Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-methyl-D-aspartate (NMDA)-type glutamate receptors perform critical functions during the development of the nervous system and in the initiation of synaptic plasticity. An important mechanism in setting the gain of NMDA receptors involves the stimulation of G-protein-coupled receptors (GPCRs), which through activation of protein tyrosine kinases leads to an upregulation of NMDA receptors. In contrast, little is known about how NMDA receptors are downregulated. In the present study, we characterized a signaling pathway that mediates the depression of NMDA receptor function in response to stimulation of muscarinic acetylcholine receptors. Whole-cell patch-clamp recordings obtained from CA3 pyramidal cells in organotypic slice cultures revealed that under conditions of low intracellular calcium buffering application of muscarine-depressed NMDA receptor current. The sensitivity of this response to pirenzipine indicated that the M1 acetylcholine receptor is mediating this depression. The muscarine-induced depression of NMDA current was prevented by blocking G-protein function or after depleting intracellular Ca2+ stores with cyclopiazonic acid. Inhibitors of calmodulin prevented the depression whereas blocking calcineurin enhanced the depression of NMDA currents. Blocking tyrosine phosphatase activity with pervanandate converted the muscarine-induced depression into a potentiation of NMDA currents, whereas blocking protein kinase A (H-89), Src kinase (PP2, SU6656), or PKC (GF 109203X) failed to prevent the depression of NMDA currents. As Src tyrosine kinase is known to phosphorylate and upregulate NMDA receptors, we propose that a protein tyrosine phosphatase(s) counteracting the action of Src is the final target in the mAChR-dependent inhibitory signaling cascade. Our data are consistent with a transduction cascade comprising an M1 acetylcholine receptor-->G-protein-->Ca2+ release-->calmodulin-->tyrosine phosphatase.
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PMID:Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase. 1599 5

Kainate receptors (KARs) have been shown to be involved in hippocampal mossy fiber long-term potentiation (LTP); however, it is not known if KARs are involved in the induction or expression of long-term depression (LTD), the other major form of long-term synaptic plasticity. Here we describe LTD of KAR-mediated synaptic transmission (EPSC(KA) LTD) in perirhinal cortex layer II/III neurons that is distinct from LTD of AMPAR-mediated transmission, which also coexists at the same synapses. Induction of EPSC(KA) LTD requires a rise in postsynaptic Ca(2+) but is independent of NMDARs or T-type voltage-gated Ca(2+) channels; however, it requires synaptic activation of inwardly rectifying KARs and release of Ca(2+) from stores. The synaptic KARs are regulated by tonically activated mGluR5, and expression of EPSC(KA) LTD occurs via a mechanism involving mGluR5, PKC, and PICK1 PDZ domain interactions. Thus, we describe the induction and expression mechanism of a form of synaptic plasticity, EPSC(KA) LTD.
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PMID:Long-term depression of kainate receptor-mediated synaptic transmission. 1638 42

The induction of long-term depression (LTD) can be divided into two main forms, one dependent upon activation of postsynaptic NMDAR, and another independent of postsynaptic NMDAR. Non-postsynaptic NMDAR-LTD (non-NMDAR-LTD) occurs in many regions of the brain, and encompasses a wide variety of induction and expression mechanisms. In this article, the induction and expression mechanisms of such LTD in over 10 brain regions are described, with a number of common mechanisms compared across a large range of types of LTD. The article describes the involvement of different presynaptic or postsynaptic receptors in the induction of non-NMDAR-LTD, especially metabotropic glutamate receptors, cannabinoid receptors and dopamine receptors. An increase in presynaptic or postsynaptic intracellular Ca concentration is a key event in induction, commonly followed by activation of certain kinases, especially PKC, p38 MAPK and ERK. Expression mechanisms are either presynaptic via a reduction in release probability, or postsynaptic involving a decrease in AMPAR via phosphorylation of a glutamate receptor subunit, especially GluR2, followed by clathrin-mediated endocytosis. Retrograde signalling from postsynaptic to presynaptic occurs when induction is postsynaptic and expression is presynaptic.
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PMID:Induction and expression mechanisms of postsynaptic NMDA receptor-independent homosynaptic long-term depression. 1642 42

