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New Insights Into The Mechanisms Regulating Calcium Sensing And Parathyroid Hormone Secretion

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The control of serum calcium within a tightly defined range is essential for the normal function of all mammals. Consequently, a sensitive system of calcium sensors and regulatory hormones has evolved to maintain serum calcium within a relatively narrow range. Central to this endocrine system is the sensing of serum ionized calcium by the calcium sensing receptor (CSR). This, in turn, leads to the production of second messengers by enzymes like phospholipase C-β (PLC-­β) and the subsequent regulation of parathyroid hormone, the critical endocrine hormone for maintaining normal serum calcium levels. Also important in this regulatory system is the Gq/G11 family of trimeric G proteins, which mediate the regulation of PLC-­‐β by the CSR (1,2).


Diseases of this system are varied and result in both hypo- and hypercalcemia. Examples include familial hypocalciuric hypercalcemia (FHH), which in some cases was previously found to result from heterozygous germline inactivating mutations of the gene that encodes the CSR (CASR). This syndrome has been labeled Type 1 FHH. Conversely, activating mutations of CASR produce familial autosomal dominant hypocalcemia. Additional cases of FHH (Type 3 FHH) have been linked to missense mutations in AP2S1. This gene encodes the sigma 1 subunit of adaptor-related protein complex 2, a protein that regulates CSR endocytosis. Another class of FHH (Type 2) had previously been linked to chromosome 19p13.3. This region contains the gene GNA11 that codes for the alpha subunit of G11. Following on this clue, plus the known association of the alpha subunit of G11 with calcium receptor signaling and the finding that mice with parathyroid-specific deletion of both Gq and G11 develop hypercalcemia and hyperparathyroidism, Nesbit et al (3) investigated the role that mutations in G11 had in the development of Type 2 FHH. These authors sequence the exons and exon-intron boundaries of patients with type 2 FHH and identified heterozygous germline inactivating mutations as being associated with the disease. Furthermore, in vitro studies demonstrated that the mutations decreased the sensitivity of cells to alterations in extracellular calcium. Thus, hence, confirming their role in the development of the disease.


In a related study Nesbit et al (3) as well as Mannstadt et al (4) identified heterozygous germline mutations in GNA11 in patients with autosomal dominant hypocalcemia who did not have CASR mutations. Functional in vitro studies of these mutations demonstrated that they increased the sensitivity of cells to alterations in extracellular calcium as expected if they were causative of the disease.


Together these findings demonstrate the important role of G11 in the regulation of parathyroid hormone secretion and the regulation of serum calcium. Perhaps, most intriguing, is the fact that although these mutations are germline and, hence, present in every cell, their only significant clinical effect is on calcium sensing and parathyroid hormone secretion. These findings demonstrate the critical role of G11 in parathyroid hormone regulation and the inability of the related Gq to compensate for mutations in this gene in this function.


Joe Lorenzo

Farmington, CT, USA

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