THE CHOLINERGIC GENE LOCUS

Messenger RNAs and the cognate gene(s) encoding choline acetyltransfer ase (ChAT) and the vesicular acetylcholine transporter (VAChT) have be en cloned from mammals and several other animal classes in the last de cade. These have provided molecular tools for investigating acetylchol ine synthesis and packaging into synaptic vesicles, the genesis of cho linergic vesicles, and the development and senescence of the cholinerg ic nervous system. VAChT and ChAT have been found to share a common ge ne locus and regulatory elements for gene transcription. The cholinerg ic gene locus represents a previously undiscovered type of neuronal tr anscriptional unit controlling chemically coded neurotransmission. In vitro assays for the transport function of VAChT have shed light on th e bioenergetics of amine accumulation in secretory vesicles. Manipulat ion of VAChT expression in vivo has demonstrated unequivocally the pri macy of vesicular exocytosis as the mode of transmitting quanta of ace tylcholine at the neuromuscular junction, as in vivo manipulation of a cetylcholinesterase levels has demonstrated the importance of acetylch oline metabolism in the regulation of complex functions such as cognit ion. Light and electron microscopic visualization of VAChT, complement ing previous ChAT immunohistochemistry, has improved understanding of the genesis and function of the cholinergic vesicle, neuron, and synap se. These advances should accelerate the development of ''cholinergic' ' pharmacological and gene therapeutic approaches to treatment of huma n diseases that are associated with cholinergic surfeit and insufficie ncy.