SODIUM PUMP Close Encounters Between the Na Pump and the IP₃R

Miyakawa-Naito et al. uncovered an intriguing interaction between the Na,K-ATPase (Na⁺- and K⁺-dependent adenosine triphosphatase) and the inositol 1,4,5-trisphosphate receptor (IP₃R), implicating a possible interaction of these two proteins in cell signaling. Ouabain, a cardiac glycoside initially identified as an arrow poison and long used experimentally as an inhibitor of the Na,K-ATPase, has more recently been proposed to function as a hormone. Partial inhibition of the Na,K-ATPase by ouabain elicits oscillations in intracellular calcium concentration ([Ca²⁺]_i) and stimulates several transcription factors, suggesting that association of ouabain (a steroid) with the plasma membrane Na,K-ATPase activates a cell signaling pathway. Miyakawa-Naito et al. used pharmacological analysis to determine that ouabain-induced [Ca²⁺]_i oscillations in rat renal proximal tubule cells depended on IP₃R-mediated release of calcium from endoplasmic reticulum (ER) stores. Fluorescence resonance energy transfer (FRET) analysis in COS-7 cells indicated close proximity of Na,K-ATPase to IP₃R2 and IP₃R3 and coimmunoprecipitation indicated that the Na,K-ATPase associated with IP₃R3 in a complex. FRET and coimmunoprecipitation were increased by ouabain and abolished by disruption of the actin cytoskeleton, which also abolished ouabain-induced Ca²⁺ oscillations, implicating the cytoskeleton in the association of plasma membrane Na,K-ATPase with ER IP₃R. Oscillations persisted in cells treated with a phospholipase C inhibitor or transfected with a high-affinity IP₃-binding protein. Partial truncation of the Na,K-ATPase α-1 subunit N-terminal indicated that the ability of ouabain-stimulated Na,K-ATPase to elicit Ca²⁺ oscillations and activate nuclear factor-B depended on a region that was not required for enzymatic activity. This study thus defines a functional microdomain linking the plasma membrane to ER Ca²⁺ stores and adds weight to the possible role of the Na,K-ATPase as a hormone receptor and transducer of cell signaling.

A. Miyakawa-Naito, P. Uhlén, M. Lal, O. Aizman, K. Mikoshiba, H. Brismar, S. Zelenin, A. Aperia, Cell signaling microdomain with Na,K-ATPase and inositol 1,4,5-trisphosphate receptor generates calcium oscillations. J. Biol. Chem. 278, 50355-50361 (2003). [Abstract] [Full Text]

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