activation thus results in an antiphos-
phaturic effect.
Vezzoli et al.
Lower plasma calcium concentrations stimulate 1-
hydroxylation of 25(OH)D to 1,25(OH)2D synthesis, while
higher concentrations shift the synthetic activity to
24,25(OH)2D production [42]. The relationship between vi-
tamin D and CaSR seems to be characterized by a reciprocal
control. Although it is likely, there is no reliable experimen-
tal proof of CaSR mediating the effect of calcium on
1,25(OH)2D synthesis in proximal cells [43]. As for gene
transcription, there is a vitamin D response element in the
CaSR gene promoter such that CaSR expression is upregu-
lated by vitamin D [44]. On the other hand, CaSR was found
to induce vitamin D receptor (VDR) expression in a human
renal proximal cell line via the following sequence of events:
CaSR effect to the Gq/11 protein resulting in phospholipase
C activation, p38 MAPK phosphorylation, ATF2 activation
and ultimately in VDR gene expression. This finding was
confirmed in CaSR knockout mice, which demonstrated a
low VDR production in response to calcium [45]. There may
thus be an apparently negative feedback between CaSR and
vitamin D activity at transcriptional and functional levels. If
CaSR is responsible for the inhibition of 1
hydroxylation
of 25(OH)D, it may limit the stimulatory effect of PTH on
renal 1,25(OH)2 production, thus preventing an excessive
increase in serum calcium concentration.
THICK ASCENDING LOOP OF HENLE (TALH)
CaSR is expressed more abundantly in the TALH than in
the other nephron segments: it was identified on the baso-
lateral side of the tubulocytes using immunohistochemical
methods in rat kidney, but CaSR expression varied from cell
to cell [10]. The TALH reabsorbs 25% of filtered sodium via
transcellular and paracellular mechanisms. Cellular sodium
reabsorption through the apical membrane is managed by a
sodium/potassium/chloride carrier (NKCC2) that couples
inward transport of the three ions. NKCC2 activity is sus-
tained by the sodium-potassium pump in the basolateral
membrane, which maintains low intracellular sodium con-
centrations by driving excess sodium out of the cell [46].
Sodium reabsorption is coupled with chloride reabsorption
through specific channels (CLCNKB) located in the baso-
lateral membrane. NKCC2 activity is also supported by the
low-conductance potassium channels (ROMK) that recycle
potassium ions from the cytoplasm into the tubular lumen.
Potassium recycling keeps the luminal electrical gradient
between interstitium and tubular lumen positive, and this
becomes the driving force for the paracellular reabsorption
of sodium, calcium and other cations [47,48]. Sodium reab-
sorption in the TALH helps to maintain the hypertonicity
gradient of the kidney medulla, which is used to concentrate
urine by reabsorbing water in the collecting duct [49].
CaSR stimulation may have an inhibitory effect on
NKCC2 activity in the TALH via several mechanisms, on
which findings are conflicting (Fig. 2). CaSR inhibited
ROMK activity: by activating Gi protein, which reduced
cellular cAMP levels [50]; or by activating Gq protein, which
stimulated phospholipase A2 to produce 20-hydroxyeico-
satetraenoic acid (20-HETE) from arachidonic acid [51]; or
by stimulating phospholipase C, which led to phosphatidyli-
nositol-bisphosphate synthesis [52]. Moreover, CaSR may
inhibit the sodium-potassium pump in the medullary TALH
by stimulating protein kinase C: the consequent increase in
Roles of Calcium-Sensing Receptor (CaSR)
cellular sodium diminishes the driving force for the sodium
transport mediated by the NKCC2 carrier [53]. The inhibited
sodium reabsorption due to NKCC2 or potassium recycling
to the lumen by ROMK reduces the electrochemical poten-
tial between the interstitium and tubular lumen, which drives
the paracellular transportation of calcium in the TALH. Pas-
sive paracellular calcium reabsorption is consequently
slower in the TALH, under the effect of CaSR.
Fig. (2). CaSR in the TALH cells, where it is expressed on the ba-
solateral membrane. When the plasma calcium concentration rises,
CaSR is stimulated to inhibit NKCC2-mediated sodium reabsorp-
tion through the synthesis of phosphatidylinositol-bisphosphate or
20-HETE. This reduces the electric potential between interstitium
and lumen sustained by ROMK activity and dissipates the driving
force for paracellular passive calcium reabsorption. CaSR also in-
hibits sodium-potassium pump activity and PTH-stimulated cal-
cium reabsorption in the cortical TALH.
A significant percentage of calcium ions may also be
actively reabsorbed under the stimulus of PTH in the cortical
TALH [54]. This PTH-induced calcium reabsorption was
found to be inhibited by gadolinium and calcilytic drugs (R-
467), suggesting that CaSR regulates active calcium reab-
sorption in the TALH by antagonizing the PTH-stimulated
cAMP production [55,56]. In keeping with the reported find-
ings, we can conclude that the presence of CaSR may inhibit
sodium reabsorption in the medullary TALH, thus impairing
its urine-concentrating ability, while CaSR in the cortical
TALH may inhibit PTH-dependent calcium reabsorption.
Both effects appear to counteract the potentially pathological
consequences of higher plasma calcium concentrations.
DISTAL CONVOLUTED TUBULE
In the distal convoluted tubule of the rat, CaSR is ex-
pressed on the basolateral membrane of the tubulocytes,
where it is involved in controlling calcium excretion [10].
Though only 10% of calcium filtering is done here, calcium
reabsorption in the distal convoluted tubule is fundamental
because it is strictly adapted to the body’s needs [57]. Cal-
cium reabsorption in the distal convoluted tubule is mainly
active as it occurs through the ATP-consuming high-affinity
Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3 305
calcium pump (PMCA) on the basolateral cell membrane.
The sodium-calcium exchanger is an alternative basolateral
carrier for calcium reabsorption, driven by the sodium gradi-
ent, but it has lower affinity for calcium than PMCA [58]. At
the opposite side of the distal tubulocyte, calcium influx
through the apical membrane is passive and sustained by
TRPV5 channels [59].
