Role of phosphorylation in desensitization of acetylcholine receptors expressed in Xenopus oocytes

Hoffman, Peter W.; Ravindran, Arippa; Huganir, Richard L.

doi:10.1523/jneurosci.14-07-04185.1994

Cited by 69 publications

(47 citation statements)

References 37 publications

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“…It is well established that protein phosphorylation plays an important role in various neuroreceptors (Huganir and Greengard, 1990;Hoffman et al, 1994). Our experiments with the cortical neuron NMDA receptors indicated that PKC inhibition prevented galantamine potentiation but PKA inhibition did not.…”

Section: Discussionmentioning

confidence: 51%

Mechanism of Action of Galantamine on N-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

Moriguchi¹,

Marszalec²,

Zhao³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

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Galantamine, a new Alzheimer's drug approved in the United States, is known to inhibit acetylcholinesterase and potentiate acetylcholine-induced currents in brain neurons. However, because both cholinergic and N-methyl-D-aspartate (NMDA) systems are down-regulated in the brain of Alzheimer's patients, we studied the effects of galantamine on NMDA receptors. NMDA-induced whole-cell currents were recorded from the rat multipolar cortical neurons in primary culture. NMDA currents recorded in Mg 2ϩ -free media without addition of glycine were reversibly potentiated by bath and U-tube applications of galantamine at 10 to 10,000 nM, showing a bell-shaped doseresponse relationship. However, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate currents were not affected by galantamine. The maximum potentiation of NMDA currents to ϳ130% of the control was obtained at 1 M galantamine. The potentiation was due to a shift of the NMDA doseresponse curve in the direction of lower NMDA concentrations. Glycine at 1 to 3000 nM enhanced NMDA currents, and potentiation by 1 M galantamine and 1 to 300 nM glycine was additive. The glycine site antagonist 7-chlorokynurenic acid did not prevent the galantamine action. These results suggested that galantamine did not interact with the glycine binding site. Experiments with various concentrations of Mg 2ϩ indicated that galantamine did not affect the Mg 2ϩ blocking site of the NMDA receptor. PKC was involved in galantamine potentiation of NMDA currents, but protein kinase A, G i /G o proteins, and G s proteins were not involved. Potentiation of the activity of NMDA receptors is deemed partially responsible for the improvement of cognition, learning, and memory in Alzheimer's patients.

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Section: Discussionmentioning

confidence: 51%

Mechanism of Action of Galantamine on N-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

Moriguchi¹,

Marszalec²,

Zhao³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

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“…It is well established that protein phosphorylation plays an important role in various neuroreceptors (Huganir and Greengard, 1990;Hoffman et al, 1994). The majority of extracellular signals is mediated by the activation of membrane receptors that are coupled to transducer components located at the inner surface of the plasma membrane.…”

Section: Discussion Nnachr Subunit Dependence Of Nootropic Actionsmentioning

confidence: 99%

Nootropic Drug Modulation of Neuronal Nicotinic Acetylcholine Receptors in Rat Cortical Neurons

et al. 2001

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Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechanism of action of nefiracetam and aniracetam on neuronal nicotinic acetylcholine receptors (nnAChRs). Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell, patch-clamp technique. Two types of currents were evoked by acetylcholine (ACh): ␣-bungarotoxin-sensitive, ␣7-type currents and ␣-bungarotoxin-insensitive, ␣4␤2-type currents. Although nefiracetam and aniracetam inhibited ␣7-type currents only weakly, these nootropic agents potentiated ␣4␤2-type currents in a very potent and efficacious manner. Nefiracetam at 1 nM and aniracetam at 0.1 nM reversibly potentiated ␣4␤2-type currents to 200 to 300% of control. Nefiracetam at very high concentrations (ϳ10 M) also potentiated ␣4␤2-type currents but to a lesser extent, indicative of a bell-shaped dose-response relationship. Nefiracetam markedly increased the saturating responses induced by high concentrations of ACh. However, human ␣4␤2 subunits expressed in human embryonic kidney cells were inhibited rather than potentiated by nefiracetam. The specific protein kinase A inhibitors (H-89, KT5720, and peptide 5-24) and protein kinase C inhibitors (chelerythrine, calphostin C, and peptide 19 -63) did not prevent nefiracetam from potentiating ␣4␤2-type currents, indicating that these protein kinases are not involved in nefiracetam action. The nefiracetam potentiating action was not affected by 24-h pretreatment of neurons with pertussis toxin, but was abolished by cholera toxin. Therefore, G s proteins, but not G i /G o proteins, are involved in nefiracetam potentiation. These results indicate that nnAChRs are an important site of action of nefiracetam and G s proteins may be its crucial target.

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“…Furthermore, we studied ␣1-mutants in which the Ser-16 phosphorylated by PKC was replaced by negatively charged amino acids (Asp or Glu), which in other settings was shown to mimic constitutive phosphorylation (Hoffman et al, 1994;Pages et al, 1994). In each cell line, we analyzed the effects of the activation of phorbol ester-sensitive PKCs on the activity of Na,K-ATPase and the cell surface expression of Na,K-pumps under various experimental conditions.…”

Section: Introductionmentioning

confidence: 99%

Is Phosphorylation of the α1 Subunit at Ser-16 Involved in the Control of Na,K-ATPase Activity by Phorbol Ester–activated Protein Kinase C?

Féraille

Béguin

Carranza

et al. 2000

MBoC

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The ␣1 subunit of Na,K-ATPase is phosphorylated at Ser-16 by phorbol ester-sensitive protein kinase(s) C (PKC). The role of Ser-16 phosphorylation was analyzed in COS-7 cells stably expressing wild-type or mutant (T15A/S16A and S16D-E) ouabain-resistant Bufo ␣1 subunits. In cells incubated at 37°C, phorbol 12,13-dibutyrate (PDBu) inhibited the transport activity and decreased the cell surface expression of wild-type and mutant Na,K-pumps equally (ϳ20 -30%). This effect of PDBu was mimicked by arachidonic acid and was dependent on PKC, phospholipase A 2 , and cytochrome P450-dependent monooxygenase. In contrast, incubation of cells at 18°C suppressed the down-regulation of Na,K-pumps and revealed a phosphorylation-dependent stimulation of the transport activity of Na,K-ATPase. Na,K-ATPase from cells expressing ␣1-mutants mimicking Ser-16 phosphorylation (S16D or S16E) exhibited an increase in the apparent Na affinity. This finding was confirmed by the PDBu-induced increase in Na sensitivity of the activity of Na,K-ATPase measured in permeabilized nontransfected COS-7 cells. These results illustrate the complexity of the regulation of Na,K-ATPase ␣1 isozymes by phorbol ester-sensitive PKCs and reveal 1) a phosphorylation-independent decrease in cell surface expression and 2) a phosphorylation-dependent stimulation of the transport activity attributable to an increase in the apparent Na affinity.

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Role of phosphorylation in desensitization of acetylcholine receptors expressed in Xenopus oocytes

Cited by 69 publications

References 37 publications

Mechanism of Action of Galantamine on N-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

Mechanism of Action of Galantamine on N-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

Nootropic Drug Modulation of Neuronal Nicotinic Acetylcholine Receptors in Rat Cortical Neurons

Is Phosphorylation of the α1 Subunit at Ser-16 Involved in the Control of Na,K-ATPase Activity by Phorbol Ester–activated Protein Kinase C?

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