Related Experiment Video
Updated: Apr 11, 2026
Two Techniques to Create Hypoparathyroid Mice: Parathyroidectomy Using GFP Glands and Diphtheria-Toxin-Mediated Parathyroid Ablation
Published on: March 14, 2017
The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor
Fadil M Hannan1, Gerard V Walls1, Valerie N Babinsky1
1Academic Endocrine Unit (F.M.H., G.V.W., V.N.B., M.A.N., E.K., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LJ, United Kingdom; Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre (T.A.H., R.D.C.), MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, United Kingdom; Department of Medicine (W.D.F.), Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, United Kingdom; Laboratory of Bioorganic Chemistry (J.H.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892; and Albert Einstein College of Medicine (A.M.S.), Bronx, New York 10461.
Abstract:
Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells, and the effect of NPS 2143 on their intracellular calcium responses was determined by flow cytometry. NPS 2143 was also administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder.
Insights
NPS 2143, a calcilytic drug, effectively treats autosomal dominant hypocalcemia type 1 (ADH1) by normalizing calcium-sensing receptor (CaSR) gain-of-function mutations. This targeted therapy shows promise for ADH1 patients with hypocalcemia.
Area of Science:
- Endocrinology
- Molecular Endocrinology
- Pharmacology
Background:
- Autosomal dominant hypocalcemia type 1 (ADH1) results from calcium-sensing receptor (CaSR) gain-of-function mutations.
- This condition can cause symptomatic hypocalcemia, low parathyroid hormone (PTH) levels, and hypercalciuria.
- Calcilytics, negative allosteric CaSR modulators, offer potential targeted therapy for ADH1 by correcting CaSR dysfunction.
Purpose of the Study:
- To investigate the efficacy of NPS 2143, a calcilytic compound, in treating ADH1.
- To evaluate NPS 2143's effects on CaSR gain-of-function mutations in vitro and in a relevant mouse model.
Main Methods:
- Expressed wild-type and mutant (Leu723Gln) CaSRs in HEK293 cells for in vitro studies.
- Assessed the impact of NPS 2143 on intracellular calcium responses using flow cytometry.
- Administered NPS 2143 to wild-type and Nuf mutant mice, measuring plasma calcium, PTH, and urinary calcium.
Main Results:
- NPS 2143 dose-dependently reduced intracellular calcium responses in cells expressing the mutant Gln723 CaSR, correcting the gain-of-function.
- In Nuf mice, NPS 2143 administration significantly increased plasma calcium and PTH levels.
- Urinary calcium excretion remained unchanged in Nuf mice treated with NPS 2143.
Conclusions:
- NPS 2143 effectively normalizes the gain-of-function CaSR mutation associated with ADH1.
- This calcilytic compound demonstrates therapeutic potential for improving hypocalcemia in ADH1.
- NPS 2143 represents a promising targeted treatment for ADH1 by addressing the underlying CaSR defect.