The possible link between CaSR and active calcium reab-
sorption was explored in a line of dog distal convoluted tu-
bular cells (Madin Darby canine kidney, MDCK) expressing
the CaSR molecule. Calcium transport across an MDCK cell
monolayer was inhibited after CaSR activation via a signal-
ing pathway requiring the activation of Gq proteins and pro-
tein kinase C, but not of Gi proteins. PMCA activity was
studied in purified membranes from MDCK cells exposed to
low (0.1 mM) or high (5 mM) calcium concentrations and
was progressively reduced by calcium exposure until it was
abolished after incubation with high calcium concentrations.
These findings are consistent with calcium transport being
inhibited by PMCA in the distal tubule, mediated by CaSR
activated protein kinase C signaling [60] (Fig. 3). Nobody
knows whether the inhibitory effect of CaSR on PMCA seen
in the distal tubule affects other tubular segments too.
Fig. (3). CaSR in a distal convoluted tubule cell, where it inhibits
active calcium reabsorption mediated by the basolateral calcium
pump (PMCA) through protein kinase C activation. Another carrier
for distal cell calcium reabsorption is the sodium-calcium ex-
changer.
A recent study on distal tubulocytes hypothesized that, in
addition to its G-protein-mediated activities, CaSR interacted
directly with ion transport carriers, modifying their func-
tional rate and ion reabsorption. This interaction was ob-
served for the potassium channels Kir4.2 and Kir4.1 [61],
members of the Kir4 channel subfamily, that corrects the
inward flow of potassium ions. When expressed in HEK-293
cells transfected with CaSR gene screened from human adult
cDNA library, CaSR coimmunoprecipitated with the Kir4
channels but not with other potassium channels, including
306 Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3
ROMK. This coimmunoprecipitation did not occur in cells
transfected with the mutant CaSRR796W. Two-electrode volt-
age clamp tests in Xenopus laevis oocytes showed that CaSR
expression reduces Kir4 potassium channel currents, so
CaSR may selectively and directly interact with Kir4 potas-
sium channels, inhibiting potassium transport through the
basolateral membrane of the distal nephron. This inhibitory
activity could reduce the outward potassium recycling sup-
porting the function of the basolateral sodium-potassium
pump, thereby helping to inhibit Na reabsorption in the distal
tubule [61] (Fig. 4).
Fig. (4). CaSR in a distal convoluted tubule cell, where it reduces
potassium flux through the Kir4.1 and Kir4.2 potassium channels
by interacting directly with them. The drop in potassium efflux has
a negative effect on sodium-potassium pump activity and reduces
sodium reabsorption.
COLLECTING DUCT
In rat kidney, collecting duct cells demonstrated a
changeable, weaker CaSR expression than in the other tubu-
lar segments. Some collecting duct cells were found negative
for CaSR fluorescence, while the fluorescence pattern in the
positive cells varied from focal to complete cytosolic stain-
ing. Complete staining was detectable in the majority of tu-
bulocytes. Positive cells had the immunochemical features of
intercalated A cells, expressing the hydrogen pump [10].
When rat and human kidney medulla was analyzed with a
hypertonic solution, tubulocytes of the inner medullary col-
lecting ducts were better preserved and they were positive
for CaSR, the expression of which increased from the initial
to the terminal portion of the inner medullary collecting duct,
located in principal cells on their apical membrane and vesi-
cles of the subapical cytoplasm between the luminal mem-
brane and nuclei. CaSR colocalized with the Aquaporin 2
channel at these sites [62,63]. In these cells, a rapid and re-
versible insertion of Aquaporin 2 water channels in the lumi-
nal membrane follows the interaction of vasopressin with its
V2 receptor and the cAMP-dependent activation of protein
kinase A, eliciting water permeability and antidiuresis [64].
Hypercalcemia alters these urine concentration mechanisms,
Vezzoli et al.
giving rise to vasopressin resistance irrespective of cAMP
production [65]. The presence of CaSR on the luminal or
endosomal membrane in collecting duct cells suggests that
CaSR alters the trafficking of Aquaporin 2 and reduces urine
concentrating capacity by antagonizing vasopressin activity
(Fig. 5). It has been speculated that the lesser urine concen-
trating ability induced by CaSR activation counteracts the
higher calcium concentration in the tubular fluid, protecting
the kidney from salt precipitation in the tubule [62]. The
reported findings also point to CaSR expression in the kid-
ney tubule being modulated by environmental conditions.
Fig. (5). CaSR in a principal cell of the collecting duct: these cells
express water channels of type 2 (AQP-2), but also of other types
(AQP-3 and 4). Vasopressin (ADH) binding to their V2 receptor
leads to AQP-2 insertion in the luminal membrane and elicits an-
tidiuresis. CaSR is expressed on the luminal membrane and antago-
nizes ADH activity by altering AQP-2 trafficking, thus reducing
urine concentration capacity.
CaSR-INDUCED RENAL ION EXCRETION DIS-
ORDERS
CaSR mutations and polymorphisms cause disorders
characterized by alterations in renal excretion and serum
calcium concentrations with a severity that varies according
to their effect on CaSR function. They also occasionally
cause sodium and potassium excretion disorders. CaSR also
mediates the acute adverse renal effects of hypercalcemia,
which include a reduced sodium, potassium and water reab-
sorption.
Familial Hypocalciuric Hypercalcemia (FHH)
FHH is the most common disorder caused by CaSR gene
mutations (3q13.3-21) with a prevalence of 1:100,000 popu-
lation [66]. It was first described in 1972 and is now attrib-
uted to high-penetrance, dominant inactivating mutations of
the CaSR gene [67]. Numerous different types of mutation
have been described, located mainly in the CaSR extracellu-
lar domain and altering CaSR activity to different degrees.
