Transport mechanisms in acetylcholine and monoamine storage

Sequence-related vesicular acetylcholine transporter (VAChT) and vesicular monoamine transporter (VMAT) transport neurotransmitter substrates into sec retory vesicles. This review seeks to identify shared and differentiated as pects of the transport mechanisms. VAChT and VMAT exchange two protons per substrate molecule with very similar initial velocity kinetics and pH depen dencies. However, vesicular gradients of ACh in vivo are much smaller than the driving force for uptake and vesicular gradients of monoamines, suggest ing the existence of a regulatory mechanism in ACh storage not found in mon oamine storage, The importance of microscopic rather than macroscopic kinet ics in structure-function analysis is described, Transporter regions affect ing binding or translocation of substrates, inhibitors, and protons have be en found with photoaffinity labeling, chimeras, and single-site mutations, VAChT and VMAT exhibit partial structural and mechanistic homology with lac tose permease, which belongs to the same sequence-defined superfamily, desp ite opposite directions of substrate transport. The vesicular transporters translocate the first proton using homologous aspartates in putative transm embrane domain X (ten), but they translocate the second proton using unknow n residues that might not be conserved between them. Comparative analysis o f the VAChT and VMAT transport mechanisms will aid understanding of regulat ion in neurotransmitter storage.