Interaction of Vitamin D-Metabolites with Adenylate Cyclase/Cyclic AMP System: A Biological Model of Controlled Regulation
Parathyroid hormone and other peptide hormones convey their biological messages by combining with membrane-bound receptors and activating them. The message is advanced then by catalitically generated cyclic AMP which carries the signal to the effector components of the cytosol, leading ultimately to the physiological response. The factors which control the operation of this system have not been delineated in detail yet. Such factors if present may exert their effect at any level of the activation cascade. For example inhibitors of phosphodiesterase may enhance the effect of adenylate cyclase agonists by blocking the degradation of cyclic AMP. In contrast, depletion of intracellular ATP which serves as a substrate for the generation of cyclic AMP may abolish the response to peptide hormones. We have recently demonstrated refractoriness of the kidney to parathyroid hormone in rats with maleate-induced Fanconi syndrome.1 In these animals the absence of phosphaturic response and the absence of augmented excretion of urinary cyclic AMP after the administration of parathyroid hormone was not due to altered function of the receptor complex but due to documented lack of ATP. Addition of ATP to the in vitro system restored to normal the response to parathyroid hormone as reflected by enhanced generation of cyclic AMP. The question which requires further investigations is whether variations in intracellular ATP may play a role in the physiological response to parathyroid hormone and other adenylate cyclase agonists.
KeywordsParathyroid Hormone Adenylate Cyclase Peptide Hormone Fanconi Syndrome Renal Handling
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