Structural Mechanism of Cooperative Regulation of Calcium-Sensing Receptor-Mediated Cellular Signaling.

Calcaium sensing receptors (CaSRs) play a central role in regulating extracellular calcium (Ca2+) homeostasis and many (patho)physiological processes. This regulation is primarily orchestrated in response to extracellular stimuli via the extracellular domain (ECD). This paper first reviews the modeled structure of the CaSR ECD and the prediction and investigation of the Ca2+ and amino acid binding sites. Several recently solved X-ray structures are then compared to support a proposed CaSR activation model involving functional cooperativity. The review also discusses recent implications for drug development. These studies provide new insights into the molecular basis of diseases and the design of therapeutic agents that target CaSR and other family C G protein-coupled receptors (cGPCRs).

Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist.

Ca(2+)-sensing receptors (CaSRs) modulate calcium and magnesium homeostasis and many (patho)physiological processes by responding to extracellular stimuli, including divalent cations and amino acids. We report the first crystal structure of the extracellular domain (ECD) of human CaSR bound with Mg(2+) and a tryptophan derivative ligand at 2.1 Å. The structure reveals key determinants for cooperative activation by metal ions and aromatic amino acids. The unexpected tryptophan derivative was bound in the hinge region between two globular ECD subdomains, and represents a novel high-affinity co-agonist of CaSR. The dissection of structure-function relations by mutagenesis, biochemical, and functional studies provides insights into the molecular basis of human diseases arising from CaSR mutations. The data also provide a novel paradigm for understanding the mechanism of CaSR-mediated signaling that is likely shared by the other family C GPCR [G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor] members and can facilitate the development of novel CaSR-based therapeutics.

The calcium sensing receptor: from calcium sensing to signaling.

The Ca(2+)-sensing receptor (the CaSR), a G-protein-coupled receptor, regulates Ca(2+) homeostasis in the body by monitoring extracellular levels of Ca(2+) ([Ca(2+)]o) and responding to a diverse array of stimuli. Mutations in the Ca(2+)-sensing receptor result in hypercalcemic or hypocalcemic disorders, such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and autosomal dominant hypocalcemic hypercalciuria. Compelling evidence suggests that the CaSR plays multiple roles extending well beyond not only regulating the level of extracellular Ca(2+) in the human body, but also controlling a diverse range of biological processes. In this review, we focus on the structural biology of the CaSR, the ligand interaction sites as well as their relevance to the disease associated mutations. This systematic summary will provide a comprehensive exploration of how the CaSR integrates extracellular Ca(2+) into intracellular Ca(2+) signaling.