Person:

Brown, Edward

Ca2+-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 Mg2+ 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.

Background: Despite the reported high prevalence of osteoporosis in India, there have been no previous studies examining the risk factors for hip fracture in the Indian population. Methods: We carried out a case control investigation comprising 100 case subjects (57 women and 43 men) admitted with a first hip fracture into one of three hospitals across New Delhi. The 100 controls were age and sex matched subjects who were either healthy visitors not related to the case patients or hospital staff. Information from all subjects was obtained through a questionnaire based interview. Results: There was a significant increase in the number of cases of hip fracture with increasing age. There were significantly more women (57%) than men (43%). Univariate analysis identified protective effects for increased activity, exercise, calcium and vitamin supplements, almonds, fish, paneer (cottage cheese), curd (plain yogurt), and milk. However, tea and other caffeinated beverages were significant risk factors. In women, hormone/estrogen therapy appeared to have a marginal protective effect. For all cases, decreased agility, visual impairment, long term medications, chronic illnesses increased the risk of hip fracture. The multivariate analysis confirmed a protective effect of increased activity and also showed a decrease in hip fracture risk with increasing body mass index (odds ratio (OR) 0.024, 95% confidence interval (CI) 0.006-0.10 & OR 0.81, 95% CI 0.68-0.97 respectively). Individuals who take calcium supplements have a decreased risk of hip fracture (OR 0.076; CI 0.017-0.340), as do individuals who eat fish (OR 0.094; CI 0.020-0.431), and those who eat paneer (OR 0.152; 0.031-0.741). Tea drinkers have a higher risk of hip fracture (OR 22.8; 95% CI 3.73-139.43). Difficulty in getting up from a chair also appears to be an important risk factor for hip fractures (OR 14.53; 95% CI 3.86-54.23). Conclusions: In the urban Indian population, dietary calcium, vitamin D, increased body mass index, and higher activity levels have a significant protective effect on hip fracture. On the other hand, caffeine intake and decreased agility increase the risk of hip fracture. Future studies should be done in order to direct primary preventive programs for hip fracture in India.