Protein kinase Cε is involved in ethanol potentiation of glycine-gated Cl− current in rat neurons of ventral tegmental area

Jiang, Zheng‐Lin; Ye, J.-H.

doi:10.1016/s0028-3908(02)00409-4

Cited by 30 publications

(28 citation statements)

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“…We therefore wondered whether activin would also act through PKCε to control the response of GABA A Rs to ethanol. To specifically suppress the effects of PKCε, we used the PKCε-translocation inhibiting protein (PKCε-TIP) (Jiang and Ye, 2003;Dai et al, 2004;Lawrence et al, 2005). In wt pyramidal cells, addition of 200 μM PKCε TIP or its negative control to the pipette solution did not significantly alter the peak amplitude of evoked IPSCs, when compared with normal pipette solution within 20-40 min of whole-cell recording at a stimulus intensity of around 60 μA (696 ± 180 pA with PKCε TIP, n = 9, 819 ± 120 pA with PKCε TIP-negative control, n = 7, and 580 ± 74 pA for wt-control, n = 13, P40.05).…”

Section: Activin Targets Pkcε To Regulate Effect Of Ethanol On Ipscsmentioning

confidence: 99%

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

Zheng

Puppel

Huber

et al. 2015

Neuropsychopharmacol

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Activin, a member of the transforming growth factor-β family, exerts multiple functions in the nervous system. Originally identified as a neurotrophic and -protective agent, increasing evidence implicates activin also in the regulation of glutamatergic and GABAergic neurotransmission in brain regions associated with cognitive and affective functions. To explore how activin impacts on ethanol potentiation of GABA synapses and related behavioral paradigms, we used an established transgenic model of disrupted activin receptor signaling, in which mice express a dominant-negative activin receptor IB mutant (dnActRIB) under the control of the CaMKIIα promoter. Comparison of GABA A receptor currents in hippocampal neurons from dnActRIB mice and wild-type mice showed that all concentrations of ethanol tested (30-150 mM) produced much stronger potentiation of phasic inhibition in the mutant preparation. In dentate granule cells of dnActRIB mice, tonic GABA inhibition was more pronounced than in wild-type neurons, but remained insensitive to low ethanol (30 mM) in both preparations. The heightened ethanol sensitivity of phasic inhibition in mutant hippocampi resulted from both pre-and postsynaptic mechanisms, the latter probably involving PKCε. At the behavioral level, ethanol produced significantly stronger sedation in dnActRIB mice than in wild-type mice, but did not affect consumption of ethanol or escalation after withdrawal. We link the abnormal narcotic response of dnActRIB mice to ethanol to the excessive potentiation of inhibitory neurotransmission. Our study suggests that activin counteracts oversedation from ethanol by curtailing its augmenting effect at GABA synapses.

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Section: Activin Targets Pkcε To Regulate Effect Of Ethanol On Ipscsmentioning

confidence: 99%

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

Zheng

Puppel

Huber

et al. 2015

Neuropsychopharmacol

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“…Additional studies showed that residues in extracellular loop 2 and TM1 might contribute to the alcohol binding pockets, or exert modulatory roles on ethanol potentiation Lobo et al, 2008). However, it is also well documented that determinants of the ethanol sensitivity of a1 subunit GlyRs can be located intracellularly, such as protein kinase C phosphorylation Jiang and Ye, 2003) or direct modulation of the ion channel by G protein bg subunits (Yevenes et al, 2003(Yevenes et al, , 2006(Yevenes et al, , 2008. In addition, the relevance of Gbg signaling has been recently shown using intracellular blocking peptides designed to alter the interaction between the TM3-TM4 intracellular domain of GlyR and Gbg (Guzman et al, 2009;San Martin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Control of Ethanol Sensitivity of the Glycine Receptor α3 Subunit by Transmembrane 2, the Intracellular Splice Cassette and C-Terminal Domain

Sánchez

Yévenes

Martín

et al. 2015

J Pharmacol Exp Ther

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Previous studies have shown that the effect of ethanol on glycine receptors (GlyRs) containing the a1 subunit is affected by interaction with heterotrimeric G proteins (Gbg). GlyRs containing the a3 subunit are involved in inflammatory pain sensitization and rhythmic breathing and have received much recent attention. For example, it is unknown whether ethanol affects the function of this important GlyR subtype. Electrophysiologic experiments showed that GlyR a3 subunits were not potentiated by pharmacologic concentrations of ethanol or by Gbg. Thus, we studied GlyR a1-a3 chimeras and mutants to determine the molecular properties that confer ethanol insensitivity. Mutation of corresponding glycine 254 in transmembrane domain 2 (TM2) found in a1 in the a3 A254G -a1 chimera induced a glycine-evoked current that displayed potentiation during application of ethanol (46 6 5%, 100 mM) and Gbg activation (80 6 17%). Interestingly, insertion of the intracellular a3L splice cassette into GlyR a1 abolished the enhancement of the glycine-activated current by ethanol (5 6 6%) and activation by Gbg (21 6 7%). Incorporation of the GlyR a1 C terminus into the ethanol-resistant a3S A254G mutant produced a construct that displayed potentiation of the glycine-activated current with 100 mM ethanol (40 6 6%) together with a current enhancement after G protein activation (68 6 25%). Taken together, these data demonstrate that GlyR a3 subunits are not modulated by ethanol. Residue A254 in TM2, the a3L splice cassette, and the C-terminal domain of a3 GlyRs are determinants for low ethanol sensitivity and form the molecular basis of subtype-selective modulation of GlyRs by alcohol.

