Association between activating mutations of calcium-sensing receptor and Bartter's syndrome

Watanabe, Shigekazu; Fukumoto, Seiji; Chang, Hangil; Takeuchi, Yasuhiro; Hasegawa, Yukihiro; Okazaki, Ryo; Chikatsu, Noriko; Fujita, Toshiro

doi:10.1016/s0140-6736(02)09842-2

Cited by 363 publications

(221 citation statements)

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“…Hypercalcemia is well established as a cause of renal salt wasting, but the fact that it is receptor-mediated was not fully appreciated until the demonstration that activating mutations in the CaR lead to a Bartter-like salt-wasting syndrome (11,12). The generally accepted mechanism by which the CaR reduces distal nephron NaCl reabsorption is inhibition of the activity of transporters in the TAL such as NKCC2 and ROMK by CaR-regulated second messengers including arachidonic acid metabolites, Ca 2ϩ i , and cAMP (13,25).…”

Section: Discussionmentioning

confidence: 99%

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Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Kuy

Huang

Ding³

et al. 2011

Journal of Biological Chemistry

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The Ca 2؉ -sensing receptor (CaR) regulates salt and water transport in the kidney as demonstrated by the association of gain of function CaR mutations with a Bartter syndrome-like, salt-wasting phenotype, but the precise mechanism for this effect is not fully established. We found previously that the CaR interacts with and inactivates an inwardly rectifying K ؉ channel, Kir4.1, which is expressed in the distal nephron that contributes to the basolateral K ؉ conductance, and in which loss of function mutations are associated with a complex phenotype that includes renal salt wasting. We now find that CaR inactivates Kir4.1 by reducing its cell surface expression. Mutant CaRs reduced Kir4.1 cell surface expression and current density in HEK-293 cells in proportion to their signaling activity. Mutant, activated G␣ q reduced cell surface expression and current density of Kir4.1, and these effects were blocked by RGS4, a protein that blocks signaling via G␣ i and G␣ q . Other ␣ subunits had insignificant effects. Knockdown of caveolin-1 blocked the effect of G␣ q on Kir4.1, whereas knockdown of the clathrin heavy chain had no effect. CaR had no comparable effect on the renal outer medullary K ؉ channel, an apical membrane distal nephron K ؉ channel that is internalized by clathrin-coated vesicles. Co-immunoprecipitation studies showed that the CaR and Kir4.1 physically associate with caveolin-1 in HEK cells and in kidney extracts. Thus, the CaR decreases cell surface expression of Kir4.1 channels via a mechanism that involves G␣ q and caveolin. These results provide a novel molecular basis for the inhibition of renal NaCl transport by the CaR.Sodium transport in the distal nephron determines body volume and blood pressure as demonstrated by the fact that mutations in genes expressed in this region of the kidney can cause either salt retention and high blood pressure or salt wasting and low blood pressure (1). A number of genetically distinct syndromes caused by abnormalities of transport proteins expressed in the distal nephron lead to phenotypes characterized by salt wasting. Bartter syndrome can result from loss of function mutations of the NaK 2 Cl co-transporter (NKCC2), 2 the renal outer medullary K ϩ channel (ROMK or Kir1.1), or the ClC-Kb (basolateral Cl Ϫ channel). A variant also characterized by sensorineural deafness is caused by loss of function mutations in an accessory protein for ClC-Kb, barttin (Bartter syndrome neuraosensory deafness or BSND) (1-5). The hypocalciuric, hypomagnesemic variant of Bartter syndrome, Gitelman syndrome, is due to loss of function mutations of the thiazide-sensitive NaCl co-transporter (6). The recently described SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) or EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome is caused by loss of function mutations in Kir4.1 (KCNJ10), an inwardly rectifying K ϩ channel that is expressed in the basolateral membrane of the distal nephron (7-10). Presumably, reduced acti...

