Mathematical Model of Basal and Agonist-Dependent GIRK Channel Activity

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

Cellular Signalling ◽

10.1016/j.cellsig.2019.109418 ◽

2019 ◽

Vol 64 ◽

pp. 109418 ◽

Cited By ~ 1

Author(s):

Anne Niemeyer ◽

Andreas Rinne ◽

Marie-Cecile Kienitz

Keyword(s):

Channel Activity ◽

Girk Channel ◽

Pkc Isoforms ◽

Specific Regulation

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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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Regulation of Type 1 Inositol 1,4,5-Trisphosphate–gated Calcium Channels by InsP3 and Calcium

The Journal of General Physiology ◽

10.1085/jgp.113.6.837 ◽

1999 ◽

Vol 113 (6) ◽

pp. 837-849 ◽

Cited By ~ 52

Author(s):

I.I. Moraru ◽

E.J. Kaftan ◽

B.E. Ehrlich ◽

J. Watras

Keyword(s):

Mathematical Model ◽

Ca Channel ◽

Channel Kinetics ◽

Channel Activity ◽

Open Probability ◽

Intact Cells ◽

Data Channel ◽

Inositol 1,4,5 Trisphosphate ◽

Intracellular Ca

Cytosolic calcium acts as both a coagonist and an inhibitor of the type 1 inositol 1,4,5-trisphosphate (InsP3)–gated Ca channel, resulting in a bell-shaped Ca dependence of channel activity (Bezprozvanny, I., J. Watras, and B.E. Ehrlich. 1991. Nature. 351:751–754; Finch, E.A., T.J. Turner, and S.M. Goldin. 1991. Science. 252: 443–446; Iino, M. 1990. J. Gen. Physiol. 95:1103–1122). The ability of Ca to inhibit channel activity, however, varies dramatically depending on InsP3 concentration (Combettes, L., Z. Hannaert-Merah, J.F. Coquil, C. Rousseau, M. Claret, S. Swillens, and P. Champeil. 1994. J. Biol. Chem. 269:17561–17571; Kaftan, E.J., B.E. Ehrlich, and J. Watras. 1997. J. Gen. Physiol. 110:529–538). In the present report, we have extended the characterization of the effect of cytosolic Ca on both InsP3 binding and InsP3-gated channel kinetics, and incorporated these data into a mathematical model capable of simulating channel kinetics. We found that cytosolic Ca increased the Kd of InsP3 binding ∼3.5-fold, but did not influence the maximal number of binding sites. The ability of Ca to decrease InsP3 binding is consistent with the rightward shift in the bell-shaped Ca dependence of InsP3-gated Ca channel activity. High InsP3 concentrations are able to overcome the Ca-dependent inhibition of channel activity, apparently due to a low affinity InsP3 binding site (Kaftan, E.J., B.E. Ehrlich, and J. Watras. 1997. J. Gen. Physiol. 110:529–538). Constants from binding analyses and channel activity determinations were used to develop a mathematical model that fits the complex Ca-dependent regulation of the type 1 InsP3-gated Ca channel. This model accurately simulated both steady state data (channel open probability and InsP3 binding) and kinetic data (channel activity and open time distributions), and yielded testable predictions with regard to the regulation of this intracellular Ca channel. Information gained from these analyses, and our current molecular model of this Ca channel, will be important for understanding the basis and regulation of intracellular Ca waves and oscillations in intact cells.

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