We have previously reported a transgenic mouse that over-expresses constitutively active PKCepsilon in the myocardium and exhibits a steady progression to heart failure. Associated with the decline in function was an increased phosphorylation of sarcomeric proteins including cardiac troponin I (cTnI). To determine whether PKCepsilon phosphorylation of cTnI is sufficient to induce cardiac maladaptation, we have generated a double transgenic mouse (DbTG) that expresses constitutively active PKCepsilon and cTnI harboring non-phosphorylatable mutations in the putative PKC phosphorylation sites (S43A, S45A). We compared the hemodynamic and biochemical properties of the hearts from the DbTG mice to the non-transgenic and single transgenic lines at both 3 and 12 months of age. While no significant differences in LV function were noted in 3-month groups, the depression of function in the PKCepsilon mice was attenuated in the double transgenic mice at 12 months. The improvement in cardiac function was correlated with decreased beta-myosin heavy chain and ANF mRNA expression in the 12m DbTG mice. The extent of cTnI phosphorylation was determined using a novel one-dimensional, non-equilibrium isoelectric focusing technique. At 3 months the migration of cTnI phospho-species was different in the PKCepsilon mice and to a lesser degree in the DbTG compared to all other groups. At 12 months additional phospho-species were observed in both the PKCepsilon and DbTG samples, along with an overall shift in the distribution of phospho-species in all groups due to age. These results suggest that phosphorylation of cTnI by PKCepsilon is associated with contractile dysfunction and partial replacement of serines 43/45 improves cardiac performance. Therefore, we conclude that phosphorylation of cTnI at Ser 43 and 45 may contribute to the progression of failure.
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PMID:Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation. 1651 95

Cerebellar long-term depression (LTD) is a major form of synaptic plasticity that is thought to be critical for certain types of motor learning. Phosphorylation of the AMPA receptor subunit GluR2 on serine-880 as well as interaction of GluR2 with PICK1 have been suggested to contribute to the endocytic removal of postsynaptic AMPA receptors during LTD. Here, we show that targeted mutation of PICK1, the GluR2 C-terminal PDZ ligand, or the GluR2 PKC phosphorylation site eliminates cerebellar LTD in mice. LTD can be rescued in cerebellar cultures from mice lacking PICK1 by transfection of wild-type PICK1 but not by a PDZ mutant or a BAR domain mutant deficient in lipid binding, indicating the importance of these domains in PICK1 function. These results demonstrate that PICK1-GluR2 PDZ-based interactions and GluR2 phosphorylation are required for LTD expression in the cerebellum.
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PMID:Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. 1654 22

Long-term synaptic plasticity is an important mechanism underlying the development of cortical circuits in a number of brain regions. In barrel cortex NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) play a critical role in the development and experience-dependent plasticity of the topographical map of the rodent whiskers. However, the mechanisms underlying the induction and expression of these forms of plasticity are poorly characterised. Here we investigate the role of PKC in the regulation of synaptic strength in neonatal barrel cortex using patch-clamp recordings in brain slices. We demonstrate that PKC activity tonically maintains AMPA receptor-mediated transmission at thalamocortical synapses, and that basal transmission can be potentiated by PKC activation using postsynaptic infusion of phorbol ester. Furthermore, we show that induction of NMDAR-dependent LTP requires PKC activity. These findings demonstrate that PKC is required for the regulation of transmission at thalamocortical synapses, the major ascending sensory input to barrel cortex. Thalamocortical inputs in barrel cortex only express LTP during the first postnatal week during a critical period for experience-dependent plasticity in layer IV. Therefore, the requirement for PKC in LTP suggests an important role for this kinase in the development of the barrel cortex sensory map.
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PMID:Synaptic strength at the thalamocortical input to layer IV neonatal barrel cortex is regulated by protein kinase C. 1689 Feb 49

Serotonergic and dopaminergic systems, and their functional interactions, have been implicated in the pathophysiology of various CNS disorders. Here, we use recombinant serotonin (5-HT) 2A (5-HT2A) receptors to further investigate direct interactions between dopamine and 5-HT receptors. Previous studies in Xenopus oocytes showed that dopamine, although not the cognate ligand for the 5-HT2A receptor, acts as a partial-efficacy agonist. At micromolar concentrations, dopamine also acts as a partial-efficacy agonist on 5-HT2A receptors in HEK293 cells. Like 5-HT, dopamine also induces receptor-internalization in these cells, although at significantly higher concentrations than 5-HT. Interestingly, if the receptors are first sensitized or "primed" by subthreshold concentrations of 5-HT, then dopamine-induced internalization occurs at concentrations approximately 10-fold lower than when dopamine is used alone. Furthermore, unlike 5-HT-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by 5-HT, does not depend on PKC. Dopamine-internalized receptors recycle to the surface at rates similar to those of 5-HT-internalized receptors. Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders.
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PMID:Activation, internalization, and recycling of the serotonin 2A receptor by dopamine. 1700 23

