Homeostatic and Adaptive Energetics:
Nonequilibrium Fluctuations Beyond Detailed Balance in
Voltage-Gated Ion Channels

ABSTRACT: Stochastic thermodynamics has largely succeeded in analyzing both equilibrium and arbitrarily far-from-equilibrium systems. It remains underapplied, however, toward mesoscopic complex systems—especially biological ones—whose effective dynamics often violate detailed balance and whose microscopic degrees of freedom are often unknown or intractable. Using its tools, we review how to delineate excess and housekeeping energetics—the adaptive and homeostatic components of a system's thermodynamic behavior—before extending stochastic thermodynamics with a trajectory class fluctuation theorem for nonequilibrium steady-state, nondetailed-balanced complex systems. Then, we consider two neurobiological examples—voltage-gated sodium and potassium ion channels—to illustrate and apply these results, uncovering novel challenges—and highlighting the progress possible—in understanding the thermodynamics of complex systems without exhaustive knowledge of every underlying degree of freedom.