How are ion pumps and agrin signaling integrated?

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 beta-subunit and exploits the ouabain-binding pocket.