ION CHANNELS CONTROLLING BONE REMODELING

描述(改编自申请人的摘要)：本报告的目标 项目是定义离子通道如何调节成骨细胞的功能。这个 有待检验的假设是离子通道调节成骨细胞的功能 从而导致骨骼重塑。这一机制通过它 1，25-二羟基维生素D3和维生素D3代谢物影响通道活动 骨钙素的释放将被调查。 在具体目标#1中，研究将尝试定义作用机制 1，25(OH)2D和维生素D3代谢物在电压门控钙通道上的作用 在成骨细胞中。调查员将确定这些影响是否 1，25(OH)2D3是否需要与其胞质受体结合 蛋白质合成涉及到这方面。第二个角色 信使，如钙和蛋白激酶C，在控制 我们将探索电压门控钙通道的活性。此外， 将努力澄清是否存在直接激活的 通过绑定到通道本身或者这种影响是否被中介来实现 通过G蛋白。实验将确定维生素D3是否 代谢产物通过调节钙离子调节骨钙素的释放 事件。 在具体目标2中，申请者将确定钙是如何通过 电压依赖性钙通道控制骨钙素的释放。这个 将研究钾电导的调制和控制 调节骨钙素释放的信号对钾通道的影响 探索过了。其目的是定义ROS细胞中的钾通道是如何 受影响骨钙素释放的信号调节，包括钙， CAMP或蛋白激酶C申请人还将确定维生素 D3、雌二醇、孕酮或糖皮质激素调节钾 导电性。最后，钾对骨钙素释放的调节 去极化将被确定。

DESCRIPTION (Adapted from the Applicant's Abstract): The goal of this project is to define how ion channels regulate osteoblast function. The hypothesis to be tested is that ion channels regulate osteoblast function and therefore bone remodeling. The mechanism by which 1,25-dihydroxyvitamin D3 and vitamin D3 metabolites affect channel activity and osteocalcin release will be investigated. In Specific Aim #1, studies will attempt to define the mechanism of action of 1,25(OH)2D and vitamin D3 metabolites on voltage-gated calcium channels in osteoblast cells. The investigator will determine whether the effects of 1,25(OH)2D3 require binding to its cytosolic receptor and whether protein synthesis is involved in this regard. The role of second messengers, such as calcium and protein kinase C, in controlling of the activity of voltage-gated calcium channels will be explored. Furthermore, efforts will be made to elucidate whether there is direct activation of the channel by binding to the channel itself or whether this effect is mediated through G proteins. Experiments will determine whether vitamin D3 metabolites alter osteocalcin release by modulating calcium-mediated events. In Specific Aim #2, the applicant will determine how calcium influx through voltage-dependent calcium channels controls osteocalcin release. The modulation of potassium conductances will be investigated and the control of potassium channels by signals which regulate osteocalcin release will be explored. The intent is to define how potassium channels in ROS cells are modulated by signals which affect osteocalcin release, including calcium, cAMP or protein kinase C. The applicant will also determine whether vitamin D3, estradiol, progesterone, or glucocorticoids modulate potassium conductances. Finally, the regulation of osteocalcin release by potassium depolarization will be determined.