Neurotransmitter transport: Models in flux

Physiologists say that ions and neutral solutes can cross biological membranes via “transporters” and “channels.” We tend to think about the difference between transporters and channels in terms of gating mechanisms. Ion channels exhibit a wide range of selectivity properties and permeation rates, but their gating at the most basic level can be thought of in terms of a single barrier or gate acting as a switch. When the gate is closed, ions can’t permeate; when the gate is opened, a permeation pathway for ions allows flux, often at very high rates (up to 108/sec). Transporters and ion pumps, on the other hand, mediate flux that can be explained better by the presence of two gates—one external and one internal (1). In this canonical transport scheme, the two gates are never open simultaneously. Instead they open sequentially to allow the cytoplasmic and extracellular compartments alternating access to the permeation pathway (Fig. 1). Unlike flux through an open ion channel, there must be a gating cycle every time solute is transported, so transporters generally mediate much slower rates of solute permeation (sometimes as slow as 1/sec). An alternating access model can explain how a neurotransmitter can be accumulated against its electrochemical gradient if other ions are stoichiometrically co- or countertransported down their gradients. The kinetic scheme is formally equivalent to that of a carrier (like valinomycin) that shuttles back and forth across the membrane, although the physical process is quite distinct