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)

The modulation of beta-adrenoceptor signaling in the hearts of hindlimb unweighting (HU) simulated weightlessness rats has not been reported. In the present study, we adopted the rat tail suspension for 4 wk to simulate weightlessness; then the effects of simulated microgravity on beta-adrenoceptor signaling were studied. Mean arterial blood pressure (ABP), left ventricular pressure (LVP), systolic function (+dP/dtmax), and diastolic function (-dP/dtmax) were monitored in the course of the in vivo experiment. Single rat ventricular myocyte was obtained by the enzymatic dissociation method. Hemodynamics, myocyte contraction, and cAMP production in response to beta-adrenoceptor stimulation with isoproterenol or adenylyl cyclase stimulation with forskolin were measured, and Gs protein was also determined. Compared with the control group, no significant changes were found in heart weight, body weight and ABP, while LVP and +/-dP/dtmax were significantly reduced. The ABP decrease, LVP increase, and +/-dP/dtmax in response to isoproterenol administration were significantly attenuated in the HU group. The effects of isoproterenol on electrically induced single-cell contraction and cAMP production in myocytes of ventricles in the HU rats were significantly attenuated. The biologically active isoform, Gsalpha (45 kDa) in the heart, was unchanged. Both the increased electrically induced contraction and cAMP production in response to forskolin were also significantly attenuated in the simulated weightlessness rats. Above results indicated that impaired function of adenylyl cyclase causes beta-adrenoceptor desensitization, which may be partly responsible for the depression of cardiac function.
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PMID:Modulation of {beta}-adrenoceptor signaling in the hearts of 4-wk simulated weightlessness rats. 1851 23

Clinical observations and experimental studies have shown that hyperthermia can provoke febrile seizures, which are the most common type of pathological brain activity in children. We previously demonstrated that hyperthermia produced a depression of GABAergic neurotransmission in the hippocampus of immature rats in vitro. To investigate the possible mechanisms through which hyperthermia may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage clamp recordings were performed on CA1 pyramidal neurons in the immature rat brain slices. We found that hyperthermia (38.4-40 degrees C) when compared with baseline temperature of 32 degrees C reduced the frequency of both spontaneous inhibitory post-synaptic currents (sIPSCs) and miniature IPSCs (mIPSCs). Also, hyperthermia decreased the amplitudes of mIPSCs and reduced the mIPSC decay time constants and charge transfer. Non-stationary noise analysis of mIPSCs suggested that the number of open post-synaptic receptors but not single channel conductance was reduced during hyperthermia. Activation of adenylyl cyclase with forskolin prevented, whereas protein kinase A inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide potentiated, the hyperthermia (40 degrees C)-induced depression of evoked IPSCs (evIPSCs). But protein kinase C activator phorbol 12, 13-dibutyrate (PDBu) did not significantly affect this depression of evIPSCs induced by hyperthermia. Furthermore, hyperthermia-induced depression of evIPSCs was attenuated by 4-aminopyridine, but not by BaCl(2). These results suggest that hyperthermia reduces GABA release from pre-synaptic terminals, in part by blocking the adenylyl cyclase-protein kinase A signaling pathway and activating pre-synaptic 4-aminopyridine-sensitive K(+) channels. Also, the changes in amplitude and decay time constant of the mIPSCs may suggest that hyperthermia also decreases post-synaptic GABA(A) receptor function.
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PMID:Mechanisms of hyperthermia-induced depression of GABAergic synaptic transmission in the immature rat hippocampus. 1864 87

Monoaminergic neurotransmission is a key element in the physiopathology of depressive disorders, but information is still sparse on animal models of this disease. Here, we used the olfactory bulbectomy (OBX) model of depression to characterize cAMP-second messenger signaling pathways, i.e., adenylyl cyclase activity (basal, sodium fluoride (NaF)- and forskolin-stimulated conditions) as well as Gi and Gs protein levels in different regions of the limbic system. Two weeks after surgery and compared to sham controls, OBX rats displayed reduced NaF-stimulated adenylyl cyclase activity and increased Gi/Gs ratios in the hypothalamus, pre-frontal and cingulate cortices but not in the amygdala, hippocampus and caudate nucleus. No differences were found in basal or forskolin-stimulated conditions. The observed reduction of adenylyl cyclase activity induced by NaF and the increase in the Gi/Gs ratio could explain the changes in neurotransmission in OBX rats as well as in humans with depression.
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PMID:Effect of olfactory bulbectomy on adenylyl cyclase activity in the limbic system. 1913 18

