Eficits are certainly not wellunderstood, though Mn has been shown to target dopaminergic and GABAergic neurons in the basal ganglia and elsewhere (Crooks et al. 2007a,b; Gwiazda et al., 2002; Stanwood et al., 2009). For instance, Stanwood et al. (2009) reported Mn cytotoxicity in dopaminergic and GABAergic neurons exposed in vitro to 10?00 Mn, with levels of one hundred Mn leading to improved cytoskeletal abnormalities and modifications in neurite length and integrity. Utilizing a GABAergic AF5 neuronal cell model, Crooks et al. (2007a,b) reported altered Topoisomerase custom synthesis cellular metabolism in response to Mn exposure, including elevated intracellular GABA and disrupted cellular iron homeostasis at exposure levels of 25?00 Mn. Whilst these CDK19 Gene ID studies illuminate the pathophysiology of Mn neurotoxicity at elevated exposures (Racette et al., 2012), fairly small is understood about cellular responses to Mn exposures that only slightly exceed physiologic levels, a scenario of importance for more completely understanding the risks from environmental exposure. The transition from physiologic to toxic cellular Mn levels probably happens when homeostatic influx/efflux processes turn out to be imbalanced. Cellular Mn uptake/influx into brain cells happens via divalent metal transporter-1 (DMT1), transferrin receptor (TfR), and voltage regulated and store-operated Ca2+ channel mechanisms (Davidsson et al., 1989; Gunshin et al., 1997; Lucaciu et al., 1997; Riccio et al., 2002). Having said that, comparatively little is recognized concerning the mechanisms of cellular Mn efflux from cells in the brain. Ferroportin, SPCA (secretory pathway Ca2+ Mn2+ ATPases), and ATP13A2 have all been implicated to facilitate cellular Mn efflux (Leitch et al., 2011; Madejczyk and Ballatori, 2012; Tan et al., 2011; Yin et al., 2010). ATP13A2 may transport Mn into lysosomes and therefore could also mediate Mn trafficking inside the neuron (Tan et al., 2011). SPCA1 is really a Golgi trans-membrane protein inside the brain capable of transporting Mn in to the Golgi lumen with higher affinity (Sepulveda et. al., 2009). Research by Leitch et al. (2011) showed that SPCA1 knock down in hepatocyte derived (WIF-B) cells led to an increase in Mn particular cell death, whereas more than expression of SPCA1 in human embryonic kidney cells (HEK-293T) protected cells against Mn toxicity. Similarly, Mukhopadhyay et al. (2010) reported that enhanced activity of SPCA1 led to enhanced Mn transport into the Golgi and decreased Mn cytotoxicity in HeLa cells, while blocking Mn transport into or out on the Golgi enhanced cytotoxicity, suggesting that the Golgi might play a crucial role in Mn homeostasis and detoxification in HeLa cells. On top of that, Mukhopadhyay et al. (2010) reported that elevated (500 ) exposure and uptake of Mn in to the Golgi of HeLa cells led towards the lysosomal degradation on the cis-Golgi connected transmembrane protein Golgi Phosphoprotein 4 (GPP130; gene GOLIM4). Notably, blocking Mn uptake in to the Golgi protected against GPP130 degradation, suggesting GPP130 might also play a role in cellular Mn homeostasis (Mukhopadhyay et al., 2010). Even though the cellular functions of GPP130 are usually not fully understood, GPP130 has been shown to mediate the cellular trafficking of protein cargo directly from endosomes towards the Golgi apparatus through a pathway that bypasses late endosomes and pre-lysosomes (Puri et al., 2002). By using this bypass pathway, proteins and toxins are in a position to prevent lysosomalAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptSynapse. Aut.