Fig. 1

Overview of the calcium sensing receptor (CaSR) signaling in the regulation of parathyroid hormone (PTH) and calcitonin secretion via different G proteins. Beside calcium, various ligands show intrinsic activity on the CaSR. Depending on cell type and modulating factors such as phosphate concentration and allosteric modulators distinct signaling cascades can be triggered influencing the gene transcription. The positive allosteric modulator (PAM) cinacalcet is known to reduce PTH secretion while increasing calcitonin levels, potentially leading to hypocalcemia (dotted blue box). In contrast, the novel PAM suppresses PTH without elevating calcitonin, thereby avoiding hypocalcemia (dotted red box), which might be due to biased signalling or differences in signal transduction in different cell types. CaSR calcium sensing receptor, VFTs Venus flytrap domains, Gα_q/11/Gα_i/Gα_s/Gβγ, different subunits of G proteins, PLC phospholipase C, PIP2 phosphatidylinositol 4,5-bisphosphate, IP3 inositol 1,4,5-triphosphate, DAG diphosphoglycerate, PKC protein kinase C, Raf rapidly accelerated fibrosarcoma, MEK mitogen-activated protein kinase, ERK extracellular signal-regulated kinase, cAMP cyclic adenosine monophosphate, PAM positive allosteric modulator, PTH parathyroid hormone. Figure created with Biorender.com