Thapsigargin shifts the Ca set point of parathyroid cells to lower extracellular [Ca].
The hypothesis that cytosolic calcium concentration ([Ca2+cyt]) is the primary regulator of parathyroid hormone (PTH) secretion is supported by a number of studies that show an inverse relationship between them. One agent shown to inhibit PTH secretion is thapsigargin, a sesquiterpene lactone that raises [Ca2+cyt] by inhibiting the Ca-ATPase that pumps Ca2+ from the cytosol into the lumen of the endoplasmic reticulum. Thapsigargin may act on the parathyroid cell other than to inhibit the Ca-ATPase, however, in ways that might also affect PTH secretion. We have tested its effects on functional parameters, such as protein synthesis, the exocytic machinery, and the ability of parathyroid cells to respond to different concentrations of extracellular Ca2+ ([Ca2+ex]). In particular, we have determined whether the inhibition of PTH secretion by thapsigargin is independent of or is modulated by changes in [Ca2+ex]. The results revealed no effects of thapsigargin on protein synthesis or the exocytic mechanisms within 2 h of treatment, and showed that [Ca2+ex] can modulate PTH secretion in the presence of thapsigargin. Its inhibition of PTH secretion, therefore, appears to rest on its ability to shift [Ca2+cyt] to higher levels, but the possibility that it interacts with the Ca receptor has not been eliminated. The results support the hypothesis that the primary regulator of steady-state PTH secretion is [Ca2+cyt].
Ferzandi
T R
TR
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160, USA.
MacGregor
R R
RR
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D003864:Depression, Chemical; D004591:Electrophoresis, Polyacrylamide Gel; D005089:Exocytosis / Q000187:drug effects; D066298:In Vitro Techniques; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D014176:Protein Biosynthesis; D011863:Radioimmunoassay; D019284:Thapsigargin / Q000494:pharmacology*
D010281:Parathyroid Hormone; D019284:Thapsigargin; D002118:Calcium