Conversely, later studies of schizophrenia patients, performed with radiolabeled serotonin reuptake inhibitors (SSRIs) such as paroxetine, citalopram and RTI-55, did not find any alterations of SERT density in multiple brain regions, including PFC and cingulate cortex ( Dean et al., 1995, 1999b Gurevich & Joyce, 1997 Naylor et al., 1996). In the study of Joyce et al., SERT levels were also decreased in the anterior and posterior cingulate cortices and increased in the striatum. Two early postmortem studies using cyanoimipramine and paroxetine showed that the density of SERT is decreased in the frontal cortex ( Joyce et al., 1993 Laruelle et al., 1993a). Serotonin transporters (SERTs) are located presynaptically on serotonergic axon terminals and are thought to serve as an index of serotonergic innervation ( Abi-Dargham & Krystal, 2000). Halberstadt, in Handbook of Behavioral Neuroscience, 2020 D Serotonin transporter These studies suggest a significant role in lipid rafts modulating SERT activity, and ultimately serotonergic signal propagation.īoris B. Conversely, downregulation of SERT activity via protein kinase C (PCK) occurs by translocating SERT from lipid raft microdomains to non-raft regions ( Samuvel, Jayanthi, Bhat, & Ramamoorthy, 2005). In fact, upregulation of SERT activity occurs on SERT localized to lipid raft domains via p38 MAPK ( Chang et al., 2012). These studies suggest a role for lipid rafts promoting a high-affinity, high-activity state of SERT. Moreover, SERT's affinity for serotonin decreases after cholesterol depletion ( Magnani, Tate, Wynne, Williams, & Haase, 2004 Scanlon, Williams, & Schloss, 2001). Cholesterol chelation and reduction by MβCD increases lateral motility of SERT in RN46A serotonergic neuronal cells, which is accompanied by a 50% reduction in mean transporter activity. One group localizes to non-raft regions and displays increased motility compared to its less mobile counterpart present in ganglioside rich (specifically GM1) lipid rafts ( Chang et al., 2012). Interestingly, SERT resides in two distinct populations in the plasma membrane. Inhibiting SERT increases the amount serotonin available in the synapse, which in turn leads to downstream cellular and molecular adaptations that are thought to mediate antidepressant's efficacy. SERT is inhibited by nearly all antidepressants to varying degrees. Rasenick, in Advances in Pharmacology, 2019 3.3.3 Serotonin transporters
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