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Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 10, Number 3, April 2009
Contents
The Calcium-Sensing Receptor: Pathophysiology and
Pharmacological Modulation
Guest Editor: Ubaldo Armato
Editorial Pp. 268-269
Ubaldo Armato
[PMID:
19355936 PubMed - indexed for MEDLINE]
Regulation of Cellular Signal Transduction
Pathways by the Extracellular Calcium-Sensing Receptor Pp.
270-281
Sarah C. Brennan and Arthur D. Conigrave
[Abstract] [Purchase
Article] [PMID:
19355937 PubMed - indexed for MEDLINE]
Expression and Role of the Calcium-Sensing
Receptor in the Blood Vessel Wall Pp. 282-288
Guerman Molostvov, Rosemary Bland and
Daniel Zehnder
[Abstract] [Purchase
Article] [PMID:
19355938 PubMed - indexed for MEDLINE]
The Role of the Calcium-Sensing Receptor
in Bone Biology and Pathophysiology Pp.
289-301
Todd A. Theman and Michael T. Collins
[Abstract] [Purchase
Article] [PMID:
19355939 PubMed - indexed for MEDLINE]
Roles of Calcium-Sensing Receptor (CaSR)
in Renal Mineral Ion Transport Pp. 302-310
Giuseppe Vezzoli, Laura Soldati and
Giovanni Gambaro
[Abstract] [Purchase
Article] [PMID:
19355940 PubMed - indexed for MEDLINE]
The Calcium-Sensing Receptor - A Driver
of Colon Cell Differentiation Pp. 311-316
James F. Whitfield
[Abstract] [Purchase
Article] [PMID:
19355941 PubMed - indexed for MEDLINE]
Calcium-Sensing Receptor (CaSR) in Human
Brain’s Pathophysiology: Roles in Late-Onset Alzheimer’s
Disease (LOAD) Pp. 317-326
Anna Chiarini, Ilaria Dal Pra, Maddalena
Marconi, Balu Chakravarthy, James F. Whitfield and
Ubaldo Armato
[Abstract] [Purchase
Article] [PMID:
19355942 PubMed - indexed for MEDLINE]
General Articles
Umbilical Cord Stem Cell: An Overview
Pp. 327-334
S. Ruhil, V. Kumar and P. Rathee
[Abstract] [Purchase
Article] [PMID:
19355943 PubMed - indexed for MEDLINE]
Multiple Myeloma Bone Marrow Niche
Pp. 335-346
Grzegorz Wladyslaw Basak, Anand S. Srivastava,
Rakesh Malhotra and Ewa Carrier
[Abstract] [Purchase
Article] [PMID:
19355944 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [PMID:
19355936 PubMed - indexed for MEDLINE]
Editorial: The Calcium-Sensing Receptor: Pathophysiology
and Pharmacological Modulation
Being one of the most abundant cations in nature, calcium
plays crucial roles both outside and inside the cells as a
signaling ion. Changes in the extracellular free calcium concentration
[Ca2+o]
activate the plasmalemmal calcium-sensing receptor (CaSR or
CaR), a sevenfold transmembrane spanning protein encoded by
genes mapped in human chromosome 3 (and also 19). The CaSR
is activated by various ligands, such as divalent and polyvalent
cations, aromatic L-amino acids, aminoglycosides, spermine,
and amyloid β
(Aβ)peptides.
A member of family C (or III) of G-protein coupled receptors
(GPCRs), acting in the form of a disulfide-linked homodimer,
the CaSR signals through both heterotrimeric and monomeric
G-proteins, thereby inhibiting adenylate cyclase activity,
but increasing the production of diacylglycerol (DAG) and
inosiltol-1,4,5-triphosphate (IP3),
mobilizing intracellular calcium, activating diverse protein
kinases (PKB, PKCs, MAPKs), phospholipases (A2,
C, D) and cyclooxygenase-2 (COX-2), and transactivating the
EGF receptor (EGFR). CaSR signaling controls mineral ion homeostasis
via parathyroid hormone (PTH) and calcitonin (CT) secretion
and, in addition, modulates a variety of vital processes including
chemotaxis, cell proliferation, differentiation, and malignant
transformation, membrane excitability, cell survival, and
programmed death (apoptosis). Notably, the expression of CaSR
mRNA is widespread, occurring not only in the thyroid and
the parathyroid glands (where it was first discovered), but
even in kidney, bone, cardiovascular system, liver, gastrointestinal
tract, and central nervous system (CNS). This broad expression
implies multiple relevant functional roles for the CaSR in
the same tissues and organs, the elucidation of which is still
ongoing, being somewhat hampered by the facts that (i)
not all of the CaSR-expressing cell types (e.g. in the CNS)
have hitherto been identified with certainty, and (ii)
in each cell-type considered the CaSR-evoked responses to
[Ca2+o]
changes exhibit a discrete degree of specificity. It goes
without saying that, given this background, in pathologic
conditions the CaSR also plays relevant roles, most of which
however wait to be clarified. Besides hereditary conditions
due to loss-of-function or gain-of-function mutations and
polymorphisms of the CaSR, several pathophysiological conditions
associated with local and/or general reductions in the [Ca2+o],
oxidative stress and/or extracellular acidification appear
to elicit significant changes in CaSR signaling. Therefore,
a panoply of agents targeting the CaSR, both calcimimetics
(or calcium agonists) and calcilytics (or calcium antagonists),
is being developed and tested in specific clinical settings.