Affected subjects are heterozygotic for the mutated allele
Roles of Calcium-Sensing Receptor (CaSR)
and feature mild-moderate hypercalcemia associated with
normal or mildly elevated concentrations of circulating PTH
[68, 69]. The characteristic feature of patients with FHH is a
low urinary calcium excretion, which is fundamental to dis-
tinguishing FHH from primary hyperparathyroidism and thus
avoiding a pointless parathyroidectomy [70]. FHH patients
also have a tendency to develop hypermagnesemia. The inac-
tivating mutations reduce CaSR function, interfering with its
ability to inhibit PTH secretion and calcium reabsor-
ption. The serum PTH-calcium curve and parathyroid gland
set-point (the calcium concentration at which PTH secretion
is half the maximal level) consequently shift to the right due
to the CaSR’s lower sensitivity to circulating calcium, so the
serum PTH and calcium values are set to higher than normal
[71]. The biohumoral changes in FHH patients resemble
those observed in primary hyperpara-thyroidism, but they are
not corrected by parathyroidectomy, because the hypercal-
cemia is also sustained by a more efficient renal reabsorption
and intestinal absorption of calcium, not just by PTH secre-
tion. FHH is benign and, as concerns the complications of
chronic hypercalcemia, patients only seem to be at risk of
pancreatitis [72]. Individuals with FHH do not seem to risk
developing kidney stones or nephrocal-cinosis, probably
because hypercalcemia stimulates the antidiuretic activity of
CaSR, antagonizing the effect of vasopressin in the collect-
ing duct [62], although these patients do not lose their abso-
lute capacity for urine concentration [73]. FHH is a hetero-
geneous disorder in that it may be associated with two other
loci on the short and long arms of chromosome 19, as well as
with the CaSR locus: these alternative loci account for
around one in three cases and the mutations on chromosome
19q are the rarest. The phenotype is indistinguishable in
FHH patients carrying mutations at different loci [74].
FHH may also be caused by an autoantibody inducing an
allosteric conformational transition of CaSR that activates Gq
but not Gi proteins [75, 76]. CaSR autoantibody may develop
in autoimmune polyendocrine syndrome or in other autoim-
mune disorders, and glucocorticoid therapy has succeeded in
controlling the related hypercalcemia [75, 77].
It is not necessary to correct hypercalcemia in FHH pa-
tients, unless major complications, e.g. pancreatitis, develop.
Calcimimetic drugs (Cinacalcet) have been recommended
for symptomatic patients [78].
Neonatal Severe Hyperparathyroidism (NSHPT)
Patients with NSHPT are homozygotic for a CaSR gene
inactivating mutation, so NSHPT is the homozygous variant
of FHH [79]. Immediately after birth NSHPT patients have
more severe hypercalcemia than in FHH. Patients living be-
yond early infancy develop a bone disease characterized by
failure to thrive, chest deformity and bone fractures [80].
Circulating PTH is usually very high and parathyroid glands
are enlarged, with histological evidence of hyperplasia
[81,82]. The disorder may be lethal within a few days unless
patients undergo parathyroidectomy. Pharmacological treat-
ment with the most powerful bisphosphonates has been used
to control the clinical condition and may maintain a picture
resembling FHH [83]. The recent introduction of calci-
mimetics might provide new therapeutic options for NSHPT.
Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3 307
Autosomal Dominant Hypocalcemia (ADH)
Patients with this disorder have hypocalcemia and an
abnormally high calcium excretion that is exacerbated by
therapy with vitamin D; serum PTH levels are normal. The
condition is usually due to CaSR gene activating mutations,
though patients with activating autoantibodies have also been
described [84]. CaSR autoantibodies can be found in about
half the patients with idiopathic hypoparathyroidism [85].
Unlike the case of FHH, in ADH the calcium-PTH curve set-
point shifts to the left, showing the mutated CaSR’s greater
sensitivity to circulating calcium [86]. Hypocalcemia often
needs no treatment, unless seizures or other severe signs of
hypocalcemia develop. Around 25 mutations have been iden-
tified so far, usually located in the extracellular domain of
the CaSR molecule. A model of this condition exists, i.e. a
mutated mouse with an overactive CaSR, called Nuf [87].
Heterozygous Nuf mice have ectopic calcifications, in the
renal cortical tubules in 50% of cases and in the renal papil-
lary tubules in 63%.
Treatment with calcium salts and vitamin D is necessary
but exposes patients to the risk of nephrocalcinosis and kid-
ney stones due to the very high calcium excretion. The use of
recombinant human PTH has recently been proposed [88].
Familial Hypercalcemia with Hypercalciuria
An inactivating mutation of the CaSR’s cytoplasmic do-
main, leading to familial hypercalciuric hypercalcemia syn-
drome with inappropriately high serum PTH, has been de-
scribed in a large Swedish kindred [89]. In addition to a his-
tory of renal stones, family members also had hypermagne-
semia and parathyroid chief cell hyperplasia.
Bartter Syndrome
Five different disorders come under this name, all due to
sodium and chloride wastage from the distal tubule and char-
acterized by secondary hyperaldosteronism and renal hypo-
potassemia [90]. Type 5 Bartter Syndrome is due to CaSR
gene activating mutations that amplify the inhibitory effect
of CaSR on NKCC2 activity through production of the ara-
chidonic acid metabolite, 20-HETE, in the TALH cells (Fig.
2). Sodium reabsorption mediated by the NKCC2 carrier in
the TALH consequently decreases and the resulting secon-
dary hyperaldosteronism leads to hypokalemia [47, 48]. Two
works first described the clinical picture of Bartter Syndrome
in subjects with ADH, who had hypokalemia, inappropriate
urinary potassium excretion, renin-angiotensin-aldosterone
system activation and alkalosis, in addition to the defects
typical of ADH. Functional in vitro study of the mutated
CaSR transfected in embryonic renal cells (HEK-293)
showed that these mutations caused a massive gain of func-
tion for CaSR activity [91, 92]. The presence of a strongly
activating mutation probably explained why sodium reab-
sorption was inhibited in the TALH, while this usually is not
the case in ADH patients. Another work described two twin
sisters with ADH due to a potent CaSR gene activating mu-
tation: the two girls had a weak, inconstant clinical picture
consistent with Bartter syndrome and administering fu-
rosemide (an NKCC2 inhibitor) prompted a natriuretic re-
sponse, suggesting a normal NKCC2 activity; the authors
308 Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3
concluded that the NKCC2 inhibition is not enough to ex-
plain Bartter Syndrome type 5 [93]. The recent observation
of an interaction between CaSR and Kir4 potassium channels
in the distal tubules helps to clarify these findings (Fig. 4).
