RESUMO
Intercellular communication is pivotal in optimizing and synchronizing cellular responses to keep homeostasis and to respond adequately to external stimuli. In the central nervous system (CNS), glutamatergic and GABAergic signals are postulated to be dependent on the glutamate/GABA-glutamine cycle for vesicular loading of neurotransmitters, for inactivating the signal and for the replenishment of the neurotransmitters. Islets of Langerhans release the hormones insulin and glucagon, but share similarities with CNS cells in for example transcriptional control of development and differentiation, and chromatin methylation. Interestingly, CNS proteins involved in secretion of the neurotransmitters and emitting their responses as well as the regulation of these processes, are also found in islet cells. Moreover, high levels of glutamate, GABA, and glutamine and their respective vesicular and plasma membrane transporters have been shown in the islet cells and there is emerging support for these amino acids and their transporters playing important roles in the maturation and secretion of insulin and glucagon. In this review, we will discuss the feasibility of recent data in the field in relation to the biophysical properties of the transporters (Slc1, Slc17, Slc32, and Slc38) and physiology of hormone secretion in islets of Langerhans.
RESUMO
Glutamate mediates several modes of neurotransmission in the central nervous system including recently discovered retrograde signaling from neuronal dendrites. We have previously identified the system N transporter SN1 as being responsible for glutamine efflux from astroglia and proposed a system A transporter (SAT) in subsequent transport of glutamine into neurons for neurotransmitter regeneration. Here, we demonstrate that SAT2 expression is primarily confined to glutamatergic neurons in many brain regions with SAT2 being predominantly targeted to the somatodendritic compartments in these neurons. SAT2 containing dendrites accumulate high levels of glutamine. Upon electrical stimulation in vivo and depolarization in vitro, glutamine is readily converted to glutamate in activated dendritic subsegments, suggesting that glutamine sustains release of the excitatory neurotransmitter via exocytosis from dendrites. The system A inhibitor MeAIB (alpha-methylamino-iso-butyric acid) reduces neuronal uptake of glutamine with concomitant reduction in intracellular glutamate concentrations, indicating that SAT2-mediated glutamine uptake can be a prerequisite for the formation of glutamate. Furthermore, MeAIB inhibited retrograde signaling from pyramidal cells in layer 2/3 of the neocortex by suppressing inhibitory inputs from fast-spiking interneurons. In summary, we demonstrate that SAT2 maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate.
Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Dendritos/fisiologia , Ácido Glutâmico/metabolismo , Neocórtex/fisiologia , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologia , Sistema A de Transporte de Aminoácidos/imunologia , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Especificidade de Anticorpos , Células Cultivadas , Feminino , Glutamina/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Técnicas Imunoenzimáticas , Masculino , Neocórtex/citologia , Técnicas de Patch-Clamp , Gravidez , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , beta-Alanina/análogos & derivados , beta-Alanina/farmacologiaRESUMO
Vesicular glutamate transporters (VGLUTs) 1 and 2 are expressed by neurons generally accepted to release glutamate as a neurotransmitter, whereas VGLUT3 appears in populations usually associated with a different classical transmitter. We now demonstrate VGLUT2 as well as the vesicular GABA transporter (VGAT) in a subset of presynaptic terminals in the dentate gyrus of the rat hippocampal formation. The terminals are distributed in a characteristic band overlapping with the outer part of the granule cell layer and the inner zone of the molecular layer. Within the terminals, which make asymmetric as well as symmetric synapses onto the somatodendritic compartment of the dentate granule cells, the 2 transporters localize to distinct populations of synaptic vesicles. Moreover, the axons forming these terminals originate in the supramammillary nucleus (SuM). Our data reconcile previous apparently conflicting reports on the physiology of the dentate afferents from SuM and demonstrate that both glutamate and GABA may be released from a single nerve terminal.
Assuntos
Hipocampo/metabolismo , Neurônios/metabolismo , Terminações Pré-Sinápticas/metabolismo , Vesículas Sinápticas/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Animais , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
Many neuropsychiatric disorders appear to involve a disturbance of chemical neurotransmission, and the mechanism of available therapeutic agents supports this impression. Postsynaptic receptors have received considerable attention as drug targets, but some of the most successful agents influence presynaptic processes, in particular neurotransmitter reuptake. The pharmacological potential of many other presynaptic elements, and in particular the machinery responsible for loading transmitter into vesicles, has received only limited attention. The similarity of vesicular transporters to bacterial drug resistance proteins and the increasing evidence for regulation of vesicle filling and recycling suggest that the pharmacological potential of vesicular transporters has been underestimated. In this review, we discuss the pharmacological effects of psychostimulants and therapeutic agents on transmitter release.
Assuntos
Proteínas de Transporte de Neurotransmissores/efeitos dos fármacos , Proteínas de Transporte de Neurotransmissores/metabolismo , Vesículas Secretórias/efeitos dos fármacos , Vesículas Secretórias/metabolismo , Proteínas Vesiculares de Transporte de Neurotransmissores/metabolismo , Animais , Canais de Cloreto/metabolismo , Humanos , Ionóforos/metabolismo , Neurotransmissores/metabolismo , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas Vesiculares de Transporte de Neurotransmissores/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Neurotransmissores/fisiologiaRESUMO
The excitability of dopaminergic (DA) neurons in the substantia nigra is controlled by the convergent activity of multiple glutamatergic afferents. Here, we show that vesicular glutamate transporter 3 (VGLUT3)-immunoreactive (ir) terminals segregate to the perisomatic region of DA neurons in the substantia nigra pars compacta, and VGLUT3 decorates a synapse population distinct from those marked by vesicular glutamate transporters 1 and 2. VGLUT3-ir nerve endings form asymmetric terminals on DA neurons. Retrograde tracing suggests the superior colliculus as an origin of excitatory VGLUT3-ir afferents. Collectively, our data indicate that VGLUT3 identifies a novel excitatory terminal subset that contributes to the tuning of DA cell excitability in the substantia nigra.
Assuntos
Neurônios/citologia , Terminações Pré-Sinápticas/metabolismo , Substância Negra/citologia , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Animais , Biotina/análogos & derivados , Biotina/metabolismo , Western Blotting/métodos , Cromonas , Dextranos/metabolismo , Imunofluorescência/métodos , Microscopia Imunoeletrônica/métodos , Neurônios/metabolismo , Neurônios/ultraestrutura , Fosfopiruvato Hidratase/metabolismo , Terminações Pré-Sinápticas/ultraestrutura , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/metabolismo , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
Natural killer (NK) cells perform multiple biological functions including tumor cell lysis and eradicating virally infected cells. Here, we report for the first time that D-galactosyl-beta1-1' sphingosine and D-glucosyl-beta1- 1' sphingosine damage human NK cells. We show that these cells express T-cell-associated gene-8, the receptor for glycosphingolipids. D-galactosyl-beta1-1' sphingosine and D-glucosyl-beta1-1' sphingosine induce the in vitro chemotaxis of human NK cells. Both D-galactosyl-beta1-1' sphingosine and D-glucosyl-beta1-1' sphingosine inhibit the cytotoxicity and IFN-gamma secretion by these cells. Further analysis shows that the glycosphingolipids D-galactosyl-beta1-1' sphingosine and D-glucosyl-beta1-1' sphingosine but not any other lipid examined, which include D-lactosyl-beta1-1' sphingosine, sphingosine 1-phosphate, sphingosine, lysophosphatidic acid, and phosphatidic acid, induce the apoptosis, globoid-like formation, and multinucleation in human NK cells. These results may have important implications on diseases where glycosphingolipids accumulate.