Ceramide Is a Potent Activator of Plasma Membrane Ca super(2+)-ATPase from Kidney-promixal Tubule Cells with Protein Kinase A as an Intermediate

• Published in: The Journal of biological chemistry Vol. 282; no. 34; pp. 24599 - 24606
• Main Authors: Cabral, Lindsey MP, Wengert, Mira, da Ressurreicao, Alexandre AA, Feres-Elias, Pedro HP, Almeida, Fernando G, Vieyra, Adalberto, Caruso-Neves, Celso, Einicker-Lamas, Marcelo
• Format: Journal Article
• Language: English
• Published: 01.08.2007
• ISSN: 0021-9258; 1083-351X

The kidney-proximal tubules are involved in reabsorbing two-thirds of the glomerular ultrafiltrate, a key Ca super(2+)-modulated process that is essential for maintaining homeostasis in body fluid compartments. The basolateral membranes of these cells have a Ca super(2+)-ATPase, which is thought to be responsible for the fine regulation of intracellular Ca super(2+) levels. In this paper we show that nanomolar concentrations of ceramide (Cer sub(50) = 3.5 nM), a natural product derived from sphingomyelinase activity in biological membranes, promotes a 50% increase of Ca super(2+)-ATPase activity in purified basolateral membranes. The stimulatory effect of ceramide occurs through specific and direct (cAMP-independent) activation of a protein kinase A (blocked by 10 nM of the specific inhibitor of protein kinase A (PKA), the 5-22 peptide). The activation of PKA by ceramide results in phosphorylation of the Ca super(2+)-ATPase, as detected by an anti-Ser/Thr specific PKA substrate antibody. It is observed a straight correlation between increase of Ca super(2+)-ATPase activity and PKA-mediated phosphorylation of the Ca super(2+) pump molecule. Ceramide also stimulates phosphorylation of renal Ca super(2+)-ATPase via protein kinase C, but stimulation of this pathway, which inhibits the Ca super(2+) pump in kidney cells, is counteracted by the ceramide-triggered PKA-mediated phosphorylation. The potent effect of ceramide reveals a new physiological activator of the plasma membrane Ca super(2+)-ATPase, which integrates the regulatory network of glycerolipids and sphingolipids present in the basolateral membranes of kidney cells.