Wiggle Wiggle Not a Trickle: How do Membrane Transporters Work (to concentrate ions 1000 fold)?

Transmembrane channels and facilitators can be highly selective in mediating the transport of nutrients and ions across membranes ‘downhill’, down their concentration gradient. Transporters can drive and concentrate nutrients or ions ‘uphill’ (energetically) across membranes achieving gradients of >1000:1 driven by ‘downhill’ movement of other coupled ions, protons, metabolites or electrochemical gradients1,2,3,4. How do such 'secondary transporters' accomplish this? Using three examples1,2,4 we seek to understand the mechanisms by which this coupling or two equilibria achieves the necessary structural transitions that drive uphill transport. In each case we derive mechanistic insight into the basis for how this is accomplished. What emerges is already surprising in many ways. For example it might seem that to concentrate ions or nutrients against a 1000:1 gradient, the affinity for the nutrient should change from high‐affinity on one side to low on the other. But this is not so; the affinity is the same from either side. How do they achieve concentration without either getting blocked by a bound nutrient ‘stuck’ in the sequestered state? And how do they not leak substrates, driving ions, or even protons across the membrane?