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Section: Discussionmentioning

confidence: 99%

“…The CaR is an additional gene which can lead to a Bartter-like phenotype. However, in contrast to the other genes for which loss-of-function mutations lead to this phenotype, the CaR mutations are gain-of-function (11,12). All of these transporters and CaR are present in the distal nephron, but precisely how the CaR reduces NaCl transport is not defined.…”

mentioning

confidence: 99%

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Kuy

Huang

Ding³

et al. 2011

Journal of Biological Chemistry

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“…This mechanism will, however, require further study. Activating mutations of the calcium sensing receptor are associated with Bartter's syndrome [Watanabe et al, 2002], which is a renal calcium reabsorption defect, and no osteoblast-related phenotype is known. Purinergic receptors are known to be present on osteoblasts and ATP or UTP coordinate osteoblast activity in bone remodeling [Hoebertz et al, 2002].…”

Section: Calcium-dependent Cellular Regulation In the Osteoblast And mentioning

confidence: 99%

Calcium Signalling and Calcium Transport in Bone Disease

Blair

Schlesinger

Huang

et al.

Subcellular Biochemistry

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Calcium transport and calcium signalling mechanisms in bone cells have, in many cases, been discovered by study of diseases with disordered bone metabolism. Calcium matrix deposition is driven primarily by phosphate production, and disorders in bone deposition include abnormalities in membrane phosphate transport such as in chondrocalcinosis, and defects in phosphate-producing enzymes such as in hypophosphatasia. Matrix removal is driven by acidification, which dissolves the mineral. Disorders in calcium removal from bone matrix by osteoclasts cause osteopetrosis. On the other hand, although bone is central to management of extracellular calcium, bone is not a major calcium sensing organ, although calcium sensing proteins are expressed in both osteoblasts and osteoclasts. Intracellular calcium signals are involved in secondary control including cellular motility and survival, but the relationship of these findings to specific diseases is not clear. Intracellular calcium signals may regulate the balance of cell survival versus proliferation or anabolic functional response as part of signalling cascades that integrate the response to primary signals via cell stretch, estrogen, tyrosine kinase, and tumor necrosis factor receptors Keywords Hypophosphatasia; chondrocalcinosis; osteopetrosis; osteoporosis Although bone is not considered a major calcium sensing organ in humans, the cells of bone tissue control over 99% of the human body's calcium content. The principal calcium sensors that regulate bone calcium uptake and release are in the parathyroid glands. Bone function is also modified by vitamin D and by calcium transport in the kidney and intestine. These indirect mechanisms of controlling bone calcium metabolism are beyond the scope of our considerations here. In spite of processing such massive quantities of the Ca 2+ bone cells use calcium in their homeostatic control processes. The massive movement of calcium is carried out by specialized and regulated transporters. Defects in the transporters cause diseases with affect bone structure or function. Indeed, inborn errors have been very important in defining the calcium transport mechanisms in bone.Additionally, calcium is used by bone forming and bone degrading cells as a secondary mediator of hormone and cytokine action. These actions include roles in intercellular communication within groups of osteoblasts, which are connected by gap junctions [Henriksen et al., 2006]. These osteoblast groups function in a coordinated fashion in bone synthesis and maintenance, and are collectively known as the osteon. Osteoblasts in these groups are connected by gap junctions which are capable of propagating signals in the cell groups, including calcium waves [Xia and Ferrier, 1992]. Calcium is also an important regulator of

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“…There is substantial evidence that the classical Ca receptor also plays a role in the regulation of calcitonin secretion in the thyroid (7) and ion transport in the kidney, not only for calcium, but also, probably indirectly, for potassium (8). The receptor has also been identified in many other tissues including bone cells.…”

Section: Is Casr Important In Bone?mentioning

confidence: 99%

The hunting of the snark: the elusive calcium receptor(s)

Raisz¹

2003

J. Clin. Invest.

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Association between activating mutations of calcium-sensing receptor and Bartter's syndrome

Cited by 363 publications

References 4 publications

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Calcium Signalling and Calcium Transport in Bone Disease

The hunting of the snark: the elusive calcium receptor(s)

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