Kir4 channels maintain sodium-potassium pump activity and
sodium reabsorption by carriers that dissipate the potassium
gradient, so Kir4 channel inactivation by CaSR may lead to
urinary sodium and potassium loss via a completely different
mechanism from the one thought to justify the onset of type
5 Bartter syndrome in the two earlier works [61, 89, 90].
Primary Hypercalciuria
This disorder is characterized by an abnormally high cal-
cium excretion with no changes in serum calcium and PTH
concentrations. It is a complex disorder due to the contribu-
tion of several genes and environmental variables, predispos-
ing to kidney stones and osteoporosis [94]. The CaSR gene
polymorphism Arg990Gly was found associated with pri-
mary hypercalciuria in stone-forming and non-stone-forming
patients [95]. In vitro study on the CaSR’s response to ex-
tracellular calcium in HEK-293 embryonic renal cells trans-
fected with CaSR gene revealed that Arg990Gly prompted a
gain of function for CaSR [96]. We thus formulated the hy-
pothesis that this activating SNP limited the ability to reab-
sorb calcium ions in the TALH and distal convoluted tu-
bules, where CaSR modulates PMCA activity and the elec-
trochemical gradient across the tubular wall (Fig. 3). Other
studies have found Arg990Gly polymorphism associated
with secondary hyperparathyroidism in patients with uremia
or primary hyperparathyroidism, or with calcemia values in
the general population consistent with the hypothesis of the
990Gly allele inducing a gain of function for CaSR [97-100].
CaSR ACTIVITY IN RENAL ION HANDLING: A
TELEOLOGICAL PERSPECTIVE
CaSR expression is greatest in the parathyroid glands,
where it regulates PTH secretion, but CaSR activity is func-
tionally noteworthy in the kidney too, where it influences
electrolyte and water reabsorption. CaSR has only one iso-
form, but may activate numerous G proteins and different
signaling pathways [101, 102], so its activity in the tubular
cells is heterogeneous and may modulate the intracellular
signaling pathways used to regulate the reabsorption of dif-
ferent substances.
The main effect of CaSR in the kidney is to inhibit tubu-
lar calcium reabsorption, as demonstrated by hypercalcemia
persisting in FHH patients after parathyroidectomy because
the less active CaSR permits a greater tubular calcium reab-
sorption.
The changes occurring in the course of hypercalcemia
also point to the important effects of CaSR on kidney func-
tion, especially in acute hypercalcemia. The rise in calcium
concentrations in the tubular fluid is sensed by CaSR located
on the luminal membrane of the tubulocytes, giving rise to
an antiphosphaturic effect in the proximal tubule (Fig. 1) and
blunting the capacity to concentrate urine in the collecting
duct [39, 62] (Fig. 5). These effects are probably designed to
reduce the risk of calcium-phosphate precipitation in the
tubular lumen. CaSR is located instead on the basolateral
membrane, in the distal tubulocytes of the TALH and convo-
Vezzoli et al.
luted tubule, and is therefore stimulated by plasma calcium
concentrations. Here, the higher serum calcium concentra-
tion stimulates CaSR to reduce the active (PMCA-
dependent) (Fig. 3) and passive (sodium-dependent) reab-
sorption of calcium, and the PTH-stimulated calcium reab-
sorption in the cortical TALH (Fig. 2) in an attempt to deal
with the calcium overload [50, 60]. These effects also seem
to protect the kidney against calcium salt precipitation in the
renal tissue. Such a putative framework makes it difficult,
however, to interpret the findings of spontaneous ectopic
calcifications in the kidney in Nuf mice [87].
The proposed speculative picture attributes CaSR a pro-
tective role against calcium overload and deposition in the
tissues, and specifically against nephrocalcinosis, kidney
stones and tubule obstruction. The CaSR-induced alterations
in kidney function become unsafe when the original stimulus
is a hypercalcemic state, since this causes sodium and water
wastage, dehydration, increased vascular tone, acute kidney
injury and failure, and chronic kidney disease. According to
this view, a decreased CaSR activity could be associated
with a declining ability to preserve tissues and kidney from
calcium overload and calcification. Recent findings suggest
that calcium kidney stone production is associated with po-
lymorphisms of the CaSR gene 5’-untranslated region [103],
the functional effect of which is still not known, but they
have been thought to reduce CaSR expression. A putative
role for CaSR in calcium stone disease was hypothesized
some years ago in the light of its potential for altering distal
tubular cell function in the inner medulla, predisposing to
calcium salt supersaturation and precipitation [104]. (Fig. 5).
Principal cells in the collecting duct may express CaSR when
cultured in a hypertonic environment, suggesting that the
particular hypertonic environment of the medulla might in-
duce CaSR expression [63].
Seeing CaSR as a defender against ectopic calcification
may appear restrictive by comparison with the key role at-
tributed in recent years to CaSR in calcium homeostasis.
This is not the case, however, if we consider that the human
body is constantly working to maintain calcium and phos-
phate stores in bone and, with aging, calcium and phosphate
are shifted from bones to soft tissues (and arterial vessels in
particular), exposing the body to the simultaneous onset of
osteoporosis, arterial calcification and cardiovascular mortal-
ity [105-107] Since mechanisms of calcification in bone and
soft tissues seem to be mediated by osteogenic cells, it has
been hypothesized that bone loss and arterial calcification
are not independent events, but are mediated by common
mechanisms [108-110]
Some studies have claimed an important role for CaSR in
sodium metabolism because calcium load affects sodium
handling in humans [111] and a high dietary calcium intake
was associated with a blood pressure drop in hypertensive
rats and men, and in the general population [112-114] In
keeping with these observations, some researchers have sug-
gested that CaSR significantly contributes to regulating so-
dium balance, predisposing to hypertension [109]. Such
theories have not been supported by clear and definitive ex-
perimental data, however, and current knowledge in this
field suggests that CaSR has little influence on sodium han-
dling.
