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Regulation of Ca(2+)-conducting currents in parathyroid cells by extracellular Ca(2+) and channel blockers
1Department of Medicine, Veterans Affairs Medical Center, San Francisco 94121, USA.
Abstract:
High extracellular Ca2+ concentrations ([Ca2+]o) produce sustained intracellular Ca2+ responses in parathyroid cells that correlate with suppression of parathyroid hormone release. Using whole cell patch clamping, we identified two types of Ca(2+)-conducting currents in these cells. Type 1 currents were enhanced by raising [Ca2+]o and blocked by Cd2+ and nifedipine, whereas type 2 currents were resistant to blockade by these agents. Both types of membrane currents were cation nonselective, voltage independent over a broad range of membrane potentials, and blocked by the trivalent ions La3+ and Gd3+ (> 98%). Cd2+, La3+, and Gd3+ had biphasic effects on membrane conductance (Gm). At submicromolar concentrations, these ions increased Gm, whereas at higher concentrations they reduced Gm. In contrast to ionic channel blockers, nifedipine had only an inhibitory effect on the Ca(2+)-conducting currents that were sensitive to changes in [Ca2+]o (dose inhibiting 50% of maximal response = approximately 3-10 x 10(-8) M). Microfluorimetric ratio-imaging analysis of single parathyroid cells loaded with fura 2 showed that Gd3+ inhibited sustained intracellular Ca2+ responses to high [Ca2+]o. These findings suggest that the Ca(2+)-conducting currents identified in these studies may play a role in regulating intracellular Ca2+ responses in this system.
Insights
High extracellular calcium ([Ca2+]o) affects parathyroid cells by activating specific calcium currents. Gadolinium (Gd3+) and other agents modulate these currents, influencing intracellular calcium and hormone release.
Area of Science:
- Cellular physiology
- Ion channel research
- Endocrinology
Background:
- High extracellular calcium ([Ca2+]o) suppresses parathyroid hormone (PTH) release.
- Intracellular calcium ([Ca2+]i) dynamics are crucial for regulating PTH secretion.
- Parathyroid cells possess calcium-permeable ion channels that respond to extracellular calcium levels.
Purpose of the Study:
- To characterize calcium-conducting currents in parathyroid cells.
- To investigate the role of these currents in mediating intracellular calcium responses to elevated [Ca2+]o.
- To identify specific blockers or modulators of these calcium currents.
Main Methods:
- Whole-cell patch-clamp electrophysiology to record membrane currents.
- Microfluorimetric ratio-imaging using fura 2 to measure intracellular calcium.
- Application of various ions (Cd2+, La3+, Gd3+) and drugs (nifedipine) to assess current properties and effects.
Main Results:
- Two types of Ca(2+)-conducting currents were identified, differing in their sensitivity to [Ca2+]o and nifedipine.
- Both current types were cation nonselective, voltage-independent, and blocked by La3+ and Gd3+.
- Gd3+ inhibited sustained intracellular calcium responses induced by high [Ca2+]o, suggesting a role in calcium signaling.
Conclusions:
- Calcium-conducting currents in parathyroid cells are modulated by extracellular calcium and specific ions.
- These currents likely play a significant role in regulating intracellular calcium dynamics and, consequently, parathyroid hormone release.
- Further research into these ion channels could offer insights into parathyroid function and related disorders.