ReviewThe choline transporter-like family SLC44: Properties and roles in human diseases☆
Introduction
The organic cation choline is an essential component of membrane phospholipids including phosphatidylcholine and sphingomyelin, both required for the synthesis of cell membranes. Choline plays an additional role in the brain as a precursor for the synthesis of the neurotransmitter acetylcholine. Choline uptake is dependent upon carrier-mediated transport, since a charged cation under physiological pH does not cross cell membranes readily by passive diffusion. During the last decades, two main transport systems have been characterized biochemically: a high-affinity, Na+-dependent system localized in pre-synaptic cholinergic nerve terminals and likely coupled with acetylcholine synthesis, and a low-affinity, Na+-independent system found throughout various tissues proposed to supply choline for the synthesis of phospholipids in the cellular membrane (for review, Lockman and Allen, 2002). More recently, proteins have been associated with each of these transport systems. The high affinity (Km ∼ 2 μM) choline transporter, CHT1 (SLC5A7), belongs to the Na+/glucose co-transporter family, is sensitive to the choline analogue hemicholinium-3 (HC-3) and is thought to be part of the rate-limiting step in acetylcholine synthesis (Apparsundaram et al., 2001, Apparsundaram et al., 2000, Okuda et al., 2000). Choline is also a substrate for the low affinity (Km ∼ 200 μM) organic cation transporters or OCTs (SLC22) widely expressed in peripheral tissues as well as in the CNS (for review, Michel et al., 2006) and which recognize multiple endogenous and exogenous organic cations with low specificity. The concentrations of free choline in plasma or in CSF (12 and 7 μM in rats, respectively; Klein et al., 1992) being low in comparison to the affinities of these low affinity carriers, the physiological relevance of a general metabolic high affinity choline transporter that would supply choline for membrane phospholipid synthesis remained obvious. Ten years ago, candidate proteins were proposed to play such a role. They were called choline transporter-like proteins or CTL. Now, they constitute the SLC44 family since their inclusion in the solute carrier series (see http://www.genenames.org/genefamilies/SLC). Among the five SLC44 gene family members found in the human genome (Fig. 1A), the first to be identified, CTL1/CDw92/SLC44A1, was proposed to encode a protein involved in supplying choline to several cell types including a specific subset of cholinergic neurons (O’Regan et al., 2000) and to be present on various cells of the hematopoietic system (Wille et al., 2001).
This review will focus on the molecular identification and tissue distribution of SLC44 family members, their activity in choline transport, their implication in the development of diverse immune diseases, their role in the maturation of the respiratory system or in cell growth. We will also present the most recent data indicating that the members of this family should be considered both as potentially therapeutic targets themselves and for the development of new screening assays in auto- and allo-immune syndromes related to these proteins.
Section snippets
Molecular characterization of the SLC44 family
CTL1 was initially cloned from Torpedo marmorata and was first characterized as a suppressor for a yeast choline transport mutation derived from a Torpedo electric lobe yeast expression library (O’Regan et al., 2000, O’Regan and Meunier, 2003). The rat Slc44a1 (69% identity with its Torpedo counterpart) was then cloned from a brain cDNA library and its protein sequence found to display 96% identity with its human ortholog itself isolated from a cDNA expression library derived from myeloid KG1a
The transcripts of SLC44 family members are widely expressed in tissues
The distribution of Slc44a1-4 transcripts has been determined by Northern blot analysis in rat tissues. Slc44a1 was detected as a major 3.5 kb transcript in all brain regions studied including the striatum, cerebral cortex, hippocampus, hypothalamus, cerebellum, midbrain, thalamus and olfactory bulbs and also in the spinal cord. A minor 5.0 kb form was prominently detected in the colon and in a notable manner in the lung and spinal cord (O’Regan et al., 2000, Traiffort et al., 2005).
