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

Abstract

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.

FXYD protein isoforms differentially modulate human Na/K pump function

“…The multiexponential relaxation rates of the transient current during each voltage step reflect the rates of partial reactions during the pump’s Na + translocation steps; the slowest component of the relaxation rate represents the Na + reocclusion/deocclusion reaction ( Castillo et al, 2011 ; Holmgren et al, 2000 ; Moreno et al, 2020 ). The fastest components (corresponding to the reaction E2P(2Na + ) ↔ E2P + 2 Na + o , Fig.…”

“…We observed statistically significant shifts of the Q-V curves by each FXYD protein ( Fig. 4 B and Table 2 ): to the right with FXYD4 (+30 mV) and FXYD7 (+20 mV) and to the left by FXYD2 (−30 mV), FXYD6 (−20 mV), and FXYD1 (−10 mV), which indicates an approximately twofold increase or decrease in apparent affinity for Na + o , per 25-mV shift to the right or to the left, respectively ( Moreno et al, 2020 ). A previous report measuring the effect of cow FXYD2 on sheep α1β1 did not observe a shift of the Q-V curve ( Dempski et al, 2008 ).…”

Physiological Effects of the Electrogenic Current Generated by the Na /K Pump in Mammalian Articular Chondrocytes

“…These considerations, when combined with the demonstration that the healthy bovine and human chondrocytes expresses a number of different isoforms of the a, b, and g subunits of the Na + /K + pump protein complex 39,41 , raise important questions concerning the relative sizes of the electrogenic current and related changes in membrane potential that would be expected due to predominant expression of speci c combinations of the a, b, and g subunits 42,45 . We have approached this by simulating several of the combinations of expression of a and b subunits that are speci ed in a comprehensive review of the molecular physiology of the Na + /K + pump 68 and more recent studies of the kinetic transitions of the movement of Na + and K + ions through the pump 69 . Results expressed in terms of temperature-dependent development of steady-state electrogenic currents for ve subsets of data are shown in Figure 4.…”

“…These additions and other improvements will be needed before the mathematical modeling approach used in this study can be extended to analysis of ion homeostasis and the chondrocyte channelome 16,22 in a more physiological context, speci cally in chondron units, which represent the chondrocyte and its immediate pericellular environment 95 . Further model development is also needed before our simulations can provide insights into the altered articular joint electrolyte homeostasis resulting from disease-producing point mutations in one or more of the Na + /K + pump subunits or accessory proteins 69 .…”

Physiological Effects of the Electrogenic Current Generated by the Na+/K+Pump in Mammalian Articular Chondrocytes

“…95 Further model development is also needed before our simulations can provide insights into the altered articular joint electrolyte homeostasis resulting from disease-producing point mutations in one or more of the Na + /K + pump subunits or accessory proteins. 69 From a tissue engineering perspective, there is ongoing interest in the Na + /K + pump, ion transport, and the modulation of intracellular Na + by pharmacological agents such as ouabain and bumetanide as in vitro treatments for altering intracellular ion concentrations as a viable method for manipulating ECM synthesis by chondrocytes and enhancing the mechanical properties of engineered articular cartilage. 96 Finally, in the context of drug development and screening for diseases such as OA, which is known to be characterized by cellular senescence, or ''chondrosenescence,'' 29,97 the Na + /K + pump has already been identified as a candidate target for modulation by cardiac glycosides, re-entering the limelight as classical cardiotonic drugs reinvented as senolytic compounds.…”