Cotransporter

A cotransporter is a membrane protein that couples the movement of different solutes in a transport cycle. In common same-direction cotransport, a symporter moves the coupled species toward the same side; an antiporter exchanges species moving in opposite directions. Coupling lets a favorable electrochemical gradient for one solute help drive another against its own gradient, providing secondary active transport.

NKCC2 illustrates same-direction coupling: one sodium ion, one potassium ion and two chloride ions move together in the kidney transport system. The net transported charge per cycle is $1+1-2=0$. Electrically silent transport can therefore involve substantial ion movement; zero net charge is not zero flux.^[ref]

For an idealized one-to-one symporter carrying a monovalent cation $A$ and a neutral solute $B$ inward,Here $a$ denotes chemical activity and $\psi$ electric potential. With zero electric potential difference, an activity ratio of $0.01$ for $A$ and $10$ for $B$ gives a logarithm argument $0.1$: inward cotransport is thermodynamically favorable even though $B$ is more concentrated inside. This example assumes the stated coupling and stoichiometry; it is not an assignment of that stoichiometry to every transporter.

Cloning followed by expression in frog oocytes helped identify the kidney transporters experimentally. Comparing transport, ion dependence and inhibition distinguished related sequences with different functions. A cotransporter is thus defined by coupled movement, rather than merely by sequence resemblance to another carrier.^[ref]

An antiporter is a membrane protein that couples movement of different substances in opposite directions across a cell membrane. In an idealized exchange cycle, one substrate moves inward while another moves outward. The ratio transported, or stoichiometry, depends on the transporter; opposite directions do not imply equal numbers or zero net electric charge.

NhaA provides a measured example. In a 1993 study, purified Escherichia coli NhaA was reconstituted in sodium-loaded membrane vesicles. Parallel measurements of sodium efflux and proton influx supported exchange of two protons for each sodium ion. An independent method based on the generated membrane electric potential difference and ion gradients agreed under the stated coupling assumptions.^[ref]

The charge accounting is revealing. In the tested direction, two inward singly positive ions and one outward singly positive ion produce one net positive charge moving inward per exchange cycle. Thuswhere $e$ is the magnitude of the elementary charge. An antiporter can therefore be electrogenic. Directional exchange, charge balance and the energy available from an electrochemical gradient must be assessed separately.

NhaA is a sodium/proton antiporter exemplified by the Escherichia coli membrane protein. It couples the movement of sodium ions to proton movement in the opposite direction across a cell membrane, contributing to ion and pH regulation. The name of this particular protein should not be confused with every sodium/proton exchanger.

A 1993 experiment purified NhaA and placed it in sodium-loaded proteoliposomes: artificial membrane vesicles containing the transport protein. Parallel sodium-efflux and proton-influx measurements supported two protons per sodium ion over the tested pH range 7.2–8.1. A second determination used membrane electric potential difference and equilibrium gradients, under assumptions of coupled transport.^[ref]

For an illustrative cycle with two protons entering and one sodium ion leaving, the inward transfer of electric charge is $2e-e=e$, where $e$ is the elementary charge. Reversing the cycle reverses that transfer. Opposite transport directions therefore do not imply electrical neutrality, nor do they alone determine which direction is energetically favored; the electrochemical gradients matter.

A 2005 X-ray crystallography study supplied a different kind of evidence: a structure of downregulated NhaA, including a cytoplasm-facing funnel toward a putative ion-binding region. The authors proposed a mechanism in which access changes between the two sides. A static structure helps constrain such a mechanism but does not directly measure the transported ratio or film a working exchange cycle.^[ref]

A symporter is a membrane protein coupling the movement of different substances toward the same side of a cell membrane. The favored movement of one substrate can help drive another against its own gradient, a form of secondary active transport. Same-direction transport does not by itself say whether the combined movement carries net charge.

A functional experiment identifies coupled transport rather than merely a promising sequence. The 1994 kidney-cotransporter study expressed cloned transporters in Xenopus laevis oocytes and tested their transport activity. Related proteins differed in their potassium requirement and inhibitor response, connecting molecular identity to distinct transport functions.^[ref]

A deliberately simplified energy example uses two neutral solutes, $A$ and $B$, coupled 1:1 from outside to inside. Assume dilute ideal solutions, a tenfold larger concentration of $A$ outside, and a fivefold larger concentration of $B$ inside. Their combined free energy change iswhich is negative. Favorable inward movement of $A$ can therefore pay for inward movement of $B$ against its concentration gradient. Charged substrates require additional electrical terms; the toy calculation is not a measured stoichiometry of the kidney transporters.