The First Annual Bayard D. Catherwood Memorial Lecture. Ca2+-receptor-mediated regulation of parathyroid and renal function.
The recent cloning of an extracellular calcium (Ca2+o)-sensing receptor (CaR) from the parathyroid gland and the kidney has provided novel insights into the mechanisms that underlie the direct actions of Ca2+o on various cells. The receptor is a member of the superfamily of G protein-coupled receptors, activating phospholipase C (PLC) and probably also inhibiting adenylate cyclase in target tissues. In the parathyroid gland it is a key mediator of the inhibition by high Ca2+o of parathyroid hormone (PTH) secretion and, perhaps, PTH gene expression and parathyroid cellular proliferation. It also appears to represent the major mechanism through which Ca2+o stimulates the secretion of calcitonin from the thyroidal C-cells. In the kidney, the CaR directly inhibits tubular reabsorption of calcium and magnesium in the thick ascending limb, and may be responsible for the long-recognized, but poorly understood inhibition of urinary concentrating ability by hypercalcemia. The demonstration that activating and inactivating mutations of the CaR, respectively, are the proximate causes of the inherited hypocalcemic disorder, autosomal dominant hypocalcemia (ADH) and the hypercalcemic diseases, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), has provided additional strong support for the physiologic importance of the CaR in human mineral ion homeostasis. Therefore, when Ca2+o acts through its own G protein-coupled cell surface receptor, it acts as an extracellular first messenger in addition to serving its better recognized role as a key intracellular second messenger.
Brown
E M
EM
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Hebert
S C
SC
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology; D006996:Hypocalcemia / Q000209:etiology; D007668:Kidney / Q000502:physiology*; D051379:Mice; D010280:Parathyroid Glands / Q000502:physiology*; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction
D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium