Regulation of renal 25(OH)D3 1 alpha-hydroxylase: signal transduction pathways.
In vitro, activation of the cAMP signalling pathway stimulates, whereas activation of PKC inhibits, 1,25(OH)2D3 synthesis. Since PTH activates both pathways, the ultimate effect of PTH on 1 alpha-hydroxylation in vivo likely depends on other endocrine-autocrine factors that impinge onto these signal transduction cascades. For example, 1,25(OH)2D3, a known repressor of 1 alpha-hydroxylation, may increase renal PKC amount-activity, thereby enhancing the inhibitory arm and preventing PTH stimulation of the 1-OHASE. In contrast, studies with diabetic rats suggest that insulin may allow cAMP-mediated stimulation to override PKC-mediated inhibition of 1-OHASE activity. Analogous to models proposed for regulation of adrenal steroid hydroxylases, it is likely that regulation of renal vitamin D hydroxylation involves both acute (reversible phosphorylation) and chronic (modulation of gene expression) mechanisms. However, the molecular details of these regulatory mechanisms remain to be resolved.
Welsh
J
J
Department of Biochemistry, University of Ottawa, Ont., Canada.
Weaver
V
V
Simboli-Campbell
M
M
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D006900:Hydroxylation; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction
D010281:Parathyroid Hormone; D010716:Phosphatidylinositols; D000242:Cyclic AMP; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D011493:Protein Kinase C; D002117:Calcitriol