Chapter 20: Acetylcholine transporter — vesamicol receptor pharmacology and structure

Publisher Summary Acetylcholine (ACh) is stored by synaptic vesicles at about 100-fold higher concentration than present in the cytoplasm. As vesicular ACh is free in solution, energy input is required to establish the gradient of concentration. This is accomplished in a process having at least two macromolecular components that reside in the vesicular membrane. The first component is a proton-pumping ATPase known as a V-type ATPase. It pumps protons into the synaptic vesicle, thus acidifying the vesicle core to about pH 5.4. The enzyme is found in the vacuolar-type intracellular organelles, and it is evolutionally related to the mitochondria1 ATPase. The second component is the ACh transporter (AChT). It exchanges one or more vesicular protons for cytoplasmic ACh, thus accomplishing secondary active transport of ACh. The ACh exhibits a transport Michaelis dissociation constant (KM) of about 0.3 mM, which is less than the 4 mM that can be estimated for the concentration of ACh in the cytoplasm. Proton-exchanging transporters appear to account for vesicular storage of all of the classical neurotransmitters. As a class, these transporters are poorly characterized. A structure-activity study has demonstrated that the potency of vesamicol analogues, as assessed by inhibition of active transport, is highly dependent upon the structure of the analogue. This chapter reports the results of the recent ligand-interaction experiments that were directed toward making a choice between models 1 and 2, and toward the identification of the macromolecular structures of the AChT and VR.