Roles of Calcium-Sensing Receptor (CaSR) Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3 309

In the light of present knowledge, CaSR seems to us to [21] Smajilovic, S. and Tfelt-Hansen. (2007) Cardiovasc. Res., 75, 457-
be an important player in regulating renal calcium handling, 467.
[22] Ortiz-Capisano, M.C.; Ortiz, P.A. and Garvin, J.L. (2007) Hyper-
and calcium metabolism in general. Its activity enables tension, 50(4), 737-743.
plasma calcium concentrations to be controlled by regulating [23] Komlosi, P.; Fintha, A. and Bell, P.D. (2006) Kidney Int., 70, 865-
PTH secretion and kidney tubular calcium reabsorption. 871.
CaSR thus protects human tissues against calcium excess in [24] Antonipillai, I. and Horton, R. (1985) Endocrinology, 117, 601-
606.
extracellular fluids, but its protective effect in the kidney [25] Odenwald, T.; Nakagawa, K.; Hadtstein, C.; Roesch, F.; Gohlke,
also includes stimulating diuresis and phosphate retention, P.; Ritz, E.; Schaefer, F. and Schmitt, C.P. (2006) J. Am. Soc.
and potentially preventing calcium deposition. Consistently Nephrol., 17, 655-662.
with this protective renal effect, CaSR is expressed through- [26] Hofer, A.M.; Gerbino, A.; Caroppo, R. and Curci, S. (2004) Cell
out the nephron. Further research is needed to better under- Calcium, 35, 297-306.
[27] Riccardi, D.; Park, J.; Lee, W.S.; Gamba, G.; Brown, E.M. and
stand the relevance of CaSR to human physiological and Hebert, S.C. (1995) Proc. Natl. Acad. Sci. USA, 92, 131-135.
physiopathological processes, as it is expressed in a consid- [28] Yang, T., Hassan, S., Huang, Y.G., Smart, A.M., Briggs, J.P. and
erable number of human tissues. The effects of its activity on Schnermann, J.B. (1997) Am. J. Physiol., 272, F751-F758.
the cardiovascular system are now attracting the researchers’ [29] Ba, J. and Friedman, P.A. (2004) Cell Calcium, 34, 229-237.
[30] Walton, R.J. and Bijvoet, O.L.M. (1975) Lancet, 2, 309-10
attention and this might contribute some important informa- [31] Murer, H.; Forster, I. and Biber, J. (2000) Physiol. Rev., 80, 1373-
tion to help us understand how ion handling is regulated in 1409
the kidney. It will also be important to elucidate the func- [32] Forster, I.C.; Hernando, N.; Biber, J. and Murer, H. (2000) Kidney
tional effects of CaSR in the renal medullary hypertonic en- Int., 70, 1548-1559.
vironment, where the early events leading to kidney stones [33] Traebert, M.; Roth, J.; Biber, J.; Murer, H. and Kaissling, B. (2000)
Am. J. Physiol. Renal Physiol., 280, F148-F154.
and nephrocalcinosis may take place. [34] Miyamoto, K. and Itho, M. (2001) Kidney Int., 60, 412-415.
[35] The ADHR Consortium. (2000) Nature Genet., 26, 345-348.
REFERENCES [36] The HYP Consortium. (1995) Nature Genet., 11, 130-136.
[37] Shimada, T.; Mizutani, S.; Muto, T.; Yoneya, T.; Hino, R.; Takeda,
[1] Su, A.I.; Wiltshire, T.; Batalov, S.; Lapp, H.; Ching, K.A.; Block, S.; Takeuchi, Y.; Fujita, T.; Fukumoto, S. and Yamashita, T.
D.; Zhang, J.; Soden, R.; Hayakawa, M.; Kreiman, G.; Cooke, (2001) Proc. Natl. Acad. Sci. USA, 98, 6500-6505.
M.P.; Walker, J.R. and Hogenesch, J.B. (2004) Proc. Natl. Acad. [38] Quarles, L.D. (2003) Am. J. Physiol. Endocrinol. Metab., 285, E1-
Sci. USA, 101, 6062-6067. E9.
[2] Egbuna, O.I. and Brown, E.M. (2008) Best Pract. Res. Clin. Rheu- [39] Ba, J.; Brown, D. and Friedman, P.A. (2003) Am. J. Physiol. Renal
matol., 22, 129-148. Physiol., 285, F1233-F1243.
[3] Brown, E.M.; Gamba, G.; Riccardi, D.; Lombardi, M.; Butters, R.; [40] Mathias, R.S. and Brown, E.M. (1991) Endocrinology, 128, 3005-
Kifor, O.; Sun, A.; Hediger, M.A.; Lytton, J. and Hebert, S.C. 3012.
(1993) Nature, 366, 575-580. [41] Riccardi, D.; Traebert, M.; Ward, D.T.; Kaissling, B.; Biber, J.;
[4] Hofer, A.M. and Brown, E.M. (2003) Nature, 4, 530-538. Hebert, S.C. and Murer, H. (2000) Pflugers Arch., 441, 379-387.
[5] Kifor, O.; Diaz, R.; Butters, R. and Brown, E.M. (1997) J. Bone [42] Christakos, S.; Dhawan, P.; Liu, Y.; Peng, X. and Porta, A. (2003)
Miner. Res., 12, 715-725. J. Cell Biochem., 88, 695-705.
[6] Pi, M.; Spurney, R.F.; Tu, Q.; Hinson, T. and Quarles, L.D. (2002) [43] Bland, R.; Zehnder, D.; Hughes, S.V. and Molostvov, G. (2002) J.
Endocrinology, 143, 3830-3838. Am. Soc. Nephrol., 13, 28A.
[7] Dvorak, M.M.; Chen, T.H.; Orwoll, B.; Garvey, C.; Chang, W.; [44] Canaff, L. and Hendy, G.H. (2002) J. Biol. Chem., 277, 30337-
Bikle, D.D. and Shoback, D.M. (2007) Endocrinology, 148, 3156- 30350.
3163. [45] Maiti, A.; Hait, N.C. and Beckman, M.J. (2008) J. Biol. Chem.,
[8] Chattopadhyay, N.; Cheng, I.; Rogers, K.; Riccardi, D.; Hall, A.; 283, 175-183.
Diaz, R.; Hebert, S.C.; Soybel, D.I. and Brown, E.M. (1998) Am. J. [46] Molony, D.A.; Reeves, W.B. and Andreoli, T.E. (1989) Kidney
Physiol. Gastrointest. Liver Physiol., 274, G122-G130. Int., 36, 418-426.
[9] Yang, T.; Hassan, S.; Huang, Y.G.; Smart, A.M.; Briggs, J.P. and [47] Lorenz, J.N.; Baird, N.R.; Judd, L.M.; Noonan, W.T.; Andringa,
Schnermann, J.B. (1997) Am. J. Physiol., 272, F751-758. A.; Doetschman, T.; Manning, P.A.; Liu, L.H.; Miller, M.L. and
[10] Riccardi, D.; Hall, A.E.; Chattopadhyay, N.; Hu, J.Z.; Brown, E.M. Shull, G.E. (2002) J. Biol. Chem., 277, 37871-37880.
and Hebert, S.C. (1998) Am. J. Physiol. Renal Physiol., 43, F611- [48] Bettinelli, A.; Vezzoli, G.; Colussi, G.; Bianchetti, M.G.; Sereni, F.
F622 and Casari, G. (1998) J. Nephrol., 11, 61-69.
[11] Kwak, J.O.; Kwak, J.; Kim, H.W.; Oh, K.J.; Kim, Y.T.; Jung, S.M. [49] Fenton, R.A. and Knepper, M.A. (2007) Physiol. Rev., 87, 1083-
and Cha, S.H. (2005) Exp. Mol. Med., 37, 457-465. 1112.
[12] Stockand, J.D. and Sansom, S.C. (1998) Physiol. Rev., 78, 723- [50] Liou, H.H.; Zhou, S.S. and Huang, C.L. (2004) Proc. Natl. Acad.
744. Sci. USA, 96, 5820-5825.
[13] Latta, H. (1992) J. Am. Soc. Nephrol., 2(10 Suppl), S65-S73. [51] Handlogten, M.E.; Huang, C.; Shiraishi, N.; Awata, H. and Miller,
[14] Schlöndorff, D. (1996) Kidney Int., 49, 1583-1585. R.T. (2000) J. Biol. Chem., 276, 13941-13948.
[15] Deen, W.M.; Lazzara, M.J. and Myers, B.D. (2001) Am. J. Physiol. [52] Zheng ,W.Z.; Li, X.J.; Hilgemann, D.W. and Huang, C.L. (2003) J.
Renal Physiol., 281, F579-F596. Biol. Chem., 278, 16852-16856.
[16] Weston, A.H.; Absi, M.; Ward, D.T.; Ohanian, J.; Dodd, R.H.; [53] Yu, M.; Lopez, B.; Dos Santos, E.A.; Falck. J.R. and Roman, R.J.
Dauban, P.; Petrel, C.; Ruat, M. and Edwards, G. (2005) Circ. Res., (2007) Am. J. Physiol. Integr. Comp. Physiol., 292, R2400-R2405.
97, 391-398. [54] Gesek, F.A. and Friedman, P.A. (1992) J. Clin. Invest., 90, 749-
[17] Edwards, G.; Dora, K.A.; Gardener, M.J.; Garland, C.J. and Wes- 758.
ton, A.H. (1998) Nature, 396, 269-272. [55] Motoyama, H.I. and Friedman, P.A. (2002) Am. J. Physiol. Renal
[18] Ziegelstein, R.C.; Xiong, Y.; He, C. and Hu, Q. (2006) Biochem. Physiol., 283, F399-F406.
Biophys. Res. Commun., 342, 153-163 [56] De Jesus Ferreira, M.C. and Bailly, C. (1998) Am. J. Physiol., 275,
[19] Molostvov, G.; James, S.; Fletcher, S.; Bennett, J.; Lehnert, H.; F198-F203.
Bland, R. and Zehnder, D. (2007) Am. J. Physiol. Renal. Physiol., [57] Rouse, D. and Suki, W.N. (1990) Kidney Int., 38, 700-708.
293, F946-F955. [58] Friedman, P.A. and Gesek, F.A. (1995) Physiol. Rev., 75, 429-471.
[20] Odenwald, T.; Nakagawa, K.; Hadtstein, C.; Roesch, F.; Gohlke, [59] Peng, J.B.; Chen, X.Z. and Berger, U.V. (2000) J. Biol. Chem.,
P.; Ritz, E.; Schaefer, F. and Schmitt, C.P. (2006) J. Am. Soc. 275, 28186-28194.
Nephrol., 17, 655-662.
 310 Current Pharmaceutical Biotechnology, 2009, Vol. 10, No. 3
[60] Blankenship, K.A.; Williams, J.J.; Lawrence, M.S.; McLeish, K.R.;
Dean, W.L. and Arthur, J.M. (2001) Am. J. Physiol. Renal Physiol.,
280, F815-822.
[61] Huang, C.; Sindic, A.; Hill, C.E.; Hujer, K.M.; Chan, K.W.; Sas-
sen, M.; Wu, Z.; Kurachi, Y.; Nielsen, S.; Romero, M. and Miller,
R.T. (2007) Am. J. Physiol. Renal Physiol. 292, F1073-1081.
