ACETYLCHOLINE TRANSPORT, STORAGE, AND RELEASE

This chapter discusses the storage of acetylcholine(ACh) by synaptic vesicles and the relationship of storage to other aspects of presynaptic ACh metabolism. The chapter focuses on those features of cholinergic nerve terminal function that have been clarified as a result of the availability of a newly developed pharmacology for the ACh transporter (AChT) based on the compound tranr-2-(4-phenylpiperidino)cyclohexanol, analogs of ACh, and other compounds. Vesamicol binds to and inhibits the AChT, much as reserpine inhibits the catecholamine transporter of catecholaminergic synaptic vesicles. The different approaches utilized for the study of presynaptic ACh metabolism have resulted in broad agreement in some areas and disagreement in others. The AChT exhibits the lowest binding specificity among known ACh-binding proteins. It is driven by efflux of protons pumped into the vesicle by the V-type ATPase. A potent pharmacology of the AChT based on the allosteric VR has been developed. It has promised for clinical applications that include in vivo evaluation of the density of cholinergic innervation in organs based on PET and SPECT. The microscopic kinetics model that has been developed and the very low transport specificity of the vesicular AChT-VR suggest that the transporter has a channel-like or multidrug resistance protein-like structure. The AChT-VR is shown to be tightly associated with proteoglycan, which is an unexpected macromolecular relationship. © 1993 Academic Press Inc.