Fig 1.

(A) Markovian state transition behavior exemplified for the human cardiac ether-a-go-go related gene (hERG) potassium channel between closed (C1, C2, and C3), open (O) and inactivated states (I) underlying the state probability curves in (B) [4]. The rate constants are labeled with Greek letters. (B) Molecular populations of hERG “flow” from one specific state to another based on intrinsic voltage-dependent rates of entry and exit. Multiple fluxes occur in parallel between specific states, speeding and slowing in response to dynamic perturbations. For example, the open (orange) and inactive (blue) states are fed by the closed state (magenta); the open and closed states are fed by the inactive state; and the inactive and closed states are fed by the open state. The time-dependent output of the overall system (i.e. the membrane potential in this case) is solved in cardiomyocytes via integration of the full complement of sodium, potassium, and calcium ion channel MDEs (which can be simulated using the O’Hara-Rudy model of the human cardiac AP [5]).