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Insulin and Brain Reward Systems
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Brian C. Liu, Qingchen Zhang, Emmanuel N. Pothos
First, insulin modulates dopamine release through the vesicular nucleotide transporter in astrocytes. Astrocytes potentially regulate dopamine release by modulating ATP release. When active, the ATP receptor in the presynaptic neuron will open Ca2+ channels and increase the release of dopamine. In astrocytes, ATP is released by the formation of N -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (151). Munc-18 is an inhibitory protein that binds to the SNAREs to prevent their formation. The tyrosine phosphorylation of Munc-18 will increases the formation of SNAREs (115, 152). Insulin signaling has been confirmed to catalyze the tyrosine phosphorylation of Munc-18. Loss of insulin will cause a decrease in SNAREs and a decrease in ATP release, followed by a decrease in dopamine release (115).
Exocytosis of Nonclassical Neurotransmitters
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Xiao Su, Vincent R. Mirabella, Kenneth G. Paradiso, Zhiping P. Pang
It has been proposed that endocrine exocytosis shares similar mechanisms as synaptic vesicle exocytosis. For example, chromaffin granule exocytosis in chromaffin cells requires Munc18. The study of Munc18-1 lacking mouse chromaffin cells showed 10-fold reduction of Ca2+-dependent LDCV exocytosis and morphologically docked LDCVs without changing the kinetic properties of the remaining release, suggesting that Munc18-1 functions upstream of SNARE-complex formation and promotes LDCV docking (Voets et al., 2001). Moreover, nearly all of Ca2+-triggering is mediated equally by Syt 1 and Syt 7 (Schonn et al., 2008). The deletion of Syt 1 reduced the overall secretion only 20%, largely due to the persistence of slow exocytosis mediated by Syt 7. Syt 7 knockout or knock in of mutant Syt 7 decreased the Ca2+-triggered exocytosis dramatically. Double knockout of Syt 1 and Syt 7 results in exocytosis levels that are 30% of WT exocytosis levels, and this remaining level of exocytosis is due to a very slow release component that persists (Schonn et al., 2008).
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The first step in fusion of the synaptic vesicles is tethering, where the vesicles are translocated from a reserve pool and make a physical contact with the cell membrane (Figure 1.12). At the membrane, Munc-18 is initially bound to syntaxin 1A in a closed structure. The dissociation of Munc-18 from the complex frees syntaxin 1A to bind with the v-SNARE proteins. The next step is docking of the vesicles, whereby the v- and t-SNARE proteins transiently associate in a calcium-independent manner. During vesicular priming, the SNARE motifs form a stable interaction between the vesicle and membrane, while complexin proteins stabilize the primed SNARE-complex and render the vesicles ready for exocytosis.
Phagocytosis: Phenotypically Simple Yet a Mechanistically Complex Process
Published in International Reviews of Immunology, 2020
The GTP-loaded Rab7 also promotes phagosome–lysosome fusion via the HOPS complex [comprising of four-subunit core (Vps11, Vps13, Vps16 and Vps33) and two Rab7-interacting subunits, Vps39 and Vps41] during the PU and clearance of apoptotic cells [289,293,294]. Thus, HOPS can tether two Rab7-positive compartments to initiate fusion. Once bound to GTP-bound Rab7, HOPS chaperones and proofreads SNAREs, directly interacting with the quaternary SNARE complex consisting of a single R-SNARE and 3 Q-SNARES [295,296]. The Sec1/Munc18-family protein Vps33 catalyzes the SNARE complex assembly through SANRE motif recognition via serving as a template for SNARE assembly [297]. Rab7-RILP also coordinates tubular membrane extensions facilitating the phagosome–lysosome fusion to form phagolysosome and directly recruits H+-ATPase from lysosomes to develop the acidic environment (Figure 3) [291,298]. The caspase 1 (CASP1) and NLRP3 inflammasome activation govern the acidic environment in phagosomes containing Gram-positive bacteria. The active CASP1 accumulates on phagosomes and acts locally to control the pH of the phagosome by modulating NOX2 (Figure 3) [299]. The NOX2-centred NADPH oxidase transfers electrons from cytoplasmic NADPH to the molecular oxygen in phagosomes producing oxidants to maintain the optimum antimicrobial action of the phagocytes [300].
Platelet Rho GTPase regulation in physiology and disease
Published in Platelets, 2019
Rho GAPs, including ARHGAP17 (also known as Nadrin or Rich1; reviewed in [6]), can antagonize Rac1 activation and platelet function following Ser702 phosphorylation by protein kinase A (PKA) or protein kinase G (PKG) [28,29]. Interestingly, PKA activity solicited by prostacyclin treatment antagonizes platelet hemostatic function through RhoA regulation [30]. The Rho GAP oligophrenin1 (OPHN1) regulates platelet RhoA, Rac1, and Cdc42 activities [31] in vitro, and mediates GPVI as well as PAR signaling for thrombus formation in vivo [32,33]. Recent studies find that RhoA-mediated signaling pathways downstream of platelet Gα12/13-coupled GPCRs are regulated through activities involving the proline-rich tyrosine kinase (Pyk2) [34] as well as the scaffolding protein Disabled-2 (Dab2) [35]. The 3-phosphoinositide-dependent protein kinase 1 (PDK1) also regulates platelet Rac1 function [36]. RhoA and Rac1 associated systems are also activated by platelet integrin signaling via the integrin β binding protein and Sec1/Munc18 family member VPS33B [37], providing another link between platelet integrins and Rho GTPase activation in mediating platelet function [5].
Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents—a life-threatening disease: analysis of 133 cases from a single center
Published in Hematology, 2018
Wenyuan Lai, Yini Wang, Jingshi Wang, Lin Wu, Zhili Jin, Zhao Wang
EBV infection can be found in EBV-HLH, familial HLH, and lymphoma-associated HLH patients. Familial HLH is divided into non-EBV-induced familial HLH, EBV-induced familial HLH, and immune deficiency syndrome-associated HLH. The latter 2 forms of familial HLH are associated with EBV infection. The presence of an EBV infection is differentiated from 4 types of familial HLH (familial HLH type 2 (FHL2) with PRF1 mutation, familial HLH type 3 (FHL3) with Munc 13-4 or Unc13D mutation, familial HLH type 4 (FHL4) with syntaxin-11 mutation, and familial HLH type 5 (FHL5) with Munc 18-2 or STXBP2 mutation [9,10]. In addition, Marsh et al. [11] reports that patients with a 60% SAP gene defect and a 30% XIAP gene defect may develop EBV-HLH. Therefore, EBV-HLH relapses especially in young children and adolescents, and screening to exclude familial HLH is necessary. In adult patients, EBV infection is often associated with lymphoma and is most commonly found in NK/T cell lymphoma. Since lymphoma-associated HLH accompanied by EBV infection is difficult to distinguish from EBV-HLH, pathological biopsies obtained from multiple sites or PET/CT are necessary to exclude the lymphoma cases. In our center, more than one-fourth of the HLH patients with EBV infection were categorized as lymphoma-associated HLH, and NK/T cell lymphoma was the most common. A very small number of HLH patients with EBV infection was familial HLH; thus, familial HLH and lymphoma-associated HLH cases should be excluded from the HLH patients with EBV infection before the diagnosis of EBV-HLH.