cAMP-dependent and -independent downregulation of type IINa-P-i cotransporters by PTH

Parathyroid hormone (PTH) leads to the inhibition of Na-P-i cotransport act ivity and to the downregulation of the number of type II Na-P-i cotransport ers in proximal tubules, as well as in opossum kidney (OK) cells. PTH is kn own also to lead to an activation of adenylate cyclase and phospholipase C in proximal tubular preparations, as well as in OK cells. In the present st udy, we investigated the involvement of these two regulatory pathways in OK cells in the PTH-dependent downregulation of the number of type II Na-P-i cotransporters. We have addressed this issue by using pharmacological activ ators of protein kinase A (PKA) and protein kinase C (PKC), i.e., 8-bromo-c AMP (8-BrcAMP) and beta-12-O-tetradecanoylphorbol 13-acetate (beta-TPA), re spectively, as well as by the use of synthetic peptide fragments of PTH tha t activate adenylate cyclase and/or phospholipase C, i.e., PTH-(1-34) and P TH-(3-34), respectively. Our results show that PTH signal transduction via cAMP-dependent, as well as cAMP-independent, pathways leads to a membrane r etrieval and degradation of type II Na-P-i cotransporters and, thereby, to the inhibition of Na-P-i cotransport activity. Thereby, the cAMP-independen t regulatory pathway leads only to partial effects (similar to 50%).