Review
The choline transporter-like family SLC44: Properties and roles in human diseases

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Abstract

The Na+-independent, high affinity choline carrier system proposed to supply choline for the synthesis of cell membrane phospholipids was recently associated with SLC44 family members (SLC44A1-5) also called choline-like transporter family. SLC44A1 is widely expressed throughout the nervous system in both neurons and oligodendrocytes, while SLC44A2-4 are mainly detected in peripheral tissues. The subcellular localization of the proteins was mainly addressed for SLC44A1 through the development of specific antibodies. SLC44A1 is detected in both the plasma and mitochondrial membranes where the protein is able to transport choline at high affinity and in a Na+-independent manner. The physiological relevance of SLC44A1 as a choline carrier is indicated by its likely involvement in membrane synthesis for cell growth or repair, and also by its role in phospholipid production for the generation of lung surfactant. Moreover, an autoimmune disease has been related to the blockade of SLC44A2 function, which results in the alteration of hair cells in the inner ear and leads to autoimmune hearing loss. In the alloimmune syndrome called transfusion-related acute lung injury, antibodies to SLC44A2 cause a deleterious aggregation of granulocytes. Therefore transporters of the SLC44 family represent attractive and promising targets for therapeutic and diagnostic applications regarding both immune and degenerative 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

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    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.

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