[62] Sands, J.M.; Naruse, M.; Baum, M.; Jo, I.; Hebert, S.C.; Brown,
E.M. and Harris, H.W. (1997) J. Clin. Invest., 99, 1399-1405.
[63] Bustamante, M.; Hasler, U.; Leroy, V.; deSeigneux, S.; Dimitrov,
M.; Mordasini, D.; Rousselot, M.; Martin, P.Y. and Ferraille, E.
(2008) J. Am. Soc. Nephrol., 19, 109-116.
[64] Nielsen, S.; Chou, C.L.; Marples, D.; Christensen, E.I.; Kishore,
B.K. and Knepper, M.A. (1995) Proc. Natl. Acad. Sci. USA, 92,
1013-1017.
[65] Levi, M.; Peterson, L. and Berl, T. (1983) Kidney Int., 23, 489-497.
[66] Chou, Y.H.; Brown, E.M.; Levi, T.; Crowe, G.; Atkinson, A.B.;
Arnqvist, H.J.; Toss, G.; Fuleihan, G.E.; Seidman, J.G. and Seid-
man, C.E. (1992) Nature Genet., 1, 295-300.
[67] Foley, T.P.; Harrison, H.C.; Arnaud, C.D. and Harrison, H.E.
(1972) J. Pediatr., 81, 1060-1067.
[68] Pollak, M.R.; Brown, E.M.; Chou, Y.H.; Hebert, S.C.; Marx, S.J.;
Steinmann, B.; Levi, T.; Seidman, C.E. and Seidman, J.G. (1993)
Cell, 75, 1297-1303.
[69] Nissen, P.H.; Christensen, S.E.; Heickendorff, L.; Brixen, K. and
Mosekilde, L. (2007) J. Clin. Endocrinol. Metab., 92, 4373-4379.
[70] Gunn, I.R. and Wallace, J.R. (1992) Ann. Clin. Biochem., 29, 52-
58.
[71] Auwerx, J.; Demedts, M. and Bouillon, R. (1984) Acta Endocri-
nol., 106, 215-218.
[72] Felderbauer, P.; Klein, W.; Bulut, K.; Ansorge, N.; Dekomien, G.;
Werner, I.; Epplen, J.T.; Schmitz, F. and Schmidt, W.E. (2006)
Scand. J. Gastroenterol., 41, 343-348.
[73] Marx, S.J.; Attie, M.F.; Stock, J.L.; Spiegel, A.M. and Levine,
M.A. (1981) J. Clin. Endocrinol. Metab., 52, 736-740.
[74] Lloyd, S.E.; Pannett, A.A.; Dixon, P.H.; Whyte, M.P. and Thakker,
R.V. (1999) Am. J. Hum. Genet., 64, 189-195.
[75] Pallais, J.C.; Kifor, O.; Chen, Y.B.; Slovik, D. and Brown, E.M.
(2004) N. Engl. J. Med., 351, 362-369.
[76] Makita, N.; Sato, J.; Manaka, K.; Shoji, Y.; Oishi, A.; Hashimoto,
M.; Fujita, T. and Iiri, T. (2007) Proc. Natl. Acad. Sci. USA, 104,
5443-5448.
[77] Gavalas, N.G.; Kemp, E.H.; Krohn, K.J.E.; Brown, E.M.; Watson,
P.F. and Weetman, A.P. (2007) J. Clin. Endocrinol. Metab., 92,
2107-2114.
[78] Festen-Spanjer, B.; Haring, C.M.; Koster, J.B. and Mudde, A.H.
(2007) Clin. Endocrinol., 68, 324-325.
[79] Pollak, M.R.; Chou, Y.-H.; Marx, S.J.; Steinmann, B.; Cole, D.E.;
Brandi, M.L.; Papapoulos, S.; Menko, F.; Hendy, G.E.; Brown,
E.M.; Seidman, C.E. and Seidman, J.G. (1994) J. Clin. Invest., 93,
1108-1112.
[80] Pidasheva, S.; D'Souza-Li, L.; Canaff, L.; Cole, D.E. and Hendy,
G.N. (2004) Hum. Mutat., 24, 107-111.
[81] Pearce, S.H. and Steinmann, B. (1999) Clin. Endocrinol., 50, 691-
693.
[82] Marx, S.J.; Lasker, R.D.; Brown, E.M.; Fitzpatrick, L.A.; Sweezey,
N.B.; Goldbloom, R.B.; Gillis, D.A. and Cole, D.E. (1986) J. Clin.
Endocrinol. Metab., 62, 445-449.
[83] Waller, S.; Kurzawinski, T.; Spitz, L.; Thakker, R.V.; Cranston, T.;
Pearce, S.H.; Cheetham, T. and van’t Hov, W.G. (2004) Eur. J.
Pediatr., 163, 589-594.
[84] Kifor, O.; McElduff, A.; Leboff, M.; Moore, F.; Butters, R.; Gao,
P.; Cantor, T.L.; Kifor, I. and Brown, E.M. (2004) J. Clin. Endo-
crinol. Metab., 89, 548-556.
[85] Goswami, R.; Brown, E.M.; Kochupillai, N.; Gupta, N.; Rani, R.;
Kifor, O. and Chattopadhyay, N. (2004) Eur. J. Endocrinol., 150,
9-18.
[86] Pollak, M.R.; Brown, E.M.; Estep, H.L.; McLaine, P.N.; Kifor, O.;
Park, J.; Hebert, S.C.; Seidman, C.E. and Seidman, J.G. (1994) Na-
t. Genet., 8, 303-307.
Received: August 18, 2008 Revised: August 20, 2008 Accepted: August 25, 2008
View publication stats
Vezzoli et al.
[87] Hough, T.A.; Bogani, D.; Cheeseman, M.T.; Favor, J.; Nesbit,
M.A.; Thakker, R.V. and Lyon, M.F. (2004) Proc. Natl. Acad. Sci.
USA, 101,13566-13571.
[88] Mittelman, S.D.; Hendy, G.N.; Fefferman, R.A.; Canaff, L.;
Mosesova, I.; Cole, D.E.C.; Burkett, L. and Geffner, M.E. (2006) J.
