Metabolic Energy is Stored in a Homeostatic Trans-Membrane Water Barochemical Gradient

Trans-membrane water transport and co-transport is ubiquitous in cell biology. Integrated over all the cell's H₂O transporters and co-transporters, the rate of homeostatic, bidirectional trans-cytolemmal water "exchange" is synchronized with the metabolic rate of the crucial Na⁺,K⁺-ATPase (NKA) enzyme: the active trans-membrane water cycling (AWC) phenomenon. Is AWC futile, or is it consequential? Conservatively representative literature metabolomic and proteinomic results enable comprehensive free energy (ΔG) calculations for the many transport reactions with known water stoichiometries. Including established intracellular pressure (P_i) magnitudes, these reveal an outward trans-membrane H₂O barochemical ΔG gradient comparable to that of the well-known inward Na⁺ electrochemical ΔG gradient. For most co-influxers, these two gradients are finely balanced to maintain intracellular metabolite concentration values near their consuming enzyme Michaelis constants. Our analyses include glucose, glutamate^-, gamma-aminobutyric acid (GABA), and lactate^- transporters. 2%-4% P_i alterations can lead to disastrous metabolite concentrations. For the neurotransmitters glutamate^- and GABA, very small astrocytic P_i changes can allow/disallow synaptic transmission. Unlike the Na⁺ and K⁺ electrochemical steady-states, the H₂O barochemical steady-state is in (or near) chemical equilibrium. The analyses show why the presence of aquaporins (AQPs) does not dissipate trans-membrane pressure gradients. A feedback loop inherent in the opposing Na⁺ electrochemical and H₂O barochemical gradients regulates AQP-catalyzed water flux as integral to AWC. A re-consideration of the underlying nature of P_i is also necessary. AWC is not a futile cycle but is inherent to the cell's "NKA system"-a new, fundamental aspect of biology. Metabolic energy is stored in the trans-membrane water barochemical gradient.