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Physiological Reviews, Vol. 81, No. 1, January 2001, pp. 239-297
Copyright ©2001 by the American Physiological Society
Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Brown, Edward M. and
R. John MacLeod.
Extracellular Calcium Sensing and Extracellular Calcium
Signaling. Physiol. Rev. 81: 239-297, 2001.
The cloning of a G protein-coupled extracellular
Ca2+ (Cao2+)-sensing receptor (CaR) has
elucidated the molecular basis for many of the previously recognized
effects of Cao2+ on tissues that maintain systemic
Cao2+ homeostasis, especially parathyroid chief cells
and several cells in the kidney. The availability of the cloned CaR
enabled the development of DNA and antibody probes for identifying the
CaR's mRNA and protein, respectively, within these and other tissues. It also permitted the identification of human diseases resulting from
inactivating or activating mutations of the CaR gene and the subsequent
generation of mice with targeted disruption of the CaR gene. The
characteristic alterations in parathyroid and renal function in these
patients and in the mice with "knockout" of the CaR gene have
provided valuable information on the CaR's physiological roles in
these tissues participating in mineral ion homeostasis. Nevertheless,
relatively little is known about how the CaR regulates other tissues
involved in systemic Cao2+ homeostasis, particularly
bone and intestine. Moreover, there is evidence that additional
Cao2+ sensors may exist in bone cells that mediate some
or even all of the known effects of Cao2+ on these
cells. Even more remains to be learned about the CaR's function in the
rapidly growing list of cells that express it but are uninvolved in
systemic Cao2+ metabolism. Available data suggest that
the receptor serves numerous roles outside of systemic mineral ion
homeostasis, ranging from the regulation of hormonal secretion and the
activities of various ion channels to the longer term control of gene
expression, programmed cell death (apoptosis), and cellular
proliferation. In some cases, the CaR on these "nonhomeostatic"
cells responds to local changes in Cao2+ taking place
within compartments of the extracellular fluid (ECF) that communicate
with the outside environment (e.g., the gastrointestinal tract). In
others, localized changes in Cao2+ within the ECF can
originate from several mechanisms, including fluxes of calcium ions
into or out of cellular or extracellular stores or across epithelium
that absorb or secrete Ca2+. In any event, the CaR and
other receptors/sensors for Cao2+ and probably for
other extracellular ions represent versatile regulators of numerous
cellular functions and may serve as important therapeutic targets.
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