Clin. Endocrin. Metab., 91, 2474-2479.
[89] Carling, T.; Szabo, E.; Bai, M.; Ridefelt, P.; Westin, G.; Gustavs-
sonì, P.; Trivedi, S.; Hellman, P.; Brown, E.M.; Dahl, N. and
Rastad, J. (2000) J. Clin. Endocrinol. Metab., 85, 2042-2047.
[90] Hebert, S.C. (2003) Curr. Opin. Nephrol. Hypertens., 12, 527-432.
[91] Watanabe, S.; Fukumoto, S.; Chang, H.; Takeuchi, Y.; Hasegawa,
Y.; Okazaki, R.; Chikatsu, N. and Fujita, T. (2002) Lancet, 360,
692-694.
[92] Vargas-Poussou, R.; Huang, C.; Hulin, P.; Houillier, P.; Jeunemi-
tre, X.; Paillard, M.; Planelles, G.; DeChaux, M.; Miller, R.T. and
Antignac, C. (2002) J. Am. Soc. Nephrol., 13, 2259-2266.
[93] Vezzoli, G.; Arcidiacono, T.; Vera, P.V.; Terranegra, A.; Biasion,
R.; Weber, G.; Mora, S.; Syren, M.L.; Coviello, D.; Cusi, D.; Bian-
chi, G. and Soldati, L. (2006) J. Nephrol., 19, 525-528.
[94] Vezzoli, G.; Soldati, L. and Gambaro, G. (2008) J. Urol., 179,
1676-1682
[95] Vezzoli, G.; Soldati, L.; Arcidiacono, T.; Terranegra, A.; Biasion,
R.; Russo, C.R.; Lauretani, F.; Bandinelli, S.; Bartali, B.; Cherubi-
ni, A.; Cusi, D. and Ferrucci, L. (2005) Kidney Int., 67, 2006-2014.
[96] Vezzoli, G.; Terranegra, A.; Arcidiacono, T.; Biasion, R.; Coviello,
D.; Syren, M.L.; Paloschi, V.; Giannini, S.; Mignogna, G.; Rubi-
nacci, A.; Ferraretto, A.; Cusi, D.; Bianchi, G. and Soldati, L.
(2007) Kidney Int., 71, 1155-1162.
[97] Yano, S.; Sugimoto, T.; Kanzawa, M.; Tsukamoto, T.; Hattori, T.;
Hattori, S. and Chihara, K. (2000) Nephron, 85, 317-323.
[98] Yokoyama, K.; Shigematsu, T.; Tsukada, T.; Hara, S.; Yamada, A.;
Kawaguchi, Y. and Hosoya, T. (2002) Clin. Nephrol., 57, 131-135.
[99] Scillitani, A.; Guarnieri, V.; De Geronimo, S.; Muscarella, L.A.;
Battista, C.; D’Agruma, L.; Bertoldo, F.; Florio, C.; Minisola, S.;
Hendy, G.N. and Cole, D.E.C. (2004) J. Clin. Endocrinol. Metab.,
89, 5634-5638.
[100] Yamauchi, M.; Sugimoto, T.; Yamaguchi, T.; Yano, S.; Kanzawa,
M.; Kobayashi, A. and Chihara, K. (2001) Clin. Endocrinol., 55,
373-379.
[101] Brown, E.M. and MacLeod, R.J. (2001) Physiol. Rev., 81, 239-297.
[102] Chang, W. and Shoback, D. (2004) Cell Calcium, 35, 183-196.
[103] Terranegra, A.; Arcidiacono, T.; Biasion, R.; Paloschi, V.; Borghi,
L.; Brandi, M.L.; Croppi, E.; Caudarella, R.; Tanini, A.; Gambaro,
G.; Mossetti, G.; Strazzullo, P.; Trinchieri, A.; Cusi, D.; Soldati, L.
and Vezzoli, G. (2006) Nephrol. Dial. Transplant., 21(suppl 4),
292.
[104] Bushinsky, D.A. (2003) J. Clin. Invest., 111, 602-605.
[105] Kiel, D.P.; Kauppila, L.I.; Cupples, L.A.; Hannan, M.T.;
O’Donnell, C.J. and Wilson, P.W.F. (2004) Calcif. Tissue Int., 68,
271-276.
[106] Hasserius, R.; Karlsson, M.K.; Jónsson, B.; Redlund-Johnell, I. and
Johnell, O. (2005) Calcif. Tissue Int., 76, 235-242.
[107] Tankó, L.B.; Christiansen, C.; Cox, D.A.; Geiger, M.J.; McNabb,
M.A. and Cummings, S.R. (2005) J. Bone Miner. Res., 20, 1912-
1920.
[108] Vattikuti, R. and Towler, D.A. (2004) Am. J. Physiol. Endocrinol.
Metab., 286, E686-E896.
[109] Shanahan, C.M.; Cary, N.R.; Salisbury, J.R.; Proudfoot, D.; Weiss-
berg, P.L. and Edmonds, M.E. (1999) Circulation, 100, 2168-2176.
[110] Doherty, T.M.; Fitzpatrick, L.A.; Inoue, D.; Qiao, J.H.; Fishbein,
M.C.; Detrano, R.C.; Shah, P.K. and Rajavashisth, T.B. (2004) En-
docr. Rev., 25, 629-672.
[111] Huang, C. and Miller, R.T. (2007) Curr. Opin. Nephrol. Hyper-
tens., 16, 437-443.
[112] McCarron, D.A.; Morris, C.D. and Cole, C. (1982) Science, 217,
267-269.
[113] Svetkey, L.P.; Simons-Morton, D.; Vollmer, W.M.; Appel, L.J.;
Conlin, P.R.; Ryan, D.H.; Ard, J. and Kennedy, B.M. For the
DASH Research Group. (1999) Arch. Intern. Med., 159, 285-293.
[114] Ayachi, S. (1979) Metabolism, 28, 1234-1238.