ORGANIC LIGANDS THAT ALTER PARATHYROID CELL FUNCTION

RECENT STUDIES HAVE PROVIDED EVIDENCE FOR THE PRESENCE OF A CA(2+) RECEPTOR ON THE SURFACE OF PARATHYROID CELLS THAT ENABLES THESE CELLS TO DETECT SMALL CHANGES IN THE CONCENTRATION OF EXTRACELLULAR CA(2+) AND THEREBY ALTER PARATHYROID HORMONE (PTH) SECRETION. THIS CA(2+) RECEPTOR IS COUPLED TO THE MOBILIZATION OF INTRACELLULAR CA(2+) AND SHOWS MANY OF THE BIOCHEMICAL FEATURES COMMON TO MORE CONVENTIONAL CA(2+)-MOBILIZING RECEPTORS. THE ONLY AGENTS KNOWN TO ACT AT THE CA(2+) RECEPTOR ARE DI- AND TRIVALENT METAL CATIONS. THIS RESEARCH WILL EXAMINETHE POSSIBILITY THAT CERTAIN ORGANIC COMPOUNDS MIGHT BEHAVE SIMILARLY TO EXTRACELLULAR CA(2+) AND REGULATE PTH SECRETION BY ACTING AS LIGANDS AT THE CA(2+) RECEPTOR. ORGANIC POLYCATIONS (MOST NOTABLY SPERMINE) WILL BE EXAMINEDFOR THEIR ABILITY, USING BOVINE AND HUMAN PARATHYROID CELLS,TO 91) MOBILIZE INTRACELLULAR CA(2+), (2) INCREASE INOSITOL PHOSPHATE FORMATION, (3) DECREASE CYCLIC AMP FORMATION, AND (4) INHIBIT PTH SECRETION. COMPARISONS OF THESE RESULTS WILL BE MADE WITH THOSE OBTAINED WITH EXTRACELLULAR CA(2+) TO DETERMINE IF BOTH ORGANIC AND INORGANIC AGENTS ACT THROUGH THE SAME RECEPTOR-DEPENDENT MECHANISM. ORGANIC COMPOUNDS ACTING SIMILARLY TO EXTRACELLULAR CA(2+) MIGHT THEN PROVIDE LEAD STRUCTURES FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS EFFECTIVE IN THE TREATMENT OF VARIOUS BONE AND MINERAL-RELATED DISORDERS SUCH AS HYPERPARATHYROIDISM AND OSTEOPOROSIS.