Depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the SGZ. regulate the neurogenic process. This review summarizes the field of adult neurogenesis and its methods and specifies the roles of various GPCRs and their signal transduction pathways that are involved in the regulation of adult neural stem cells and their progenitors. Current evidence supporting Tonapofylline adult neurogenesis Rabbit Polyclonal to BAGE3 as a model for self-repair Tonapofylline in neuropathologic conditions, adult neural stem cell therapeutic strategies, and potential avenues for GPCR-based therapeutics are also discussed. I. Introduction Only a few decades ago, scientists thought that certain cells in the body, such as cardiac myocytes and brain cells, were nonrenewable. We now know that these cells can be regenerated through specific processes involving stem cells that exist throughout life. The first evidence of adult neurogenesis was reported in the 1960s by Joseph Altman, who showed that neurons in adult rats incorporated [3H]thymidine (Altman, 1962). However, it was not until the 1990s that the idea of adult neurogenesis became widely accepted, when it was shown that the subventricular zone (SVZ1) of the lateral ventricles (Reynolds and Weiss, 1992; Richards et al., 1992) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (Gage et al., 1995; Palmer et al., 1997) contain self-renewing neural stem cells (NSCs) that give rise to Tonapofylline new neural cells. The existence of adult neurogenesis in humans was confirmed in 1998 (Eriksson et al., 1998). G-protein-coupled receptors (GPCRs) are the largest Tonapofylline family of membrane receptors in eukaryotes. Although the exact number of GPCRs is unknown, nearly a thousand genes encoding Tonapofylline for GPCRs have been identified in the human genome (Takeda et al., 2002), of which approximately half are receptors for endogenous ligands. Also called heptahelical receptors, GPCRs are integral membrane proteins composed of an extracellular N terminus, seven transmembrane -helices connected by intracellular and extracellular loops, and an intracellular C terminus. When activated, GPCRs transduce signals from outside the cell to intracellular pathways, resulting in cellular responses. GPCRs affect the transduction of signals through heterotrimeric G-proteins, which exist bound to the inner side of the cytoplasmic membrane. G-proteins consist of three subunits, , , and , that are altered by activated GPCRs. When a ligand binds the GPCR on the cell’s outside surface, it drives a conformational change, thus activating the receptor. The activated receptor then functions as a guanine-nucleotide exchange factor, exchanging GDP for GTP on the G subunit of the G-protein. Subsequently, the G-GTP subunit dissociates from the G dimer and the GPCR. Both the GTP-bound G and free G subunits can induce different intracellular signaling cascades and/or downstream effector proteins (e.g., adenylyl cyclases, phospholipase C, various ion channels). Because the G subunit possesses intrinsic enzymatic GTPase activity, it eventually hydrolyzes the GTP back to GDP, allowing G to reassemble with the G subunit and GPCR, returning the GPCR and G-protein to their original states. The activity of the G subunit is modulated by other proteins, such as the regulators of G protein signaling proteins, a type of GTPase-activating protein that accelerates GTP hydrolysis, thereby reducing the signaling (Sj?gren et al., 2010). In addition, GPCRs can transduce signals without G protein involvement through G protein-independent signaling (noncanonical) pathways (Wei et al., 2003; Shenoy et al., 2006). GPCRs are essential in the processes of neurotransmission, cell proliferation, and organ-specific function (Luttrell, 2008). Not surprisingly, GPCRs are important drug targets with at least 30% of all modern therapeutics acting at these receptors (Overington et al., 2006; Lagerstr?m and Schi?th, 2008). The GPCR neurotransmitter systems involved in adult neurogenesis are discussed in this review. These encompass those primarily considered neuromodulators such as norepinephrine (NE), dopamine, and serotonin. Neuromodulators regulate long-range paracrine or nonsynaptic signaling through neuronal projections into the SVZ and SGZ, the two major neurogenic areas of the adult mammalian brain. Therefore, it is not surprising that the GPCRs are involved in the regulation of NSCs and their progenitors. Furthermore, increasing evidence points to the involvement of other GPCR ligands in adult neurogenesis, such as chemokines, peptide hormones, endogenous opioids, and Wnt proteins, to name a few. In this review, the general features of NSCs, methods for studying adult neurogenesis, and role of the brain vascular.