The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia, and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by alpha(2A) adrenergic receptors and required the functions of Galpha(i) proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated by activation of TREK-2, a type of two-pore domain K(+) channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine. Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels.
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PMID:Noradrenergic depression of neuronal excitability in the entorhinal cortex via activation of TREK-2 K+ channels. 1924 46

Serotonergic receptors take their physiologic effects by affecting adenylyl cyclase (AC) catalytic activity and cyclic adenosine monophosphate (cAMP) concentration. AC-cAMP second messenger pathway has been recently suggested to play an important role in depression. Therefore, the compound that regulates the signal pathway may have potential as antidepressant. Curcumin is the main component of Curcuma longa L, a well-known indigenous herb with comprehensive bioactivities. In the present study, we investigated the effects of chronic unpredictable mild stress (CUMS) and curcumin on behaviours and serotonergic receptor-coupled AC-cAMP signal pathway in rats. Curcumin produced beneficial effects on the stressed rats by effectively improving CUMS-induced low sucrose consumption and reducing serum corticosterone levels in rats. Moreover, curcumin enhanced AC activity and cAMP levels in platelet and various brain regions, and up-regulated mRNA expressions of AC subtypes AC 2, AC 8 and cAMP response element binding protein (CREB) in the hippocampus, cortex and hypothalamus of the CUMS rats. Curcumin also attenuated CUMS-induced reductions of 5-hydroxytryptamine (5-HT) levels and high expressions of central 5-HT(1A/1B/7) receptors in rats. These results suggested that the potent antidepressant property of curcumin might be attributed to its improvement of AC-cAMP pathway as well as CREB via suppressing central 5-HT(1A/1B/7) receptors in the CUMS rats. Our findings provided a basis for examining the interaction of serotonergic receptors and AC-cAMP pathway in depression and curcumin treatment.
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PMID:Antidepressant-like effects of curcumin on serotonergic receptor-coupled AC-cAMP pathway in chronic unpredictable mild stress of rats. 1930 28

Most forms of Parkinson's disease (PD) are sporadic in nature, but some have genetic causes as first described for the alpha-synuclein gene. The alpha-synuclein protein also accumulates as insoluble aggregates in Lewy bodies in sporadic PD as well as in most inherited forms of PD. The focus of the present study is the modulation of synaptic plasticity in the corticostriatal pathway of transgenic (Tg) mice that overexpress the human alpha-synuclein protein throughout the brain (ASOTg). Paired-pulse facilitation was detected in vitro by activation of corticostriatal afferents in ASOTg mice, consistent with a presynaptic effect of elevated human alpha-synuclein. However basal synaptic transmission was unchanged in ASOTg, suggesting that human alpha-synuclein could impact paired-pulse facilitation via a presynaptic mechanism not directly related to the probability of neurotransmitter release. Mice lacking alpha-synuclein or those expressing normal and A53T human alpha-synuclein in tyrosine hydroxylase-containing neurons showed, instead, paired-pulse depression. High-frequency stimulation induced a presynaptic form of long-term depression solely in ASOTg striatum. A presynaptic, N-methyl-d-aspartate receptor-independent form of chemical long-term potentiation induced by forskolin (FSK) was enhanced in ASOTg striatum, while FSK-induced cAMP levels were reduced in ASOTg synaptoneurosome fractions. Overall the results suggest that elevated human alpha-synuclein alters presynaptic plasticity in the corticostriatal pathway, possibly reflecting a reduction in glutamate at corticostriatal synapses by modulation of adenylyl cyclase signaling pathways. ASOTg mice may recapitulate an early stage in PD during which overexpressed alpha-synuclein dampens corticostriatal synaptic transmission and reduces movement.
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PMID:Alterations in corticostriatal synaptic plasticity in mice overexpressing human alpha-synuclein. 1936 78

