Transporter reversal

Transporter reversal or reverse transport is a phenomenon in which the substrates of a membrane transporter are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when membrane transport proteins undergoes phosphorylation by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.

Most neurotransmitter transporters are involved in the reuptake of neurotransmitters back into the cell which released them; during neurotransmitter reuptake, these transporter will move specific types of neurotransmitters from the extracellular space into the cytosol of a neuron or glial cell. When these transporters operate in reverse, they produce neurotransmitter efflux (i.e., the movement of neurotransmitters from the cytosol to the extracellular space). In neurons, transporter reversal facilitates the release of neurotransmitters into the synaptic cleft, which subsequently increases the binding of these neurotransmitters at their associated neurotransmitter receptors. For example, many monoamine releasing agents produce monoamine efflux (i.e., the release of monoamine neurotransmitters from neurons into the synaptic cleft) by triggering reverse transport at vesicular monoamine transporters (specifically VMAT1 and VMAT2) and other monoamine transporters that are located along the plasma membrane of neurons (specifically, DAT, NET, and SERT).

Mechanism

Amphetamine and similar "releasing agents" are able to reverse the transport direction of monoamine transporters through the activation of an intracellular receptor, trace amine-associated receptor 1 (TAAR1), which is located within the axon terminal of associated monoamine neuron.^[1] TAAR1 signals through protein kinase A and protein kinase C to phosphorylate monoamine transporters. Dependent upon the phosphorylating protein kinase, the phosphorylated transporters will either reverse transport direction, causing neurotransmitter efflux and reuptake inhibition, or withdrawal into the cytoplasm, causing only reuptake inhibition.^[1] Amphetamine is also known to release the vesicular stores of monoamines in monoamine neurons through VMAT2, although the precise mechanism has not been established.

Additional mechanisms, such as DAT phosphorylation by CAMKII, have also been implicated in transporter reversal by amphetamine and related compounds.

See also

• Active transport
• Releasing agent

References