It is known that secondary transporters, which utilize transmembrane ionic gradients to drive their substrates up a concentration gradient, can reverse the uptake and instead release their substrates. Unfortunately, the Michaelis-Menten kinetic scheme, which is popular in transporter studies, does not include transporter reversal, and it completely neglects the possibility of equilibrium between the substrate concentrations on both sides of the membrane. We have developed a complex two-substrate kinetic model that includes transport reversal. This model allows us to construct analytical formulas allowing the calculation of a “heteroexchange” and “transacceleration” using standard Michaelis coefficients for respective substrates. This approach can help to understand how glial and other cells accumulate substrates without synthesis and are able to release such substrates and gliotransmitters. 1. Introduction Unlike “primary” or ATP dependent transporters that create the major ionic gradients of K/Na/H and Cl/CO2 ions across cellular membranes harnessing the energy reserved in ATP, the “secondary transporters” utilize the energy available from transmembrane ionic and/or pH gradients and membrane potential to drive their substrates up a steep concentration gradient. Transporters on neurons and astrocytes clearing neurotransmitters from the synaptic cleft and extracellular space mainly belong to different “secondary transporters” families. Recently, it has been shown that astrocytes and other glial cells accumulate monoamines [1] and polyamines [2, 3] while lacking the enzymes for their synthesis [1, 4–6]. One among many known representatives of the “secondary transporters” that utilize the transmembrane ionic gradients and membrane potential is the family of organic cation transporters (OCT). These transporters take up different mono- and polyamines [7], and cells expressing such transporters also release these substrates using possibly two pathways: (i) large pores and (ii) transport reversal. Here we analyze one of transport reversal mechanisms. Energy Calculations. Experimentally, it has been shown that secondary transporters can reverse their uptake releasing their substrates instead [8–10]. Energy based calculations were introduced to analyze the conditions for substrate release or uptake for this kind of transporter [11, 12]. It was established that substrate transport depends on the energy balance of coupled transport of the substrate and simultaneously transported ions (see Appendix A). Most secondary transporters could be reversed by membrane
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