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Molecular mechanisms underlying the sensing of extracellular Ca²⁺ by parathyroid and kidney cells

Brown EM, Pollak M, Hebert SC. Molecular mechanisms underlying the sensing of extracellular Ca²⁺ by parathyroid and kidney cells. Eur J Endocrinol 1995;132:523–31. ISSN 0804–4643

Mineral ion homeostasis in mammalian species is maintained by a complex mechanism comprising sensors of the extracellular calcium concentration (Ca₀²⁺) (i.e. parathyroid cells) as well as effectors that modify their translocation of mineral ions into and out of the extracellular fluid (e.g. kidney) in response to calciotropic hormones. Indirect evidence accumulated over the past decade suggested that parathyroid cells sense Ca₀²⁺ through a cell surface receptor coupled to intracellular second messenger systems via one or more guanine nucleotide regulatory (G) proteins. More recently, Brown et al. employed expression cloning in Xenopus laevis oocytes to isolate a cDNA encoding a Ca₀²⁺-sensing receptor from bovine parathyroid. The expressed receptor activates phospholipase C in a G-protein dependent manner and shows pharmacological properties almost identical to those of the native parathyroid receptor. Agonists for the receptor include not only divalent cations (e.g. Ca²⁺ and Mg²⁺) but also trivalent cations and even organic polycations such as neomycin. The deduced amino acid sequence of the cloned receptor confirms that it is a member of the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid as well as in kidney, thyroid and brain. Therefore, this receptor may mediate the sensing of Ca₀²⁺ not only by parathyroid cells but also by other tissues directly regulated by Ca₀²⁺ (e.g. the thyroidal C cells and certain kidney cells) as well as those not currently known to be involved in calcium homeostasis (viz. in the brain). Further evidence for the physiological relevance of the receptor comes from the discovery that mutations in the human homolog of the Ca₀²⁺-sensing receptor gene cause three inherited disorders of mineral ion homeostasis. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are the clinical expression of inactivating mutations of the receptor when present in the heterozygous and homozygous state, respectively. An autosomal dominant form of hypocalcemia, on the other hand, results from an activating mutation of the receptor. Thus, this Ca₀²⁺-sensing receptor permits Ca₀²⁺ to act, in effect, as an extracellular first messenger in addition to its more widely recognized role as an intracellular second messenger.

Edward M Brown, Endocrine–Hypertension Division, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA02115, USA

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