Signal Crosstalk between Calcium-Sensing and Prostanoid Receptors and its Role in Parathyroid Hormone Secretion

Abstract

The calcium-sensing receptor (CaR) maintains extracellular calcium Ca2+o homeostasis by suppressing parathyroid hormone (PTH) secretion. However, the underlying cellular driving force for tonic PTH secretion remains unclear. It is believed that agonists that generate intracellular cyclic-AMP levels may increase PTH secretion and therefore bidirectional crosstalk between CaR signalling and cAMP levels could be of physiological importance. In order to identify possible contributors to parathyroid cAMP accumulation I first confirmed the gene and protein expression of EP4R (prostanoid) and CALCRL (calcitonin receptor-like receptor) in bovine PT gland by using RT-PCR and western blotting respectively. Also, I confirmed the gene expression of the PGE synthase enzyme required for the PGE2 synthesis in bovine PT gland by RT-PCR. And I further confirmed the gene expression of the CALCRL’s associated components particularly the RAMPs and adrenomedullin. Next, I investigated the influence of cAMP on CaR signalling as determined first by Ca2+i mobilisation. Cyclic AMP-generating agonists including PGE2, isoprenaline and histamine enhanced CaR-induced Ca2+i mobilisation at subthreshold Ca2+o concentrations. Indeed, PGE2 and isoprenaline lowered the EC50 for Ca2+o-induced Ca2+i mobilisation (2.5 ± 0.1 for PGE2 and 2.7 ± 0.2 for isoprenaline vs. 4.0 ± 0.3 mM for control, P

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Donald Ward (Supervisor) & Mark Dunne (Supervisor)