Monoamine transporters in the brain structure and function

Abstract

Monoamine transporters mediate the uptake of serotonin (SERT), norepinephrine (NET), and dopamine (DAT). They are closely related, share many conserved sequence elements and thus overlapping specificities for binding of inhibitors and substrates. The transporter is thought to undergo a conformational cycle that allows for transmembrane translocation of the monoamine substrate and the cosubstrate ions Na+ and Cl-. In addition, transporters are known to support currents that are substantially larger than those anticipated from the movement of charges during a translocation cycle. The recently solved structure of the distantly related bacterial leucine transporter (LeuTAa) offers insights that allow to reconcile the channel-like mode in which transporters can operate with the original alternate access model. Access to the substrate and cosubstrate permeation pathway is shielded by juxtamembrane residues, which can operate as gates. When simultaneously open, they allow for large ion fluxes which give rise to excess currents. SERT, NET, and DAT and the other (related) members of the Na+-dependent neurotransmitter family form constitutive oligomers. Oligomerization is a prerequisite for export of the proteins from the endoplasmic reticulum (ER) because it supports the recruitment of COPII components, most notably Sec24-family members. In addition, the action of amphetamines which induce reverse transport and thus monoamine efflux is proposed to be contingent on the oligomeric assembly of transporters. © 2007 Springer-Verlag US.