Accordingly, the CaSR has now fittingly become an exciting
topic of the impetuously growing Translational Medicine. This
has led to the proposal of collecting in the present issue
the reviews from several research groups with the aim of bringing
up to date, from different viewpoints, novel facets of the
several CaSR roles and the known or possible benefits of the
CaSR-targeting drugs concerning the pathophysiology of the
the cardiovascular system, bone, kidney, colon, and CNS.
The first review of this series, contributed by Drs. Brennan
and Conigrave, enlightens the quite intricate CaSR’s
signaling cascades, which change membrane lipids metabolism,
several protein kinases’ activities and their substrates’
phosphorylation, and intracellular cAMP, calcium ions and
fatty acids levels via G-proteins’ activations. Thus,
consistent with its expression site(s) and local signaling
pathways, CaSR responses to changes in [Ca2+o]
modulate vital cell activities including, amongst others,
peptide hormone secretion, vitamin D metabolism, and ion and
water transport. This updated information also underscores
the need of further studies to better clarify the intricate
yet enticing CaSR signaling mechanisms.
Most remarkably, CaSR is intensely expressed by all the cells
of the cardiovascular system. It regulates vascular myogenic
tone (hence, resistance of peripheral vessels) possibly via
the production of nitric oxide (NO). Although solid ties link
calcium, CaSR, and cardiovascular ailments like atherosclerosis,
arteriosclerosis, hypertension, and ischemia/reperfusion injury,
the specific role(s) played by this receptor has(ve) not as
yet been fully clarified. The review from Dr. Zehnder et
al. offer the latest viewpoints about the physiologic
and pathologic roles the CaSR plays in the myocardium, endothelial
cells, vascular smooth muscle cells, and perivascular nerves.
The prospects that the activity of myocardial and vascular
CaSRs be pharmacologically targeted are thoroughly discussed.
The latest views about other potential calcium-responding
receptors are also offered.
Chondrocytes, osteoblasts, and osteoclasts functionally respond
to changes in [Ca2+o]
just as do parathyroid chief cells, the PTH secretion of which
is CaSR-mediated. Yet, it is still unsettled whether local
CaSR expression is of any functional consequence in bone because
of the concurrent involvement of manifold endocrine loops
and of local factors (e.g. PTHrP). This complex topic is rendered
readily understandable in the review by Drs. Collins and Theman,
in which the significant animal models and the specific CaSR
roles in chondrogenesis, skeletogenesis, osteoclastogenesis,
and bone remodeling and mineralization are discussed. In addition,
human conditions elicited by gain-of-function or loss-of-function
mutations of the CaSR are examined. Moreover, emerging fields
in which the CaSR is possibly involved, like PTH-independent
serum calcium homeostasis, hematopoietic stem cell homing,
engraftment, and niche formation in mineralized bone, and
skeletal metastatization from breast and prostate cancers,
as well as the effects of CaSR-targeting drugs are also lucidly
analyzed.
The multifaceted roles played by the CaSR in the kidneys are
analyzed by Dr. Gambaro and Coworkers. Notably, all nephron
segments, excepting normal intact glomeruli, express the CaSR,
which is a telltale sign of the breadth and bewildering intricacy
of CaSR’s activities impacting on renal physiology and
pathophysiology. Moreover, a peek is given to the triggering
of modifications in renal excretory functions by mutations
and polymorphisms of the CaSR. Finally, the involvement of
the CaSR in the adverse effects of acute renal hypercalcemia
is considered. The authors reach the important conclusion
that the CaSR may defend human tissues from harmful increases
in the [Ca2+o].
