Parathyroid Calcium Sensor Proteins

A calcium sensor protein on the parathyroid cell surface was identified by monoclonal antibodies generated by immunization with human adenoma cells.49 Such a monoclonal antibody abolished the calcium-regulated Ca2+; and PTH release of normal and pathologic parathyroid cells.50 51 The antibody blocked the calcium-induced Ca2+, transient intracellular calcium mobilization as well as the steady-state elevation resulting from calcium influx. Because the antibodies also competed with calcium binding to the parathyroid cell surface, the findings supported the idea that the antibodies interfered with the calcium sensor rather than an associated calcium channel. A survey of normal human tissues revealed that this calcium sensor was also expressed by the proximal kidney tubule and placental cytotrophoblast cells.49

Cloning of the calcium sensor recognized by the antibodies revealed a 500-kd glycoprotein with a single membrane-spanning domain; this protein belongs structurally to the low-density lipoprotein (LDL) receptor superfamily.52 Particular homology was demonstrated with the rat Heymann's nephritis antigen, which constitutes a large glycoprotein of the proximal kidney tubule and possibly serves as an autoantigen of experimental nephritis. The calcium-binding motifs of the calcium sensor are probably composed of repetitive epidermal growth factor (EGF)-like modules, and calcium sensitivities of the LDL superfamily of proteins are in the range of the extracellular concentration of ionized plasma calcium. Kinetic studies of these proteins indicate the presence of positive cooperativity for the interaction of calcium, whereby multiple binding sites can efficiently alter protein signaling. Under these circumstances, cells equipped with the sensor are allowed to respond efficiently to the narrow alterations in Ca2+j, which are required for adequate maintenance of systemic calcium homeostasis. A receptor-bound 44-kd protein may help to translocate the large sensor protein to the cell surface. Interestingly, the calcium sensor is partially internalized in parathyroid carcinomas as well as in malignant tumors originating from both the kidney tubules and placental cytotrophoblasts.53 Moreover, it seems to be involved in the regulation of cell proliferation, at least in transformed cytotrophoblast cells.

Another protein with calcium-sensing function has been identified in the bovine parathyroid by expression cloning in oocytes.54 This 120-kd protein is G protein-coupled and contains the characteristic seven-transmembrane domains of peptide receptors as well as putative calcium-binding sites. Transfection of this molecule to eukaryotic cells demonstrated linkage to regulation of Ca2+„ but calcium sensitivity of this protein is within a concentration range that exceeds the ionized plasma calcium level. Receptors for this and related proteins are also present in the cortex and outer medulla of the kidney, the nervous system, and the thyroid. The protein shows significant homology to glutamate receptors mostly expressed in the central nervous system and with known association to voltage-dependent calcium channels. Coupling of this protein to PTH release is at present unclear. By linkage analysis using highly polymorphic DNA probes, the gene for benign familial hypocalciuric hypercalcemia (FHH) was mapped to chromosome 3q21-24 in four families (i.e., the location of the 120-kd protein gene).55 FHH has been coupled to mutations in this protein whereby its Ca2* regulatory property is lost.56

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