Na(+),K(+)-ATPase (NKA) has a fundamental role in ion transport across the plasma membrane of animal cells and uses approximately 50% of brain energy consumption. Recent work has uncovered additional roles for NKA in signal transduction. How might such different functions of the sodium-potassium pump be connected and regulated? We envision an integrated model of ion pumping and signaling, considering in particular the recently discovered regulation of the sodium-potassium pump by agrin, a protein that is cleaved specifically by neurotrypsin at the synapse. Based on the recently solved structure of NKA and sequence analysis, we propose a molecular model for the agrin-NKA interaction, in which agrin displaces the NKA β-subunit and exploits the ouabain-binding pocket.
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