EAAT glutamate uptake is driven

EAAT glutamate uptake is driven by the co-transport of three sodium ions and one proton, as well as the counter-transport of one potassium ion (Fig. 1B). This complex stoichiometry frees up enough energy to permit PBIT of glutamate into the cell against a steep concentration gradient. Additionally it ensures that glutamate transport only reverses under extreme conditions (Szatkowski and Attwell, 1994). For various pathological situations, acute or chronic reduction in overall glial glutamate uptake capacity contributes to increased extracellular glutamate concentrations and results in excitotoxicity (Allaman et al., 2011). Glutamate uptake by astrocytes thus not only shapes synaptic transmission by regulating the availability of glutamate to postsynaptic neuronal receptors, but also protects neurons from hyper-excitability and excitotoxic damage. The present review will focus on discussing the molecular and cellular physiology of glial sodium-dependent glutamate transporters, which are mediators of complex interactions and inter-dependence between neurons and astrocytes in the brain.
Molecular basis of glutamate transport
Glutamate transporters in astrocytes
Conclusion
Conflict of interest
Acknowledgements
Background In general, women are more sensitive to pain than men, and some painful disorders such as irritable bowel syndrome (IBS) (Chang and Heitkemper, 2002, Mogil and Bailey, 2010), chronic pelvic pain (Scialli, 1999), temporomandibular disorder (Cairns, 2010), fibromyalgia (Yunus, 2002), biliary colic (Palsson and Sandblom, 2015), esophagitis (Krarup et al., 2013), and rheumatoid arthritis (Brennan and Silman, 1995) are more prevalent in women. Similar associations have been reported in rodents, where female rats showed exaggerated visceromotor responses to colorectal distension (Holdcroft et al., 2000, Ji et al., 2006, Ji et al., 2012, Winston et al., 2014, Guo et al., 2015) as well as other types of pain (Mogil and Bailey, 2010). On the other hand, there are some reports of increased visceral and somatic hypersensitivity in male rats exposed to early life stress as compared to female rats (Prusator and Greenwood-Van Meerveld, 2015). Significant gender differences in incidence, symptomatology, and therapeutic outcome in various pain disorders indicate the necessity for gender-tailored treatment approaches. However to achieve this it is necessary to have a comprehensive understanding of the molecular mechanisms responsible for these pain-related gender differences. IBS is the most common functional gastrointestinal disorder with symptoms of altered bowel habit and visceral hypersensitivity (Kennedy et al., 2014, Hyland et al., 2015). The majority of women with IBS who seek health care are of reproductive age. Population surveys have reported that the prevalence of IBS declines after the age of 40years (Hungin et al., 2003); suggesting a role of female sex hormones in the etiology of IBS. Studies on gender differences in visceral pain are increasingly being carried out, yet few of these have evaluated the impact of menstrual cycle on pain perception (Houghton et al., 2002). Moreover, there is a paucity of information on the potential mechanism underlying sex differences in visceral pain processing. Of these, plasma levels of cytokines have been shown to vary depending on the cycle stage (O’Brien et al., 2007). Furthermore, there is growing evidence of the involvement of gonadal hormones (e.g. estrogen) in visceral and somatic pain sensitivity; however, conflicting results have been reported. Some studies have shown ovarian hormones (e.g. estrogen) to be antinociceptive (Bradshaw et al., 1999, Sanoja and Fernando, 2005, Heitkemper and Chang, 2009), whereas others indicate that these hormones may be pro-nociceptive (Ji et al., 2003, Lu et al., 2009, Chaloner and Greenwood-Van Meerveld, 2013). Noteworthy, visceromotor response to colorectal distension was shown to be higher in proestrus (high-estrogen state) than in metestrus/diestrus (low-estrogen states) (Ji et al., 2008, Peng et al., 2008). A need, therefore, arises to assess the underlying mechanisms that are implicated in visceral pain with regard to the changing levels of gonadal hormones across the female cycle.