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Protein kinase C activators induce membrane retrieval of type II Na⁺-phosphate cotransporters expressed in Xenopus oocytes

Ian C. Forster, Martin Traebert, Maciej Jankowski, Gerti Stange, Jürg Biber and Heini Murer

The rate of inorganic phosphate (P_i) reabsorption in the mammalian kidney is determined by the amount of type II sodium-coupled inorganic phosphate (Na⁺-P_i) cotransport protein present in the brush border membrane. Under physiological conditions, parathyroid hormone (PTH) leads to an inhibition of Na⁺-P_i cotransport activity, most probably mediated by the protein kinase A (PKA) and/or C (PKC) pathways.

In this study, PKC-induced inhibition of type II Na⁺-P_i cotransport activity was characterized in Xenopus laevis oocytes using electrophysiological and immunodetection techniques. Transport function was quantified in terms of P_i-activated current.

Oocytes expressing the type IIa rat renal, type IIb flounder renal or type IIb mouse intestinal Na⁺-P_i cotransporters lost > 50 % of P_i-activated transport function when exposed to the PKC activators DOG (1,2-dioctanoyl-sn-glycerol) or PMA (phorbol 12-myristate 13-acetate). DOG-induced inhibition was partially reduced with the PKC inhibitors staurosporine and bisindolylmaleimide I. Oocytes exposed to the inactive phorbol ester 4-PDD (4-phorbol 12,13-didecanoate) showed no significant loss of cotransporter function.

Oocytes expressing the rat renal Na⁺-SO₄^2- cotransporter alone, or coexpressing this with the type IIa rat renal Na⁺-P_i cotransporter, showed no downregulation of SO₄^2--activated cotransport activity by DOG.

Steady-state and presteady-state voltage-dependent kinetics of type II Na⁺-P_i cotransporter function were unaffected by DOG.

DOG induced a decrease in membrane capacitance which indicated a reduction in membrane area, thereby providing evidence for PKC-mediated endocytosis.

Immunocytochemical studies showed a redistribution of type II Na⁺-P_i cotransporters from the oolemma to the submembrane region after DOG treatment. Surface biotinylation confirmed a DOG-induced internalization of the transport protein.

These findings document a specific retrieval of exogenous type II Na⁺-P_i cotransporters induced by activation of a PKC pathway in the Xenopus oocyte.

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