Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility in male, but not female, mice

2021 ◽  
Author(s):  
Eden M. Anderson ◽  
Steven Loke ◽  
Benjamin Wrucke ◽  
Annabel Engelhardt ◽  
Skyler Demis ◽  
...  
Keyword(s):  
G Protein ◽  
Cognitive Flexibility ◽  
Pyramidal Neuron ◽  
K Channel ◽  
Cortical Function ◽  
Female Mice ◽  
Inwardly Rectifying

scholarly journals Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

2020 ◽  
Author(s):  
Eden M Anderson ◽  
Steven Loke ◽  
Benjamin Wrucke ◽  
Annabel Engelhardt ◽  
Evan Hess ◽  
...  
Keyword(s):  
Cognitive Function ◽  
G Protein ◽  
Cognitive Flexibility ◽  
Pyramidal Neuron ◽  
Pyramidal Neurons ◽  
K Channel ◽  
Cortical Function ◽  
Systemic Injection ◽  
The Impact ◽  
Inwardly Rectifying

AbstractBackgroundImbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown.MethodsIn mice harboring a ‘floxed’ version of the kcnj3 (Girk1) gene, we used a viral-cre approach to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic (PL) or infralimbic (IL) cortices. Additional studies used a novel model of chronic unpredictable stress (CUS) to determine the impact on PL GIRK-dependent signaling and cognitive function.ResultsIn males, loss of pyramidal GIRK-dependent signaling in the PL, but not IL, differentially impacted measures of affect and motivation, and impaired working memory and cognitive flexibility. CUS produced similar deficits in affect and cognition that paralleled a reduction in PL pyramidal GIRK-dependent signaling akin to viral approaches. Viral- and stress-induced behavioral deficits were rescued by systemic injection of a novel, GIRK1-selective agonist, ML-297. Unexpectedly, neither ablation of PL GIRK-dependent signaling or exposure to the CUS regimen impacted affect or cognition in female mice.ConclusionsGIRK-dependent signaling in male mice, but not females, is critical for maintaining optimal PL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

scholarly journals Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K + Channel) Channel Function

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Johanna Kuß ◽  
Birgit Stallmeyer ◽  
Matthias Goldstein ◽  
Susanne Rinné ◽  
Christiane Pees ◽  
...  
Keyword(s):  
G Protein ◽  
Sinus Node ◽  
K Channel ◽  
Channel Function ◽  
Node Disease ◽  
Sinus Node Disease ◽  
Inwardly Rectifying

scholarly journals Intrinsic gating properties of a cloned G protein-activated inward rectifier K+ channel.

1995 ◽  
Vol 106 (1) ◽  
pp. 1-23 ◽  
Author(s):  
C A Doupnik ◽  
N F Lim ◽  
P Kofuji ◽  
N Davidson ◽  
H A Lester
Keyword(s):  
G Protein ◽  
K Channel ◽  
Extrinsic Factors ◽  
Time Resolved ◽  
Time Constants ◽  
Protein Activation ◽  
G Protein Activation ◽  
Voltage Dependent ◽  
Current Activation ◽  
Inwardly Rectifying

The voltage-, time-, and K(+)-dependent properties of a G protein-activated inwardly rectifying K+ channel (GIRK1/KGA/Kir3.1) cloned from rat atrium were studied in Xenopus oocytes under two-electrode voltage clamp. During maintained G protein activation and in the presence of high external K+ (VK = 0 mV), voltage jumps from VK to negative membrane potentials activated inward GIRK1 K+ currents with three distinct time-resolved current components. GIRK1 current activation consisted of an instantaneous component that was followed by two components with time constants tau f approximately 50 ms and tau s approximately 400 ms. These activation time constants were weakly voltage dependent, increasing approximately twofold with maximal hyperpolarization from VK. Voltage-dependent GIRK1 availability, revealed by tail currents at -80 mV after long prepulses, was greatest at potentials negative to VK and declined to a plateau of approximately half the maximal level at positive voltages. Voltage-dependent GIRK1 availability shifted with VK and was half maximal at VK -20 mV; the equivalent gating charge was approximately 1.6 e-. The voltage-dependent gating parameters of GIRK1 did not significantly differ for G protein activation by three heterologously expressed signaling pathways: m2 muscarinic receptors, serotonin 1A receptors, or G protein beta 1 gamma 2 subunits. Voltage dependence was also unaffected by agonist concentration. These results indicate that the voltage-dependent gating properties of GIRK1 are not due to extrinsic factors such as agonist-receptor interactions and G protein-channel coupling, but instead are analogous to the intrinsic gating behaviors of other inwardly rectifying K+ channels.

scholarly journals Pancreatic Islet Cells Express a Family of Inwardly Rectifying K+Channel Subunits Which Interact to Form G-protein-activated Channels

1995 ◽  
Vol 270 (44) ◽  
pp. 26086-26091 ◽  
Author(s):  
Jorge Ferrer ◽  
Colin G. Nichols ◽  
Elena N. Makhina ◽  
Lawrence Salkoff ◽  
Josh Bernstein ◽  
...  
Keyword(s):  
G Protein ◽  
Pancreatic Islet ◽  
Islet Cells ◽  
K Channel ◽  
Pancreatic Islet Cells ◽  
Inwardly Rectifying
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