Involvement of SLC44A1 in membrane synthesis for cell growth
The physiological relevance of SLC44A1 as a choline transporter was addressed in several studies. The suppression of SLC44A1 via siRNA results in the impaired growth of the cholinergic hybrid neuroblastoma cell line NG108-15 cells. These data are consistent with a role for SLC44A1 in providing choline for incorporation into membrane phospholipids. However, such a role might be not true for all cerebral cells. In the same study, no growth reduction was observed in the glioma cell line C6,
Concluding remarks
Despite its recent discovery, the SLC44 family of choline transporters has yet been the focus of many studies which altogether make SLC44A1 and to a lesser extent SLC44A2, major players of the mechanisms regulating choline metabolism throughout the organism. These data open the way to further investigations of the role of choline transport in health and disease, since both proteins are implicated in physiological and pathological mechanisms. If their activity in choline transport appears to be
References (47)
- et al.
Molecular cloning of a human, hemicholinium-3-sensitive choline transporter
Biochem. Biophys. Res. Commun.
(2000) - et al.
Changes in mRNA for choline transporter-like protein following facial nerve transection
Brain Res. Mol. Brain Res.
(2002) - et al.
The neutrophil alloantigen HNA-3a (5b) is located on choline transporter-like protein 2 and appears to be encoded by an R > Q154 amino acid substitution
Blood
(2010) - et al.
Functional characterization of Na+-independent choline transport in primary cultures of neurons from mouse cerebral cortex
Neurosci. Lett.
(2006) - et al.
Choline uptake systems of rat brain synaptosomes
Biochim. Biophys. Acta
(1973) - et al.
Molecular and functional characterization of choline transporter in human colon carcinoma HT-29 cells
Arch. Biochem. Biophys.
(2009) - et al.
Choline transport via choline transporter-like protein 1 in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBT
Placenta
(2009) - et al.
Expression and functional characterization of choline transporter in human keratinocytes
J. Pharmacol. Sci.
(2009) - et al.
Molecular and functional characterization of choline transporter in rat renal tubule epithelial NRK-52E cells
Arch. Biochem. Biophys.
(2009) - et al.
Functional expression of choline transporter-like protein 1 (CTL1) in human neuroblastoma cells and its link to acetylcholine synthesis
Neurochem. Int.
(2011)
Identification and expression of a mouse muscle-specific CTL1 gene
Gene
Molecular cloning and characterization of a murine hemicholinium-3-sensitive choline transporter
Biochem. Soc. Trans.
Implication of transfected cell lines for the detection of alloantibodies against human neutrophil antigen-3
Transfusion
Epitope mapping of antibodies directed against the human neutrophil alloantigen 3a
Transfusion
Age-related changes in expression of CTL2/SLC44A2 and its isoforms in the mouse inner ear
Hear. Res.
Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis
FASEB J.
Glucocorticoids and lung development in the fetus and preterm infant
Pediatr. Pulmonol.
A quantitative atlas of mitotic phosphorylation
Proc. Natl. Acad. Sci. USA
Phosphocholine as a biomarker of breast cancer: molecular and biochemical studies
Int. J. Cancer
Genetic variation of the HNA-3a encoding gene
Transfusion
Impaired trafficking of choline transporter-like protein-1 at plasma membrane and inhibition of choline transport in THP-1 monocyte-derived macrophages
Am. J. Physiol. Cell Physiol.
Characterization of the human neutrophil alloantigen-3a
Nat. Med.
Molecular and functional characterization of an Na+-independent choline transporter in rat astrocytes
J. Neurochem.
Cited by (70)
Polymorphisms in the choline transporter SLC44A1 are associated with reduced cognitive performance in normotypic but not prenatal alcohol-exposed children
2024, American Journal of Clinical NutritionKidney transplant outcomes in patients with antibodies to human neutrophil antigen 3a
2023, Transplant ImmunologyCholine and phosphatidylcholine
2023, Encyclopedia of Human Nutrition: Volume 1-4, Fourth EditionThe mystery of the human proton-organic cation antiporter: One transport protein or many?
2022, Pharmacology and Therapeutics
- ☆
Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch.