Lithium-induced alterations in parathyroid cell function: insight into the pathogenesis of lithium-associated hyperparathyroidism

Abstract

Background: Reduced parathyroid sensitivity to changes in calcium (Ca2+) has been observed in patients treated with lithium (Li+). In order to investigate this desensitization phenomenon, the effect of Li+ on cytosolic calcium (Cai2+) regulation was examined.

Methods: Transmembrane signal transduction and Ca2+ sequestration were investigated in bovine parathyroid cells by measuring changes in [Cai2+] in response to 5 mmol/L magnesium (Mg2+), 0.5 to 2.5 mmol/L Ca2+, 25 mumol/L adenosine triphosphate (ATP), and 1 mumol/L ionomycin in cells pretreated with 1 to 10 mmol/L lithium chloride (LiCl) and control cells. Measurement of Cai2+ was made using fura-2.

Results: Increases in [Cai2+] in response to Ca2+ and Mg2+ were blunted following overnight culture with as low as 1 mmol/L LiCl. In normocalcemic medium, 1 mmol/L Ca2+ produced an 81% increase in [Cai2+] in control cells compared with a 58% increase in cells pretreated with LiCl (P < 0.01), whereas in hypocalcemic medium, increases in [Cai2+] were similar in lithium-treated and control cells (78% versus 82%, P > 0.1). The ATP produced increases in [Cai2+] from 225 +/- 9 nmol/L to 366 +/- 10 nmol/L in control cells, compared with 221 +/- 7 nmol/L to 308 +/- 10 nmol/L in cells pretreated with 5 mmol/L LiCl (P < 0.01). Ionomycin-induced increases in [Cai2+] were unaffected by Li+.

Conclusions: We concluded that the in vitro desensitizing effects of Li+ occur at therapeutic concentrations, but only in the presence of Ca2+ in concentrations that induce transmembrane signaling; and that Li+ blunts increases in [Cai2+] related to cation and ATP-induced transmembrane signal transduction without affecting ionomycin-releasable Ca2+ stores.