Ceramide-activated protein kinases A and C zeta inhibit kidney proximal tubule cell Na(+)-ATPase.
The basolateral membranes of kidney proximal tubule cells have (Na(+)+K(+))-ATPase and Na(+)-ATPase activities, involved in Na(+) reabsorption. We showed that ceramide (Cer) modulates protein kinase A (PKA) and protein kinase C (PKC), which are involved in regulating ion transporters. Here we show that ceramide, promotes 60% inhibition of Na(+)-ATPase activity (I(50) approximately 100nM). This effect was completely reversed by inhibiting PKA but did not involve the classic PKC signaling pathway. In these membranes we found the Cer-activated atypical PKC zeta (PKCzeta) isoform. When PKCzeta is inhibited, Cer ceases to inhibit the Na(+)-ATPase, allowing the cAMP/PKA signaling pathway to recover its stimulatory effect on the pump. There were no effects on the (Na(+)+K(+))-ATPase. These results reveal Cer as a potent physiological modulator of the Na(+)-ATPase, participating in a regulatory network in kidney cells and counteracting the stimulatory effect of PKA via PKCzeta.
Cabral
Lindsey M P
LM
Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro, Brazil.
Wengert
Mira
M
Almeida
Fernando G
FG
Caruso-Neves
Celso
C
Vieyra
Adalberto
A
Einicker-Lamas
Marcelo
M
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D000099221:Protein Kinase C zeta
D000251:Adenosine Triphosphatases; D027682:Cation Transport Proteins; D002518:Ceramides; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C021838:sodium-translocating ATPase