Parathyroid hormone inhibits Na(+)-K(+)-ATPase through Gq/G11 and the calcium-independent phospholipase A2.
Previous studies from this laboratory have demonstrated that the 3-34 analog of parathyroid hormone (PTH) causes a 15-30% inhibition of Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity in rat renal proximal tubules through the generation of an increase in intracellular arachidonic acid, followed by its conversion to 20-hydroxyeicosatetraenoic acid (20-HETE) [C. P. Ribeiro and L. J. Mandel. Am. J. Physiol. 262 (Renal Fluid Electrolyte Physiol. 31): F209-F216, 1992; and C. P. Ribeiro, G. Dubay, J. R. Falk, and L. J. Mandel. Am. J. Physiol. 266 (Renal Fluid Electrolyte Physiol. 35): F497-F505, 1994]. The present study also uses proximal tubule suspensions to further elucidate this signaling pathway. Guanosine 5'-O-(2-thiodiphosphate), 500 microM, an inhibitor of heterotrimeric GTP-binding proteins (G proteins), and an anti-Gq/G11 antibody (1:500) both blocked the inhibition of the Na(+)-K(+)-ATPase by PTH-(3-34). Furthermore, a 42-kDa protein was identified in proximal tubules by the anti-Gq/G11 antibody (1:1,000). Bromoenol lactone (BEL), 1 microM, a suicide inhibitor of the calcium-independent 40-kDa phospholipase A2 (PLA2), prevented PTH-(3-34) inhibition of the Na(+)-K(+)-ATPase, unless exogenous 10 microM 20-HETE was added. In addition, BEL blocked the PTH-(3-34)-induced increase in arachidonic acid release in the proximal tubules. We conclude that a member of the Gq family and the calcium-independent 40-kDa PLA2 participate in the PTH-(3-34) signaling pathway in rat proximal tubules by mediating the steps between the binding of PTH-(3-34) to its receptor and the subsequent generation of arachidonic acid.
Derrickson
B H
BH
Department of Cell Biology, Duke University, Durham, North Carolina 27710, USA.
Mandel
L J
LJ
D000818:Animals; D001426:Bacterial Proteins; D002118:Calcium / Q000502:physiology*; D002417:Cattle; D019204:GTP-Binding Proteins / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology* / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D010539:Permeability; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013301:Streptolysins / Q000494:pharmacology
D001426:Bacterial Proteins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D013301:Streptolysins; C025964:streptolysin O; C031617:parathyroid hormone (3-34); D010741:Phospholipases A; D054467:Phospholipases A2; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium