ION CHANNELS CONTROLLING BONE REMODELING

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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.