Dopamine (DA)-dependent corticostriatal plasticity is thought to underlie incremental procedural learning. A primary effector of striatal DA signaling is cAMP, yet its role in corticostriatal plasticity and striatum-dependent learning remains unclear. Here, we show that genetic deletion of a striatum-enriched isoform of adenylyl cyclase, AC5 knock-out (AC5KO), impairs two forms of striatum-dependent learning and corticostriatal synaptic plasticity. AC5KO mice were severely impaired in acquisition of a response strategy in the cross maze, a striatum-dependent task requiring a correct body turn to find a goal arm. In addition, AC5KO mice were impaired in acquisition of a motor skill, as assessed by the accelerated rotarod. Slice electrophysiology revealed a deficit in corticostriatal long-term depression (LTD) after high-frequency stimulation of tissue from AC5KO mice. LTD was rescued by activation of either presynaptic cannabinoid type 1 (CB(1)) receptors or postsynaptic metabotropic glutamate receptors (mGluRs), suggesting a postsynaptic role of AC5-cAMP, upstream of endocannabinoid release. In striatopallidal-projecting medium spiny neurons, DA D(2) receptors are negatively coupled to cAMP production, and activation of these receptors is required for endocannabinoid release and corticostriatal LTD. Recordings from striatopallidal neurons indicated that this is mediated by AC5, because coactivation of D(2) and mGluRs could induce LTD in wild-type but not in AC5KO neurons. To further examine the role of cAMP in corticostriatal plasticity, we elevated cAMP in striatal neurons of wild-type mice via the recording electrode. Under these conditions, corticostriatal LTD was eliminated. Together, these data suggest an AC5-cAMP-endocannabinoid-CB(1) signaling pathway in corticostriatal plasticity and striatum-dependent learning.
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PMID:Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. 1979 69

Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB(1)) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB(1) receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5'-O-(3-[(35)S]thio) triphosphate ([(35)S]GTP gamma S) in either area. Analysis of [(35)S]GTP gamma S-labeled G alpha subunits allowed for the detection of up-regulated CB(1) receptor coupling to G alpha(i2), G alpha(i3) in the PFC, and reduced coupling to G alpha(i3) in the cerebellum of fluoxetine-treated rats. Concomitant administration of the 5-HT(1A) receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY100635; 0.1 mg/kg/day) reduced fluoxetine-induced modulation of CB(1) receptor coupling to G alpha subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB(1) receptor signaling at the G alpha(i)-AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT(1A) receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term Delta(9)-tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB(1) receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.
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PMID:Long-term fluoxetine treatment modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat prefrontal cortex through 5-hydroxytryptamine 1A receptor-dependent mechanisms. 1999 40

CB1 receptors are G-protein coupled receptors (GPCRs) abundant in neurons, in which they modulate neurotransmission. The CB(1) receptor influence on memory and learning is well recognized, and disease states associated with CB(1) receptors are observed in addiction disorders, motor dysfunction, schizophrenia, and in bipolar, depression, and anxiety disorders. Beyond the brain, CB(1) receptors also function in liver and adipose tissues, vascular as well as cardiac tissue, reproductive tissues and bone. Signal transduction by CB(1) receptors occurs through interaction with Gi/o proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases (MAPK), inhibit voltage-gated Ca(2+) channels, activate K(+) currents (K(ir)), and influence Nitric Oxide (NO) signaling. CB(1) receptors are observed in internal organelles as well as plasma membrane. beta-Arrestins, adaptor protein AP-3, and G-protein receptor-associated sorting protein 1 (GASP1) modulate cellular trafficking. Cannabinoid Receptor Interacting Protein1a (CRIP1a) is an accessory protein whose function has not been delineated. Factor Associated with Neutral sphingomyelinase (FAN) regulates ceramide signaling. Such diversity in cellular signaling and modulation by interacting proteins suggests that agonists and allosteric modulators could be developed to specifically regulate unique, cell type-specific responses.
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PMID:CB(1) cannabinoid receptors and their associated proteins. 2016 26

Previous biochemical, cardiovascular and behavioral work has given evidence for the existence of antagonistic galanin receptor-5-HT1A receptor interactions in the brain. In this study we investigated the existence of GalR1-5-HT1A receptor heteromers and their functional characteristics. In mammalian cells transfected with GFP2-tagged 5-HT1A receptor and YFP-tagged GalR1 receptor, a proximity-based fluorescence resonance energy transfer technique was used and it has been demonstrated that GalR1-5-HT1A receptors heteromerize. Furthermore, signaling by either the mitogen-activated protein kinase (MAPK) or adenylyl cyclase (AC) pathways by these heteromers indicates a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of G(i/o) and an exaggerated inhibition of AC or stimulation of MAPK activity. The presence of these heteromers in the discrete brain regions is postulated based on the existence of GalR-5-HT1A receptor-receptor interactions previously described in the brain and gives rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5-HT1A heteromers.
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PMID:Galanin receptor-1 modulates 5-hydroxtryptamine-1A signaling via heterodimerization. 2017 Nov 59


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