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“…We found that the overexpression of a constitutively active G␣ s mutant (G␣ s Q-L) shifted the ethanol sensitivity of GlyRs toward lower ethanol concentrations (1-10 mM). In this study, we used a higher concentration of glycine than was used in other previous studies (Mihic et al, 1997;Ye et al, 1998;Jiang and Ye, 2003;Crawford et al, 2007;Yévenes et al, 2008), because the effect of ethanol became much more evident already at 1 to 10 mM, which is close to the concentration achieved during low to moderate alcohol intake. At the glycine concentration used in the study, the receptors should have a higher saturation with the agonist, somewhat closer to a synaptic condition.…”

Section: G Protein Activation Modifies Actions Of Ethanol On Inhibitorymentioning

confidence: 94%

“…In addition, previous studies have reported that the actions of ethanol on ion channels are affected by cell signaling associated with G proteins. For instance, potentiation of the glycine-activated current produced by ethanol is attenuated by protein kinase C inhibitors and guanosine 5Ј-O-(2-thiodiphosphate) in recombinant and neuronal systems (Aguayo et al, 1996;Mascia et al, 1998;Jiang and Ye, 2003;Zhu and Ye, 2005). In addition, although the inhibition of PKA was unable to alter ethanol effects on GlyRs (Aguayo et al, 1996;Mascia et al, 1998), chronic incubation with cholera toxin, which specifically affects the G␣ s pathway, strongly abolished the alcohol potentiation in spinal neurons (Aguayo et al, 1996).…”

Section: G Protein Activation Modifies Actions Of Ethanol On Inhibitorymentioning

confidence: 99%

“…On the other hand, it was also shown that ethanol modulates ion channel activity through modifications of intracellular signal transduction pathways. For instance, the sensitivity of GlyR and GABA A to ethanol was affected by G protein activation and protein kinases (Aguayo et al, 1996;Freund and Palmer, 1997;Mascia et al, 1998;Jiang and Ye, 2003;Zhu and Ye, 2005;Qi et al, 2007). Of interest, it was reported that ethanol can indeed affect specific intracellular transduction pathways (Yao et al, 2002;Morrow et al, 2004;Ron and Jurd, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Activated G Protein α_sSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors

Yévenes

Moraga-Cid²,

Romo³

et al. 2011

J Pharmacol Exp Ther

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It is well known that ethanol modulates the function of the Cys loop ligand-gated ion channels, which include the inhibitory glycine receptors (GlyRs). Previous studies have consistently shown that transmembrane and extracellular sites are essential for ethanol actions in GlyRs. In addition, recent evidence has shown that the ethanol modulation of GlyRs is also affected by G protein activation through G␤␥ subunits. However, more specific roles of G protein ␣ subunits on ethanol actions are unknown. Here, we show that the allosteric effect of ethanol on the human ␣ 1 GlyR is selectively enhanced by the expression of G␣ s Q-L. For example, constitutively active G␣ s , but not G␣ q or G␣ i , was able to displace the alcohol sensitivity of GlyRs toward low millimolar concentrations (17 Ϯ 4 versus 48 Ϯ 5% at 100 mM). Experiments under conditions that increased cAMP and protein kinase A (PKA)-mediated signaling, on the contrary, did not produce the same enhancement in sensitivity, suggesting that the G␣ s Q-L effect was not dependent on cAMP/PKAdependent signaling. On the other hand, the effect of G␣ s Q-L was blocked by a G␤␥ scavenger (9 Ϯ 3% of control). Furthermore, two mutant receptors previously shown to have impaired interactions with G␤␥ were not affected by G␣ s Q-L, suggesting that G␤␥ is needed for enhancing ethanol sensitivity. These results support the conclusion that activated G␣ s can facilitate the G␤␥ interaction with GlyRs in presence of ethanol, independent of increases in cAMP signaling. Thus, these data indicate that the activated form of G␣ s is able to positively influence the effect of ethanol on a type of inhibitory receptor important for motor control, pain, and respiration.

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Protein kinase Cε is involved in ethanol potentiation of glycine-gated Cl− current in rat neurons of ventral tegmental area

Cited by 30 publications

References 50 publications

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

Control of Ethanol Sensitivity of the Glycine Receptor α3 Subunit by Transmembrane 2, the Intracellular Splice Cassette and C-Terminal Domain

Activated G Protein α_sSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors

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Protein kinase Cε is involved in ethanol potentiation of glycine-gated Cl− current in rat neurons of ventral tegmental area

Cited by 30 publications

References 50 publications

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

Control of Ethanol Sensitivity of the Glycine Receptor α3 Subunit by Transmembrane 2, the Intracellular Splice Cassette and C-Terminal Domain

Activated G Protein αsSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors

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Product

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Activated G Protein α_sSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors