Disease relevance of Slc5a7

• A better understanding of modes of CHT regulation should allow for experimental manipulation of cholinergic signaling in vivo with potential utility in human disorders of known cholinergic dysfunction such as Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, and dysautonomia [1].
• Analysis of this hypothesis in vivo is limited in mammals because of the toxicity of CHT antagonists and the early postnatal lethality of CHT-/- mice (Ferguson et al., 2004) [2].

Psychiatry related information on Slc5a7

• In Caenorhabditis elegans, in which cholinergic signaling supports motor activity and mutant alleles impacting ACh secretion and response can be propagated, we investigated the contribution of CHT (CHO-1) to facets of cholinergic neurobiology [2].

High impact information on Slc5a7

• We also found that A beta could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release [3].
• Adult CHT+/- mice overcome reductions in CHT protein levels and sustain choline uptake activity at wild-type levels through posttranslational mechanisms [4].
• Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are specifically lost in CHT-/- mouse brains [4].
• The Torpedo homologue of the high affinity choline transporter CHT1 was cloned and its activity was reconstituted in Xenopus oocytes [5].
• Compared with wild type mice, striatal high-affinity choline transporter expression in dopamine transporter knockdown mice was significantly decreased [6].

Biological context of Slc5a7

• Expression of high affinity choline transporter during mouse development in vivo and its upregulation by NGF and BMP-4 in vitro [7].
• Pretreatment with OKA alone, but not beta-PMA, significantly augmented the phosphorylation level of CHT proteins [8].

Anatomical context of Slc5a7

• In the spinal cord, CHT mRNA was present at close to adult levels at the earliest time point examined (E14) and showed almost no changes after birth [7].
• Distribution of high affinity choline transporter immunoreactivity in the primate central nervous system [9].
• CHT-containing fibers were also present in sensory and limbic thalamic nuclei, preoptic and hypothalamic areas, and the floccular lobe of the cerebellum [9].
• In mouse crude striatal and hippocampal synaptosomes, PKC activators beta-phorbol 12-myristate 13-acetate (beta-PMA) and beta-phorbol 12,13-dibutyrate produced time- and concentration-dependent reductions in CHT function [8].
• To gain further insights into the cholinergic differentiation of presynaptic efferent terminals in the inner ear, we investigated the expression of the high-affinity choline transporter (ChT1) in comparison to other presynaptic and cholinergic markers [10].

Associations of Slc5a7 with chemical compounds

• The choline transporter, designated CHT, was recently cloned [7].
• In cholinergic neurons, the presynaptic choline transporter (CHT) mediates high-affinity choline uptake (HACU) as the rate-limiting step in acetylcholine (ACh) synthesis [1].
• Recent studies show that CHT contains canonical protein kinase C (PKC) serine and threonine residues [8].
• We examined the ability of PKC and serine/threonine protein phosphatase 1/2A (PP1/PP2A) to regulate CHT function, surface expression, and phosphorylation [8].
• However, tautomycin (PP1 inhibitor) and cyclosporin A (PP2B inhibitor) failed to alter CHT-mediated choline uptake [8].

Other interactions of Slc5a7

• PP1/PP2A inhibitors okadaic acid (OKA) and calyculin A (CL-A) produced a time- and concentration-dependent decrease in CHT function [8].
• Dual fluorescent confocal microscopy revealed that the majority of CHT immunoreactive neurons contained the specific cholinergic marker, choline acetyltransferase, at all levels of the monkey CNS [9].
• Reduced expression and capacity of the striatal high-affinity choline transporter in hyperdopaminergic mice [6].
• Cholinergic nerve fibers, identified by labeling for the high affinity choline transporter, were abundant in the sinus and atrioventricular nodes, ventricular conducting system, interatrial septum, and much of the right atrium, but less abundant in the left atrium [11].

Analytical, diagnostic and therapeutic context of Slc5a7

• We applied RT/PCR to monitor the expression of CHT in the developing mouse CNS from embryonic day 14 (E14) to postnatal day 30 (P30) [7].
• CHT protein was detected by Western blotting as a band of apparent molecular weight of 70 kDa [7].
• Molecular cloning and characterization of a murine hemicholinium-3-sensitive choline transporter [12].

References