Synapses need to encode a wide dynamic range of action potential frequencies. Essential vesicle priming proteins of the Munc13 (mammalian Unc13) family play an important role in adapting vesicle supply to variable demand and thus influence short-term plasticity characteristics and synaptic function. Structure-function analyses of Munc13s have identified a "catalytic" C-terminal domain and several N-terminal modulatory domains, including a diacylglycerol/phorbol ester [4beta-phorbol-12, 13-dibutyrate (PDBu)] binding C1 domain. Although still allowing basal priming, a Munc13-1 C1 domain mutation (H567K) prevents PDBu induced potentiation of evoked transmitter release, leads to strong depression during trains of synaptic activity, and causes perinatal lethality in mice. To understand the mechanism of C1 domain-mediated modulation of Munc13 function, we examined how PDBu increases neurotransmitter release. Analyses of osmotically induced release as well as Ca2+ triggered and spontaneous release showed that PDBu increases the vesicular release rate without affecting the size of the readily releasable vesicle pool, linking C1 domain activation to a lowering of the energy barrier for vesicle fusion. PDBu binding-deficient mutant Munc13-1(H567K) synapses mirrored the vesicular release properties of PDBu-potentiated wild-type synapses, indicating that Munc13-1(H567K) is a gain-of-function mutant, which conformationally mimics the PDBu-activated state of Munc13-1. We propose a PKC analogous two-state model of regulation of Munc13s, in which the basal state of Munc13s is disinhibited by C1 domain activation into a state of facilitated vesicle release, regardless of whether the release is spontaneous or action potential triggered.
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PMID:Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. 1726 76

Depression is a condition with a complex biologic pattern in etiology. Environmental stressors modulate subsequent vulnerability to depression. In particular, early adversity seems to induce heightened reactivity to stress through several possible mechanisms, both biologic and psychologic. This increased reactivity results in an enhancement of biologic stress-response mechanisms, especially the HPA axis. Regulators of this system, particularly signal transduction pathways involving PKA and PKC, may be important in the regulation of key genes in this system including genes for GR, BDNF, and trk-b. This system potentially is vulnerable to ROS and therefore, indirectly, to the effects of cytokines. Finally, some of these effects may be controlled by chemical modification of DNA, specifically, methylation of promoters or other gene regions. This modification is a mechanism by which long-term biologic change can be induced by environmental stressors. The brain is homeostatic, and it is possible that alterations at multiple points in this system may induce dysregulation and, as a result, vulnerability to stress. Therefore, a person may be vulnerable to depression, which may be a final common "pathway" for this family of conditions. Individuals may very considerably with regard to the locus of the problem, however. For example, functional variants in a set of genes might predispose some people to depression; others may have epigenetic imprinting; and yet different causes may be at work in others. Although this mix is complicated, it can be unraveled. Doing so could lead to the development of novel interventions that could target specific points of vulnerability, allowing an improved matching of patient to treatment based on differential abnormalities at the cellular level.
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PMID:The molecular neurobiology of depression. 1736 99

Protein kinase Calpha (PKCalpha) plays a major role in the induction of long-term depression (LTD) in a cerebellar Purkinje cell (PC). The sequential activation model for classical PKC states that PKCalpha translocates to the plasma membrane by binding Ca(++) and then becomes fully activated by binding diacylglycerol (DAG), which enables estimation of the activity by monitoring its localization. Here, we performed simultaneous electrophysiological recording and fluorescence imaging in a cultured PC expressing GFP-tagged PKCalpha. When a PC was depolarized, PKCalpha transiently translocated to the plasma membrane in a Ca(++)-dependent manner. Application of membrane permeable DAG or the blocker of DAG lipase prolonged the translocation. These results suggest that the sequential activation model is applicable to PCs. Conjunctive applications of glutamate and depolarization pulse induced LTD, but did not prolong the translocation. Thus, our results imply that persistent activation of PKCalpha is not necessary for the expression of LTD.
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PMID:Persistent activation of protein kinase Calpha is not necessary for expression of cerebellar long-term depression. 1736 67


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