Quantitative calculation of the role of the Na(+),K(+)-ATPase in thermogenesis.

The Na(+),K(+)-ATPase is accepted as an important source of heat generation (thermogenesis) in animals. Based on information gained on the kinetics of the enzyme's partial reactions we consider via computer simulation whether modifications to the function of the combined Na(+),K(+)-ATPase/plasma membrane complex system could lead to an increased body temperature, either through the course of evolution or during an individual's lifespan. The enzyme's kinetics must be considered because it is the rate of heat generation which determines body temperature, not simply the amount of heat per enzymatic cycle. The results obtained indicate that a decrease in thermodynamic efficiency of the Na(+),K(+)-ATPase, which could come about by Na(+) substituting for K(+) on the enzyme's extracellular face, could not account for increased thermogenesis. The only feasible mechanisms are an increase in the enzyme's expression level or an increase in its ion pumping activity. The major source of Na(+),K(+)-ATPase-related thermogenesis (72% of heat production) is found to derive from passive Na(+) diffusion into the cell, which counterbalances outward Na(+) pumping to maintain a constant Na(+) concentration gradient across the membrane. A simultaneous increase in both Na(+),K(+)-ATPase activity and the membrane's passive Na(+) permeability could promote a higher body temperature.