Transient Electrical Currents Mediated by the Na⁺/K⁺-ATPase: A Tour from Basic Biophysics to Human Diseases

The Na⁺/K⁺-ATPase is a chemical molecular machine responsible for the movement of Na⁺ and K⁺ ions across the cell membrane. These ions are moved against their electrochemical gradients, so the protein uses the free energy of ATP hydrolysis to transport them. In fact, the Na⁺/K⁺-ATPase is the single largest consumer of energy in most cells. In each pump cycle, the protein sequentially exports 3Na⁺ out of the cell, then imports 2K⁺ into the cell at an approximate rate of 200 cycles/s. In each half cycle of the transport process, there is a state in which ions are stably trapped within the permeation pathway of the protein by internal and external gates in their closed states. These gates are required to open alternately; otherwise, passive ion diffusion would be a wasteful end of the cell's energy. Once one of these gates open, ions diffuse from their binding sites to the accessible milieu, which involves moving through part of the electrical field across the membrane. Consequently, ions generate transient electrical currents first discovered more than 30 years ago. They have been studied in a variety of preparations, including native and heterologous expression systems. Here, we review three decades' worth of work using these transient electrical signals to understand the kinetic transitions of the movement of Na⁺ and K⁺ ions through the Na⁺/K⁺-ATPase and propose the significance that this work might have to the understanding of the dysfunction of human pump orthologs responsible for some newly discovered neurological pathologies.