Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε

Hodge, Clyde W.; Raber, Jacob; McMahon, Thomas; Walter, Henrik; Sánchez-Pérez, Ana; Mehmert, Kristin K.; Morrow, A. Leslie; Messing, Robert O.

doi:10.1172/jci15903

Cited by 68 publications

(81 citation statements)

References 33 publications

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“…Studies with PKCe null mice suggest that PKCe inhibits modulation of GABA A receptors by positive allosteric activators. In addition to altered responses to ethanol (see above), these mice show increased sensitivity to the acute behavioral effects of barbiturates, benzodiazepines and neurosteroids, and this is associated with increased in vitro sensitivity of GABA A receptors to these allosteric modulators [7,8]. Consistent with the known anxiolytic properties of neurosteroids, PKCe null mice also show reduced anxiety-like behavior and reduced plasma levels of stress hormones [8].…”

Section: Pkc Regulation Of Gaba a Receptor Sensitivity To Allosteric mentioning

confidence: 87%

“…These behaviors are associated with increased enhancement of GABA A receptor function by ethanol in microsacs from the frontal cortex of PKCe null mice [7,8]. Application of a peptide that selectively inhibits PKCe [80] increases ethanol modulation of GABA A receptors in synaptosomes from wild-type mice but not from PKCe null mice.…”

Section: Pkc Regulation Of Gaba a Receptor Sensitivity To Allosteric mentioning

confidence: 99%

“…In addition to altered responses to ethanol (see above), these mice show increased sensitivity to the acute behavioral effects of barbiturates, benzodiazepines and neurosteroids, and this is associated with increased in vitro sensitivity of GABA A receptors to these allosteric modulators [7,8]. Consistent with the known anxiolytic properties of neurosteroids, PKCe null mice also show reduced anxiety-like behavior and reduced plasma levels of stress hormones [8]. Therefore, considering these findings, it is the likely that PKCe is the PKC isozyme responsible for reducing sensitivity of GABA A receptors to neurosteroids and other positive allosteric modulators in central neurons.…”

Section: Pkc Regulation Of Gaba a Receptor Sensitivity To Allosteric mentioning

confidence: 99%

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Protein kinase C regulation of GABAA receptors

Song

Messing

2005

CMLS, Cell. Mol. Life Sci.

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Pharmacological studies with drugs that activate or inhibit several protein kinase C (PKC) isozymes have identified the PKC family of serine-threonine kinases as important in the regulation of gamma-aminobutyric acid type A (GABA(A)) receptor function. PKC modulates GABA(A) receptor surface density, chloride conductance and receptor sensitivity to positive allosteric modulators such as neurosteroids, ethanol, benzodiazepines and barbiturates. Recent studies using PKC isozyme-selective reagents and gene-targeted mice have begun to identify critical roles for three isozymes, PKCbetaII, PKCvarepsilon and PKCgamma, in various aspects of GABA(A) receptor regulation. Progress in this field touches upon therapeutic areas that are of great clinical importance such as anxiety and addiction. Increased understanding of how PKC regulates GABA(A) receptors and which PKC isozymes are involved holds promise for development of new treatments for diverse neuropsychiatric disorders.

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Section: Pkc Regulation Of Gaba a Receptor Sensitivity To Allosteric mentioning

confidence: 87%

Section: Pkc Regulation Of Gaba a Receptor Sensitivity To Allosteric mentioning

confidence: 99%

Section: Pkc Regulation Of Gaba a Receptor Sensitivity To Allosteric mentioning

confidence: 99%

See 1 more Smart Citation

Protein kinase C regulation of GABAA receptors

Song

Messing

2005

CMLS, Cell. Mol. Life Sci.

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“…Mice lacking the PKC ε self-administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABA receptors when compared with wild-type controls [77,78]. PKC ε knockout mice behave reduced ethanol consumption, sensitivity, reward and anxiety-like behavior compared with wild-type animals; even enhanced GABA receptor activity [79]. Correlation with the increased GABA transmission in the animals was confirmed by the increased sensitivity to ethanol and the higher chloridion uptake upon stimulation [80].…”

Section: Alcohol Addictionmentioning

confidence: 99%

The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases

Chen

Tian

2011

Front. Med.

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Protein kinase C epsilon (PKC ɛ) is one of major isoforms in novel PKC family. Although it has been extensively characterized in the past decade, the role of PKC ɛ in neuron is still not well understood. Advances in molecular biology have now removed significant barriers to the direct investigation of PKC ɛ functions in vivo, and PKC ɛ has been increasingly implicated in the neural biological functions and associated neurogenic diseases. Recent studies have provided important insights into the influence of PKC ɛ on cortical processing at both the single cell level and network level. These studies provide compelling evidence that PKC ɛ could regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKC ɛ signal pathway in the developing brain.

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“…Phosphorylation of gamma-aminobutyric acid (GABA A ) receptors by protein kinase C (PKC) is a regulatory mechanism implicated in anxiety, alcoholism, and epilepsy (Hodge et al 2002). The potential role of PKC on the regulation of GABA A receptor function is not clearly understood.…”

Section: Introductionmentioning

confidence: 99%