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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]

NKCC2 is the kidney-enriched sodium–potassium–chloride cotransporter that carries one $\mathrm{N}{\mathrm{a}}^{+}$, one ${\mathrm{K}}^{+}$ and two $\mathrm{C}{\mathrm{l}}^{-}$ ions together across a biological membrane in each coupled transport cycle. In the thick ascending limb of the Loop of Henle, NKCC2 supports salt uptake from the tubular lumen. It is a secondary active transport system: the coupled ion gradients provide the immediate driving force, while the sodium-potassium ATPase helps maintain those gradients.^[ref]

The stoichiometry explains why transport is electrically silent: one cycle moves net charge $1+1-2=0$. This does not mean no ions move or no energy is involved. If $r_j$ is the activity inside divided by activity outside for ion $j$, the idealized free-energy change for inward transport isThe membrane-potential contributions cancel because the coupled net charge is zero. A favorable sodium ratio can therefore help drive other ions uphill in their chemical gradients. This expression assumes tightly coupled transport with the stated stoichiometry.

The molecular identification combined cloning with a functional assay: investigators expressed the kidney transporter in Xenopus oocytes and tested ion transport and inhibition by bumetanide. Comparison with a related thiazide-sensitive sodium–chloride transporter separated similar-looking sequences by their potassium requirement and drug sensitivity. The experiment illustrates why sequence similarity alone does not establish identical transport function.^[ref]