Can Passive Asymmetric Vacant Carrier Distributions Counterbalance Asymmetric Carrier Affinities?

Abstract

There is a popular fallacy that asymmetric vacant carrier distributions account for asymmetric transporter affinities, e.g. GLUT1 and SGLT1. An alternating site transporter can be passively asymmetrically distributed, because of differences in standard free energy, μ′c, or activity coefficients, γc of the vacant carrier isoforms, ci between the opposing membrane sides; i.e. either μ′cin < μ′cout or γcin < γcout. Thus, at equilibrium the Gibbs free energy difference, ΔGc of the vacant carrier distribution, ΔGc = Δμc′ + RTLn(ccout/ccin) = 0. Alternatively, if only the activity coefficients are unequal, ΔGc = RTLn((ccout.γcout ) /(ccin.γcin)) = 0. In both cases, at equilibrium, when ΔGc = 0, ccout < ccin.The carrier partition coefficient between the inside and outside membrane phases Pin/out = ccin/ccout hence Δμ′cout-in = - RTLn(Pin/out) and ΔGc = RTLn(ccout/(Pin/out..ccin)) = 0 Since at equilibrium, unidirectional vacant carrier flows kij.ci are equal, kout-in.ccout = kin-out.ccin, hence ccin/ccout = kout-in/kin-out = Pin/out The flux ratio equation, ΔGc = RTLN(kout-in/kin-out), applicable to reactions in homogeneous membrane phases, requires a correction for asymmetric carrier equilibration between heterogeneous membrane phases, becoming: ΔGc = RTLn(kout-in/(Pin/out.kin-out) = 0, or ΔGc = RTLn(γcout.kout-in/(γcin.kin-out) = 0. However, when these corrections are applied, neither the asymmetric flux ratios, nor vacant carrier distributions compensate for the energetic difference existing from the asymmetric ligand affinities, i.e. if KDout < KDin then ΔGcaffinities = RTLn(KDout/KDin) < 0. Since a passively acquired asymmetric distribution at equilibrium generates no force, no energy is available from the vacant carrier distribution to counterbalance any energy difference between the asymmetric ligand affinities. Therefore, asymmetric transport needs another rationalization.