Lanthanum activates calcium-sensing receptor and enhances sensitivity to calcium.
BACKGROUND
The aim of this study was to investigate whether nanomolar concentrations of lanthanum could influence the calcium-sensing receptor (CaSR) response.


METHODS
Embryonic kidney (HEK-293) cells transiently transfected with the human CaSR were used to test the ability of lanthanum to activate the CaSR, either alone or in combination with calcium. CaSR activation was measured by flow cytometry. Parathyroid glands from 4-month-old male Wistar rats with normal renal function (n = 60) were also cultured ex vivo with different concentrations of lanthanum to measure parathyroid hormone (PTH) secreted to the medium and PTH mRNA.


RESULTS
The maximal CaSR activation induced by 1 muM lanthanum chloride (LaCl(3)) was similar to that induced by 16 mM calcium chloride (CaCl(2) 16 mM: 294 +/- 14%; LaCl(3) 1 muM: 303 +/- 11%). Lanthanum half effective concentration (EC(50)) was 77.28 nM, lower than the 2.30 mM obtained for calcium, supporting the concept that this metal is a strong agonist of the CaSR. Moreover, lanthanum was also able to enhance CaSR sensitivity to calcium. The presence of 1 nM LaCl(3) significantly left-shifted the CaSR response curve, changing the EC(50) value for calcium from 2.30 mM (calcium alone) to 1.26 mM (calcium + 1 nM lanthanum). The parathyroid glands cultured with lanthanum showed a trend to secrete less PTH compared to the control glands: 1.51 +/- 0.23 (control), 0.91 +/- 0.17 (La 100 nM) and 1.04 +/- 0.18 (La 400 nM) [(pg/h)/(pg/h), mean +/- SEM] (ANOVA P = 0.0145). A similar trend was also observed in PTH synthesis measured by PTH mRNA levels.


CONCLUSIONS
These in vitro findings demonstrate that lanthanum, at nanomolar concentrations, is an agonist of the CaSR able to activate it in the absence of calcium. In addition, it can also enhance CaSR sensitivity to calcium, modulating PTH synthesis and secretion.
Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Universidad de Oviedo, C/Julián Clavería s/n, 33006 Oviedo, Spain.
Natalia
N
Carrillo-López
José Luis
JL
Fernández-Martín
Daniel
D
Alvarez-Hernández
Ignacio
I
González-Suárez
Patricia
P
Castro-Santos
Pablo
P
Román-García
José Miguel
JM
López-Novoa
Jorge Benito
JB
Cannata-Andía
D000818:Animals; D015153:Blotting, Western; D002122:Calcium Chloride / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007811:Lanthanum / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; C028521:lanthanum chloride; D007811:Lanthanum; D002122:Calcium Chloride