br Regulation of Glu transporters The

Regulation of Glu transporters The pivotal role of Glu transporters in the fine tuning and turnover of this excitatory amino doripenem calls for a detailed characterization of its regulation. Several general mechanisms that modify Glu uptake activity have been described. These include transcription of the genes encoding the transporters, the maturation and stabilization of its encoding mRNA (Bessho et al., 1993, Testa et al., 1995), the posttranslational modifications of the transporter protein (Traynelis et al., 2010), its trafficking to and from the plasma membrane (Robinson, 2006, Robinson, 2002), and its diffusion within the plasma membrane (Benediktsson et al., 2012, Murphy-Royal et al., 2015, Shin et al., 2009). Whereas DNA transcription and protein expression events require long time periods (hours) to reflect effects on the activity of the transporter, posttranslational modifications may occur shortly (minutes). It is likely that a combination of all of these regulation mechanisms is essential for an efficient Glu uptake activity, both in neurons and glial cells.
Conclusion Until recently, astrocytes were recognized solely for their maintenance role in the regulation of brain homeostasis. Nowadays, this idea has changed, it is clear that these cells play a crucial role in the regulation of neuronal activity and signal transmission. In particular, glial Glu transporters are responsible for the vast majority of the removal of this neurotransmitter from the synaptic cleft, highlighting the importance of these cells in brain physiology. Currently, the number of diseases related to the imbalance of the glutamatergic system, is increasing. Therefore, the interest and importance on the regulation of Glu transporters gene expression and function has also increased. Glu transporters are tightly regulated at different levels including gene expression, transporter protein targeting and trafficking (Fig. 1). Posttranslational modifications of the transporter protein are also involved the regulatory mechanisms. It is clear that the establishment of the biochemical transactions involved in the regulation of Glu transporters is fundamental for the development of new therapeutic strategies for a significant number of neurological diseases associated to glutamatergic neurotransmission.
Conflicts of interest
Acknowledgments The work in the laboratory is supported by Conacyt-Mexico (255087) and Soluciones para un México Verde S.A. de C.V. grants to A.O.
Introduction The human creatine transporter 1 (hCRT-1, SLC6A8) belongs to the sodium dependent neurotransmitter family of solute carrier 6 (SLC6) transporters. It is a protein of 635 amino acid residues, organised into twelve transmembrane spanning helices (TM1-TM12). Over the past decade, a number of studies reported point mutations in the hCRT-1 protein; these have been associated with the X-linked cerebral creatine deficiency syndrome resulting from a loss of function of CRT-1: the creatine transporter deficiency syndrome affects the brain, skeletal muscle and other organs to a variable degree. Symptoms range from epilepsy, moderate to severe mental retardation, autism, development delay (in walking and speech), abnormal behaviour (attention deficit hyperactivity disorder/ADHD, shyness, aggression, self-injury) and motor dysfunction (stiff gait, coordination dysfunction and dystonia) to gastrointestinal symptoms (neonatal feeding difficulties, vomiting, constipation, ulcers) (Hahn, 2002; Rosenberg et al., 2004; Lion Francois et al., 2006; van de Kamp et al., 2013; Ardon et al., 2016; Uemura et al., 2017; Heussinger et al., 2017). Based on a study of 188 consecutive mentally retarded children, the prevalence of creatine transporter deficiency was estimated to be 2.7% (Lion-François et al., 2006). However, this percentage rises to 4.4%, if only boys are taken into account. The ratio of 2.7%–4.4% shows that girls are also affected in spite of the X-linked nature of genetic transmission. In the presence of mutations, all males and about 50% of the affected females display intellectual and cognitive dysfunction (DesRoches et al., 2015). The nature of the mutation is an important determinant for the phenotypic consequence. In fact, only mild neuropsychological impairments were observed in several cases, where female relatives were heterozygous for mutations, e.g. for the G381R and R514X variants (Lion-François et al., 2006). The estimated carrier prevalence of CTD in females in the general population is at least 0.024% (DesRoches et al., 2015). The true prevalence of creatine transporter deficiency may be underrated; the reason for this being either misdiagnosis or underdiagnosis, as most CTD patients are diagnosed with other neurological disorders such as autism, ADHD, or unexplained mental retardation.