Dietary Ca2+-activated CaSR
signalling controls the induction of proliferative quiescence
and terminal differentiation in normal colon cells while moving
along the upper half of the crypts and reaching the mucosal
surface. Conversely, dietary Ca2+
can promote the premalignant and malignant progression of
mutant, apoptosis-resistant colon cells lacking functional
CaSRs. The review by Dr. Whitfield analyzes in detail and
cogently discusses the intricate molecular mechanisms underlying
these two dramatically divergent endpoints of colon cells
development, i.e. physiological apoptosis vs. cancer. Moreover,
he surmises that the differentiation of normal CaSR-expressing
colon cells should be enhanced by the calcimimetics but hindered
by the calcilytics, a hypothesis worth testing.
Finally, Dr. Chiarini and Coworkers go over the present knowledge
about CaSR’s roles in human CNS pathophysiology–roles
hitherto mostly unidentified despite the widespread expression
of the CaSR by probably all types of nerve cells and in all
places of the CNS. The review focuses on the development of
the sporadic late-onset Alzheimer’s disease (LOAD).
CaSR-binding soluble Aβ-(1-42)
(sAβ42)
oligomers, which are incessantly released from the functioning
synapses-yet no longer effectively removed in the aging brain–accumulate
and target both neurons, which lose synapses becoming functionally
impaired (undead), and microglia that release proinflammatory
cytokines. In turn, the latter induce astrocytes to produce
huge amounts of NO–a process effectively prevented by
the calcilytic agent NPS 89636 in normal adult human astrocytes
cultured in vitro. The subsequent fibrillization
of the amassing sAβ42
oligomers results in further LOAD progression and death of
both normal and undead neurons.
PROF. DR. UBALDO ARMATO, MD
Guest Editor
Head, Histology &
Embryology Unit
Department of Biomedical &
Surgical Sciences
University of Verona Medical School
Verona, I-37134
Italy
[Back to top]
[Purchase Article] [PMID:
19355937 PubMed - indexed for MEDLINE]
Regulation of Cellular Signal Transduction Pathways
by the Extracellular Calcium-Sensing Receptor
Sarah C. Brennan and Arthur D. Conigrave
The extracellular calcium-sensing receptor (CaR) is a
class III G-protein coupled receptor that coordinates cellular
responses to changes in extracellular free Ca2+
or amino acid concentrations as well as ionic strength and
pH. It regulates signalling cascades via recruiting and controlling
the activities of various heterotrimeric G-proteins, including
Gq/11, Gi/0,
and G12/13, even Gs
in some “unusual” circumstances, thereby inducing
changes in the metabolism of membrane lipids, the phosphorylation
state of protein kinases and their targets, the activation
state of monomeric G-proteins and the levels of intracellular
second messengers including cAMP, Ca2+
ions, fatty acids and other small molecules. According to
its site(s) of expression and available signalling pathways,
the CaR modulates cell proliferation and survival, differentiation,
peptide hormone secretion, ion and water transport and various
other processes. In this article we consider the complex intracellular
mechanisms by which the CaR elicits its cellular functions.
We also consider some of the better understood CaR-regulated
cell functions and the nature of the signalling mechanisms
that support them.
[Back to top]
[Purchase Article] [PMID:
19355938 PubMed - indexed for MEDLINE]
Expression and Role of the Calcium-Sensing Receptor in the
Blood Vessel Wall
Guerman Molostvov, Rosemary Bland and
Daniel Zehnder
The calcium-sensing receptor (CaSR), which is involved
in systemic calcium homeostasis, has also been found to be
functionally expressed on cells of the vascular wall. Its
activation on perivascular nerves and endothelial cells has
been shown to regulate arterial tone, peripheral vascular
resistance and possibly local tissue perfusion. The expression
of the CaSR on immune cells involved in vascular inflammation,
such as macrophages, and its increased expression in inflammation
indicates the central role extracellular calcium plays in
vascular inflammation and repair. Further detailed analysis
will clarify the role the vascular CaSR plays as a therapeutic
target for complex disease conditions such as hypertension,
tissue hypoperfusion, atherosclerosis and vascular calcification.
[Back to top] [Purchase
Article] [PMID:
19355939 PubMed - indexed for MEDLINE]
The Role of the Calcium-Sensing Receptor in Bone Biology and
Pathophysiology
Todd A. Theman and Michael T. Collins
Bone cells, particularly osteoblasts and osteoclasts,
exhibit functional responses to calcium (Ca2+).
The identification of the calcium-sensing receptor (CaR) in
parathyroid glands as the master regulator of parathyroid
hormone (PTH) secretion proved that cells could specifically
respond to changes in divalent cation concentration. Yet,
after many years of study, it remains unclear whether this
receptor, which has also been identified in bone, has functional
import there. Various knockout and transgenic mouse models
have been developed, but conclusions about skeletal phenotypes
remain elusive. Complex endocrine feedback loops involving
calcium, phosphorus, vitamin D, and PTH confound efforts to
isolate the effects of a single mineral, hormone, or receptor
and most models fail to account for other local factors such
as parathyroid hormone related protein (PTHrP). We review
the relevant mouse models and discuss the importance of CaR
in chondro-genesis and osteogenesis. We present the evidence
for a non-redundant role for CaR in skeletal mineralization,
including our experience in patients with activating CaR mutations.
Additionally, we review emerging research on the importance
of the CaR to the regulation of serum calcium homeostasis
independent of PTH, the role of the CaR in the hematopoietic
stem cell niche with implications for bone marrow transplant,
and early evidence that implies a role for the CaR as a factor
in skeletal metastasis from breast and prostate cancer. We
conclude with a discussion of drugs that target the CaR directly
either as agonists (calcimimetics) or antagonists (calcilytics),
and the consequences for bone physiology and pathology.
[Back to top]
[Purchase Article] [PMID:
19355940 PubMed - indexed for MEDLINE]
Roles of Calcium-Sensing Receptor (CaSR) in Renal Mineral
Ion Transport
Giuseppe Vezzoli, Laura Soldati and
Giovanni Gambaro
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 extracellular
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, potassium,
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 renal 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.
[Back to top]
[Purchase Article] [PMID:
19355941 PubMed - indexed for MEDLINE]
The Calcium-Sensing Receptor - A Driver of Colon Cell Differentiation
James F. Whitfield
Dietary Ca2+
reduces colon cell proliferation and carcinogenesis,
but it becomes ineffective or even tumorpromoting during carcinogenesis.
It appears that Ca2+ and
the colon cell CaSR together brake the massive cell production
in normal colon crypts. The rapid proliferation of the transit-amplifying
(TA) progeny of the colon stem cells at the bases of the crypts
is driven by the “Wnt” signaling mechanism that
stimulates proliferogenic genes and prevents apoptogenesis.
It appears that TA cell cycling stops and terminal differentiation
starts when the cells reach a higher level in the crypt where
there is enough external Ca2+
to stimulate the expression of CaSRs, the signals from which
stimulate the expression of E-cadherin. At this point the
APC (adenomatous polyposis coli) protein appears and some
of it enters the nucleus. There it removes the apoptogenesis
shield and stops the β-catenin•Tcf-4
complex from driving further TA cell proliferation by releasing
β-catenin
from the nucleus, and delivering it to cytoplasmic APC•axin•GSK-3β
complexes for ultimate proteasomal destruction. Cytoplasmic
β-catenin
is prevented from returning to the nucleus by destruction
in APC•axin•GSK-3β
complexes or locked by the emerging E-cadherin into adherens
junctions which link the cell to proliferatively shut-down
functioning cells with APC-dependent cytoskeletons moving
up and out of the crypt. A common first step in colon carcinogenesis
is the loss of functional APC which results in the retention
of proliferogenic nuclear β-catenin•Tcf-4.
This drives the eventual appearance of mutation accumulating,
apoptosis-resistant clones the proliferation of which cannot
be inhibited by external Ca2+
because of CaSR-disabling gene mutations.
[Back to top]
[Purchase Article] [PMID:
19355942 PubMed - indexed for MEDLINE]
Calcium-Sensing Receptor (CaSR) in Human Brain’s Pathophysiology:
Roles in Late-Onset Alzheimer’s Disease (LOAD)
Anna Chiarini, Ilaria Dal Pra, Maddalena
Marconi, Balu Chakravarthy, James F. Whitfield and
Ubaldo Armato
Although the calcium-sensing receptor (CaSR) is expressed
by all types of nerve cells in widespread areas of the human
central nervous system (CNS), so far its roles in brain pathophysiology
remain largely unknown. Here, we review the available evidence
concerning the stages of development of sporadic late-onset
Alzheimer’s disease (LOAD) and the roles therein played
by CaSR signaling. As the brain ages, its ability to dispose
of dangerous synapse-targeting soluble amyloid β-(1-42)
(sAβ42)
oligomers released from normal neuronal activity declines.
As their levels slowly rise, these oligomers increasingly
target and eliminate synapses and prevent synapse formation,
thereby eroding the foundations of memory formation and cognitive
functions. In this initial stage, neurons, even though synaptically
impaired, remain alive. Concurrently, sAβ42
oligomers by binding to CaSR on human astrocytes induce via
mitogen activated protein kinase (MAPK) activity the release
of huge amounts nitric oxide (NO), which by itself and after
conversion to peroxynitrite (ONOO-) damages neighboring neurons.
When the sAβ42
oligomers increasingly aggregate into fibrillar plaques, they
attract and activate microglial macrophages that, while trying
to clear the plaques, produce via Aβ-activated
CaSR signaling several proinflammatory cytokines and reactive
oxygen species (ROS). Notably, the microglial cytokines, like
sAβ42
oligomers, induce human astrocytes to make large amounts of
NO and hence ONOO- via CaSR signal-dependent MAPK activity.
The microglial cytokines-activated astrocytes might also produce
their own sAβ42,
which would combine with neuron- and microglia-released sAβ42
to increase the fibrillar burden and promote the further production
of reactive oxygen species (ROS), NO/ONOO-, and
proinflammatory cytokines to efficiently kill both normal
and functionally impaired (undead) neurons. But, on a somewhat
positive note, we speculate that the astrocytes’ CaSR-stimulated
MAPK activities might also induce vascular endothelial growth
factor (VEGF) expression and production. This might in turn
enhance neuronal stem cells neurogenesis at least in the subgranular
zone (SGZ) of the hippocampal dentate gyrus.
[Back to top]
[Purchase Article] [PMID:
19355943 PubMed - indexed for MEDLINE]
Umbilical Cord Stem Cell: An Overview
S. Ruhil, V. Kumar and P. Rathee
In recent years, human umbilical cord blood (HUCB) has
emerged as an attractive tool for cell-based therapy. Although
at present the clinical application of human umbilical cord
blood is limited to the fields of hematology and oncology,
a rising number of studies show potential for further application
in the treatment of non-hematopoietic diseases. Stem cells
(SC) from umbilical cord blood (UCB) are now a new reliable
alternative to treat different blood diseases, if the samples
are frozen at the moment of birth. This procedure is an easy
and safe way to preserve genetic materials for future therapeutic
uses. It can be used as alternative to bone marrow. Human
umbilical cord blood, with its real abundance, simple collection
procedure and no serious ethical dilemmas, represents a valuable
alternative to the use of other stem cell sources. The aim
of this article is to review the literature on human umbilical
cord blood (HUCB) and to assess its eventual usability in
the treatment of diseases.
[Back to top]
[Purchase Article] [PMID:
19355944 PubMed - indexed for MEDLINE]
Multiple Myeloma Bone Marrow Niche
Grzegorz Wladyslaw Basak, Anand S. Srivastava,
Rakesh Malhotra and Ewa Carrier
"Niche" is defined as a specialized regulatory
microenvironment, consisting of components which control the
fate specification of stem and progenitor cells, as well as
maintaining their development by supplying the requisite factors.
Bone marrow (BM) niche has a well-organized architecture and
is composed of osteoblasts, osteoclasts, bone marrow endothelial
cells, stromal cells, adipocytes and extracellular matrix
proteins (ECM). These elements play an essential role in the
survival, growth and differentiation of diverse lineages of
blood cells, but also provide optimal growth environment for
multiple hematological malignancies including multiple myeloma
(MM). MM is a neoplastic plasma cell disorder which not only
resides in BM but also converts it into specialized neoplastic
niche. This niche aids the growth and spreading of tumor cells
by a complex interplay of cytokines, chemokines, proteolytic
enzymes and adhesion molecules. Moreover, the MM BM microenvironment
was shown to confer survival and chemoresistance of MM cells
to current therapies. However, our knowledge in this field
is still in infancy and many details are unknown. Therefore,
there is a strong need to further dissect the MM BM niche
and understand the process of how the complex interactions
with BM milieu influence MM growth, survival and development
of resistance to chemotherapy. A better and more detailed
understanding of neoplastic MM niche will provide a guiding
model for identifying and validating novel targeted therapies
directed against MM. Therefore, in the present review, we
have focused principally on the basic features, physical structures,
and functions of the BM niche and have highlighted its interaction
with MM cells.
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