Reassessment of Models of Facilitated Transport and Cotransport

Abstract

Most membrane transport models are determinate, requiring the transported ligand(s) to bind initially to a vacant site, which undergoes translation and releases ligand to the alternate side. The carrier reverts to its initial position to complete the net transport cycle. Ligand affinity may change during translation, but this must be compensated by an equivalent energy change(s) within the transport cycle. However, any asymmetric cyclic equilibrium deduced on this basis is thermodynamically fallacious. Determinate cotransport models imply lossless stoichiometric relationships between the complexed cotransported ligands. Independent ligand leakage apart from the mobile cotransport complex must occur outside the canonical cotransport pathway. In contrast, stochastic transport models assume independent ligand diffusion through a variably occluded channel(s) containing binding sites where ligands may undergo bimolecular exchanges. Energy dissipation is intrinsic to all stochastic transport models and occurs within the primary transport pathway. Frictional interactions within a shared path generate flow coupling between ligands. The primary driving forces causing transmembrane ligand flows are their electrochemical potential differences between the external solutions. Demonstrations that ligand exchanges in CLC and neurotransmitter transporters can be multimodal, encompassing both "channel"-like high and "transporter"-like lower conductance states and have independently regulated import and export exchange fluxes are major challenges to determinate models but are explicable by transient widening of a close-encounter region within the channel, leading to decreased coupling and enhanced efflux.

Understanding transporter specificity and the discrete appearance of channel-like gating domains in transporters

“…Mutational and second-site suppressor analyses have supported that idea in general (Cain et al, 2000; Johnson et al, 2001; Green et al, 2003). In some specific cases however, mutations modifying transporter specificity in LacY (Naftalin, 2010) or other transporters (see later) could not fit with the simple “rocker-switch” alternating model. This issue will be discussed in the next section of this review.…”

“…The empty inward-facing open transporter can then transit back outward-facing state and, thereby, complete the transport cycle. This model is predominantly based on the study of secondary active transporters and whether it is applicable to passive facilitators is still disputable (Naftalin, 2008, 2010). …”

Opening talk

“…Thus when is k oi k io , then the Gibbs free energy G = -RTLN(k oi/ k io ) of the process 0 (k oi is the rate of movement from outside to inside and k io is the reverse rate from inside to outside). This implies that all membrane spanning rate processes are symmetrical (6).…”

“…This is a consequence of the necessity that that all the flows of matter and energy must be zero at equilibrium. Compensation within the network between one or more energy cycles for a shortfall in another is impermissible (6).…”

The Use of Radioisotopes to Characterise the Abnormal Permeability of Red Blood Cells from Sickle Cell Patients

“…The stoichiometry of the Na + /K + pump was also established using red blood cells (Post & Jolly, 1957;Garrahan & Glynn, 1967b). Latterly, much has been learnt about the kinetics of facilitated transporters and co-/countertransporters -for example those of the glucose transporter and the amino acid transporters (Barker & Ellory, 1990;Naftalin, 2010). In addition to these physiological studies, the permeability characteristics of the red blood cell membrane can be important pathologically, as seen for example in haemolytic anaemias and hereditary stomatocytoses Stewart, 2003).…”