Receptor-specific regulation of atrial GIRK channel activity by different Ca2+-dependent PKC isoforms

ABSTRACTBackgroundDrug-induced neuroadaptations in the prefrontal cortex are thought to underlie impaired executive functions that reinforce addictive behaviors. Repeated cocaine exposure increased layer 5/6 pyramidal neuron excitability in the mouse prelimbic cortex (PL), an adaptation attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK/Kir3) channel activity. GIRK channel suppression in the PL of drug-naïve mice enhanced the motor-stimulatory effect of cocaine. The impact of cocaine on PL GABA neurons, key pyramidal neuron regulators, and the behavioral relevance of increased PL pyramidal neuron excitability, remain unclear.MethodsThe effect of repeated cocaine on mouse layer 5/6 PL GABA neurons was assessed using slice electrophysiology. Adaptations enhancing PL pyramidal neuron excitability were modeled in drug-naïve mice using persistent viral Cre ablation and acute chemogenetic approaches. The impact of these manipulations on PL-dependent behavior was assessed in motor activity and trace fear conditioning tests.ResultsRepeated cocaine treatment did not impact GIRK channel activity in, or excitability of, layer 5/6 PL GABA neurons. GIRK channel ablation in PL pyramidal neurons enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or fear learning. In contrast, direct or indirect chemogenetic activation of PL pyramidal neurons increased baseline and cocaine-induced motor activity and disrupted fear learning. These effects were mirrored by chemogenetic activation of PL pyramidal neurons projecting to the ventral tegmental area.ConclusionsManipulations enhancing the excitability of PL pyramidal neurons, including those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure.

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High Cholesterol Diet Up-Regulates Atrial and Neuronal GIRK Channel Activity

Biophysical Journal ◽

10.1016/j.bpj.2018.11.1228 ◽

2019 ◽

Vol 116 (3) ◽

pp. 223a

Author(s):

Anna N. Bukiya ◽

Avia Rosenhouse-Dantsker

Keyword(s):

High Cholesterol Diet ◽

Cholesterol Diet ◽

Channel Activity ◽

High Cholesterol ◽

Girk Channel

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Critical Determinants of the G Protein γ Subunits in the Gβγ Stimulation of G Protein-activated Inwardly Rectifying Potassium (GIRK) Channel Activity

Journal of Biological Chemistry ◽

10.1074/jbc.m308299200 ◽

2003 ◽

Vol 278 (50) ◽

pp. 50203-50211 ◽

Cited By ~ 15

Author(s):

Luying Peng ◽

Tooraj Mirshahi ◽

Hailin Zhang ◽

Jeanne P. Hirsch ◽

Diomedes E. Logothetis

Keyword(s):

G Protein ◽

Channel Activity ◽

Girk Channel ◽

Inwardly Rectifying ◽

Stimulation Of

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Mathematical Model of Basal and Agonist-Dependent GIRK Channel Activity

Biophysical Journal ◽

10.1016/j.bpj.2009.12.2696 ◽

2010 ◽

Vol 98 (3) ◽

pp. 495a

Author(s):

Daniel Yakubovich ◽

Shai Berlin ◽

Nathan Dascal

Keyword(s):

Mathematical Model ◽

Channel Activity ◽

Girk Channel

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PKC-isoform specific regulation of receptor desensitization and KCNQ1/KCNE1 K+ channel activity by mutant α1B-adrenergic receptors

Cellular Signalling ◽

10.1016/j.cellsig.2021.110228 ◽

2021 ◽

pp. 110228

Author(s):

Lina Renkhold ◽

Rike Kollmann ◽

Leonie Inderwiedenstraße ◽

Marie-Cecile Kienitz

Keyword(s):

Adrenergic Receptors ◽

K Channel ◽

Receptor Desensitization ◽

Channel Activity ◽

Specific Regulation

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Different roles of protein kinase C α and δ isoforms in the regulation of neutral sphingomyelinase activity in HL-60 cells

Biochemical Journal ◽

10.1042/bj3440921 ◽

1999 ◽

Vol 344 (3) ◽

pp. 921-928 ◽

Cited By ~ 12

Author(s):

Dora VIŠNJIĆ ◽

Drago BATINIŠ ◽

Hrvoje BANFIŠ

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Inhibitory Effect ◽

Interferon Γ ◽

Neutral Sphingomyelinase ◽

Kinase C ◽

Pkc Isoforms ◽

Ifn Γ ◽

The Difference ◽

Specific Regulation

The signalling mechanisms responsible for the hydrolysis of sphingomyelin mediated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and interferon γ (IFN-γ) in HL-60 cells were investigated. IFN-γ was found to increase selectively the activity of cytosolic, Mg2+-independent, neutral sphingomyelinase. The treatment of HL-60 cells with the combination of 1,25(OH)2D3 and IFN-γ had an additive effect on sphingomyelin hydrolysis, ceramide release and the activity of cytosolic, Mg2+-independent, neutral sphingomyelinase. The pretreatment of HL-60 cells with staurosporine, chelerythrine chloride and bisindolylmaleimide abolished the activity of sphingomyelinase in response to 1,25(OH)2D3 and IFN-γ. Calphostin C, which acts on the regulatory site of protein kinase C (PKC), and Gö 6976, a selective inhibitor of Ca2+-dependent PKC isoforms, inhibited the effect of 1,25(OH)2D3 but had no effect on the IFN-γ-mediated increase in activity of sphingomyelinase. Isoform-specific antibodies were used to deplete different PKC isoforms from cytosol before the treatment of the cytosolic fraction with 1,25(OH)2D3, arachidonic acid (AA) and PMA. The depletion of PKC isoforms β1, β2, ϵ, η, μ, ζ and λ had no effect on the activation of sphingomyelinase induced by 1,25(OH)2D3 or by AA. The depletion of PKC α from the cytosol completely abolished the effect of 1,25(OH)2D3 on sphingomyelinase activity but had no effect on the AA-induced activity of sphingomyelinase. PMA had no effect on the activity of sphingomyelinase in either untreated or α-depleted cytosol but significantly increased the activity of sphingomyelinase when added to cytosol depleted of PKC ∆. Moreover, PMA inhibited the effect of 1,25(OH)2D3 on sphingomyelinase activation but the inhibitory effect was abolished by prior depletion of PKC ∆ from the cytosol. These studies demonstrate that 1,25(OH)2D3-induced activation of sphingomyelinase is mediated by PKC α. Furthermore, PKC ∆ had an inhibitory effect on sphingomyelinase, suggesting that the difference between the 1,25(OH)2D3- and PMA-mediated effects on sphingomyelin turnover depends on the specific regulation of the PKC α and PKC ∆ isoforms.

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