Choline Transporter CHT Regulation and Function in Cholinergic Neurons

Abstract

Choline uptake into cholinergic nerve terminals by the sodium-dependent high-affinity choline transporter CHT is essential for providing choline as substrate for synthesis of acetylcholine (ACh); ACh is used by cholinergic neurons to communicate information to a wide range of tissues in central and peripheral nervous systems. CHT is expressed almost exclusively in cholinergic neurons, and is subject to transcriptional and post-translational control by factors that promote or diminish cholinergic neurotransmission. The distribution of CHT proteins within cholinergic presynaptic terminals is dynamically regulated. Thus, choline uptake activity is determined largely by the plasma membrane CHT level, and this is finely controlled by a balance between internalization and recycling of CHT proteins in endosomal compartments. CHT proteins are also in synaptic vesicle membranes, thereby allowing cell surface CHT levels to increase rapidly in conjunction with exocytotic transmitter release to provide enhanced choline for ACh re-synthesis. Little is known about post-translational modification of CHT, although data is emerging that CHT activity and subcellular trafficking is modulated by kinase-mediated phosphorylation. Recent studies have also identified proteins with which CHT interacts, but this requires further investigation to reveal the role of other proteins in regulating CHT function and activity. Polymorphisms in CHT protein and modifications in its expression are linked to neurological and psychiatric disorders, and can alter function of peripheral systems that are regulated by cholinergic innervation, such as the cardiovascular system. The critical role of CHT in maintaining cholinergic transmission indicates that it could be a target for therapeutic intervention to promote ACh synthesis, but mechanisms by which this can be accomplished have not been adequately addressed.