Rogers K V, Conklin R L, Lowe S H, Petty B A
Departments of Molecular Biology and Pharmacology, NPS Pharmaceuticals, Inc., 84108, Salt Lake City, UT, USA.
Endocrine. 1995 Nov;3(11):769-74. doi: 10.1007/BF02935679.
Extracellular ionized calcium (Ca(2+)) is the primary physiological regulator of parathyroid hormone (PTH) secretion and the G protein-coupled receptor (CaR) that mediates this response has been cloned from bovine and human parathyroid glands. The Ca(2+) set-point for the regulation of PTH secretion is right-shifted in primary hyperparathyroidism (1°HPT), but whether there is a similar shift in 2°HPT is unclear. Additionally, the molecular defects associated with such changes in the set-point remain uncharacterized. These experiments were designed to determine (1) if changes in set-point occur in rats with 2°HPT induced by chronic renal insufficiency (CRI) or dietary Ca deficiency, and (2) whether any changes in set-point are mirrored by changes in steady-state mRNA levels for the parathyroid CaR. CaR mRNA levels were quantified in pairs of glands from individual rats using a solution hybridization assay. Blood urea nitrogen and PTH levels were ∼ 4-fold higher in rats with CRI induced by 5/6 nephrectomy 7 weeks earlier. Rats with CRI were also significantly hypocalcemic and hyperphosphatemic. The setpoint was unchanged in CRI rats and CaR mRNA levels were also unaffected. Normal rats fed a 0.02% Ca diet for 6 weeks were markedly hypocalcemic, and had 10- and 15-fold increases in plasma PTH and 1,25-dihydroxyvitamin D(3) levels, respectively. Technical problems prevented assessment of the set-point in these animals, but parathyroid gland CaR mRNA levels were identical in both dietary groups. Thus, neither alterations in mRNA levels for the CaR nor changes in the set-point play demonstrable roles in the pathogenesis of 2°HPT in these models.
细胞外游离钙(Ca(2+))是甲状旁腺激素(PTH)分泌的主要生理调节因子,介导这种反应的G蛋白偶联受体(CaR)已从牛和人的甲状旁腺中克隆出来。原发性甲状旁腺功能亢进症(1°HPT)中,调节PTH分泌的Ca(2+)设定点向右偏移,但继发性甲状旁腺功能亢进症(2°HPT)中是否存在类似偏移尚不清楚。此外,与设定点这种变化相关的分子缺陷仍未明确。这些实验旨在确定:(1)慢性肾功能不全(CRI)或饮食性钙缺乏诱导的2°HPT大鼠中设定点是否发生变化;(2)甲状旁腺CaR的稳态mRNA水平变化是否反映设定点的任何变化。使用溶液杂交分析法对来自个体大鼠的成对腺体中的CaR mRNA水平进行定量。7周前接受5/6肾切除术诱导的CRI大鼠的血尿素氮和PTH水平约高4倍。CRI大鼠也明显低钙血症和高磷血症。CRI大鼠的设定点未改变,CaR mRNA水平也未受影响。喂食0.02%钙饮食6周的正常大鼠明显低钙血症,血浆PTH和1,25 - 二羟维生素D(3)水平分别升高10倍和15倍。技术问题妨碍了对这些动物设定点的评估,但两个饮食组的甲状旁腺CaR mRNA水平相同。因此,在这些模型中,CaR的mRNA水平改变和设定点变化在2°HPT的发病机制中均未发挥明显作用。