title: Parathyroid hormone (PTH) regulates the sodium chloride cotransporter via Ras guanyl releasing protein 1 (Ras-GRP1) and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway.
abstract: The sodium chloride cotransporter (NCC) is the principal salt absorptive pathway in the mammalian distal convoluted tubule (DCT) and is the site of action of thiazide diuretics. Using a mammalian cell model system to assess NCC function, we demonstrated previously that Ras guanyl releasing protein 1 (Ras-GRP1) mediates phorbol ester-induced suppression of the function and surface expression of NCC in a protein kinase C (PKC)-independent and extracellular signal-regulated kinase (ERK)1/2-dependent manner. Given that phorbol esters are functional analogs of diacylglycerol (DAG), this finding suggested a potential physiologic regulation of NCC by DAG. The parathyroid hormone (PTH) receptor is a G-protein-coupled receptor that is expressed in the DCT and activates PLC resulting in the generation of DAG. In this article, we demonstrate that PTH suppresses NCC function via a PLC/Ras-GRP1/ERK pathway. A functional assessment of NCC measuring thiazide-sensitive (22)Na(+) flux revealed that PTH suppresses NCC function. The inhibition of PLC prevented the suppression of NCC, indicating that PLC was necessary for this effect. Inhibitors of PKC and protein kinase A (PKA) had no effect on this suppression, but mitogen-activated protein kinase (MAPK) inhibitors prevented the PTH effect completely. Ras-GRP1 activates the MAPK pathway though activation of the small G-protein Ras. Gene silencing of Ras-GRP1 prevented the PTH-mediated suppression of NCC activity, the activation of the H-Ras isoform of Ras, and the activation of ERK1/2 MAPK. This finding confirmed the critical role of Ras-GRP1 in mediating the PTH-induced suppression of NCC activity through stimulation of the MAPK pathway.
authors: Department of Medicine, Section of Nephrology, University of Chicago, Ill., USA. bko@uchicago.edu
authors: Benjamin
authors: B
authors: Ko
authors: Leslie L
authors: LL
authors: Cooke
authors: Robert S
authors: RS
authors: Hoover
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D010281:Parathyroid Hormone / Q000494:pharmacology*; D049992:Sodium Chloride Symporters / Q000502:physiology*; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D010281:Parathyroid Hormone; C112278:Rasgrp1 protein, mouse; D049992:Sodium Chloride Symporters; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases