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Adenine nucleotides mobilize cellular Ca2+ and inhibit parathyroid hormone secretion
1Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
Abstract:
Measurements of the concentration of intracellular free calcium [( Ca2+]i) were used to screen for the presence of Ca2+-mobilizing receptors on dissociated and purified bovine parathyroid cells loaded with fura-2. Among a wide variety of agents known to mobilize cellular Ca2+ in other cells, only ATP and certain other nucleotides were capable of altering [Ca2+]i in parathyroid cells. The addition of ATP or adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) (10-200 microM) to parathyroid cells evoked a rapid and transient increase that was followed by a small, steady-state increase in [Ca2+]i. Cytosolic Ca2+ transients elicited by ATP or ATP gamma S persisted in the absence of extracellular Ca2+ and presence of a mitochondrial uncoupler but were blocked by pretreatment with ionomycin or fluoride. Cytosolic Ca2+ transients elicited by ATP were inhibited by increased concentrations of extracellular Ca2+, Mg2+, or Sr2+. Conversely, ATP depressed increases in [Ca2+]i elicited by these extracellular divalent cations. Parathyroid hormone (PTH) secretion was inhibited by ATP gamma S but not by those nucleotides that were without effect on [Ca2+]i. Loading cells with 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and fura-2 blocked cytosolic Ca2+ transients elicited by ATP gamma S but did not block the inhibitory effects of ATP gamma S on PTH secretion. The results show that the activation of a calcium-mobilizing receptor, in this case by ATP gamma S, is sufficient to inhibit PTH secretion. This favors the view that extracellular Ca2+ acts via a Ca2+-mobilizing receptor to regulate PTH secretion.
Insights
Adenosine triphosphate (ATP) activates calcium-mobilizing receptors on bovine parathyroid cells, influencing intracellular calcium levels and inhibiting parathyroid hormone (PTH) secretion. This suggests extracellular calcium regulates PTH secretion through similar receptors.
Area of Science:
- Endocrinology
- Cell Biology
- Biochemistry
Background:
- Parathyroid hormone (PTH) secretion is crucial for calcium homeostasis.
- The role of specific receptors in regulating PTH secretion is not fully understood.
- Intracellular calcium concentration ([Ca2+]i) is a key signaling molecule in cellular processes.
Purpose of the Study:
- To identify Ca2+-mobilizing receptors on bovine parathyroid cells.
- To investigate the effect of adenosine triphosphate (ATP) and related nucleotides on intracellular calcium and PTH secretion.
- To elucidate the mechanism by which extracellular calcium regulates PTH secretion.
Main Methods:
- Dissociated and purified bovine parathyroid cells were loaded with fura-2 to measure intracellular free calcium ([Ca2+]i).
- Various agents were screened for their ability to mobilize Ca2+.
- The effects of ATP and related nucleotides on [Ca2+]i and PTH secretion were assessed under different extracellular conditions.
- Specific inhibitors and chelators were used to probe the signaling pathways.
Main Results:
- ATP and certain other nucleotides rapidly increased [Ca2+]i in parathyroid cells.
- These calcium transients were independent of extracellular calcium and mitochondrial function but sensitive to ionomycin and fluoride.
- Increased extracellular Ca2+, Mg2+, or Sr2+ inhibited ATP-evoked calcium transients, while ATP inhibited cation-evoked calcium increases.
- ATP gamma S inhibited PTH secretion, an effect not blocked by intracellular calcium chelation, indicating a receptor-mediated mechanism.
- Nucleotides without effect on [Ca2+]i did not inhibit PTH secretion.
Conclusions:
- Bovine parathyroid cells possess Ca2+-mobilizing receptors activated by ATP.
- Activation of these receptors by ATP gamma S is sufficient to inhibit PTH secretion.
- Extracellular calcium likely regulates PTH secretion by interacting with Ca2+-mobilizing receptors, similar to ATP.
- These findings provide insights into the complex regulation of PTH secretion and calcium homeostasis.
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