scholarly journals Basal G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels activity governs synaptic plasticity that supports dorsal hippocampus-dependent cognitive functions

2020 ◽  
Author(s):  
Sara Temprano-Carazo ◽  
Souhail Djebari ◽  
Guillermo Iborra-Lazaro ◽  
Irene Sanchez-Rodriguez ◽  
Mauricio O. Nava-Mesa ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
G Protein ◽  
Cognitive Functions ◽  
Dorsal Hippocampus ◽  
Hippocampal Slices ◽  
Girk Channels ◽  
Neural Excitability ◽  
Girk Channel ◽  
Inwardly Rectifying

G-protein-gated inwardly rectifying potassium (Kir3/GirK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer and Parkinson diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. GirK channels are constitutively activated in the dorsal hippocampus contributing to resting membrane potential, and their synaptic activation compensates any excitation excess. Here, in order to elucidate the role of GirK channels activity in the maintenance of dorsal hippocampus-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined. For that purpose, basal GirK activity was pharmacologically modulated by two specific drugs: ML297, a GirK channel opener, and Tertiapin-Q, a GirK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied pharmacological GirK modulation effect on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular injections of both GirK modulators to study their contribution to CA3-CA1 synapse electrophysiological properties, synaptic plasticity, and learning and memory capabilities during hippocampal dependent tasks. We found that pharmacological disruption of basal GirK activity in dorsal hippocampus, causing either function gain or loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GirK activity must take place in the hippocampus to sustain cognitive functions. Significance Statement: The dorsal hippocampus mostly performs cognitive functions related to contextual/spatial associations. These functions rely on synaptic plasticity processes that are critically ruled by a finely tuned neural excitability. Being the downstream physiological effectors of a variety of G-coupled receptors, activation of G protein-gated inwardly rectifying K+ (GirK) channels induces neurons to hyperpolarize, contributing to neural excitability throughout the control of excitatory excess. Here, we demonstrate that modulation of basal GirK channels activity, causing either function gain or loss, transforms HFS-induced LTP into LTD, inducing deficits in dorsal hippocampus-dependent learning and memory. Together, our data show a crucial GirK activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

scholarly journals G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channels govern synaptic plasticity that supports hippocampal-dependent cognitive functions in male mice

2021 ◽  
pp. JN-RM-2849-20
Author(s):  
Souhail Djebari ◽  
Guillermo Iborra-Lázaro ◽  
Sara Temprano-Carazo ◽  
Irene Sánchez-Rodríguez ◽  
Mauricio O. Nava-Mesa ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
G Protein ◽  
Cognitive Functions ◽  
Male Mice ◽  
Girk Channels ◽  
Inwardly Rectifying

Human Adrenal Glomerulosa Cells Express K2P and GIRK Potassium Channels that are inhibited by AngII and ACTH

2021 ◽  
Author(s):  
John J. Enyeart ◽  
Judith A. Enyeart
Keyword(s):  
G Protein ◽  
Zona Glomerulosa ◽  
Time Dependent ◽  
Aldosterone Secretion ◽  
Girk Channels ◽  
Whole Cell ◽  
Whole Cell Patch Clamp ◽  
Girk Channel ◽  
Inwardly Rectifying ◽  
G Protein Coupled

In whole-cell patch clamp recordings, it was discovered that normal human adrenal zona glomerulosa (AZG) cells express members of the three major families of K+ channels. Among these are a two pore (K2P) leak-type and a G-protein-coupled, inwardly-rectifying (GIRK) channel, both inhibited by peptide hormones that stimulate aldosterone secretion. The K2P current displayed properties identifying it as TREK-1 (KCNK2). This outwardly-rectifying current was activated by arachidonic acid and inhibited by angiotensin II (AngII), adrenocorticotrophic hormone (ACTH), and forskolin. The activation and inhibition of TREK-1 was coupled to AZG cell hyperpolarization and depolarization, respectively. A second K2P channel, TASK-1 (KCNK3), was expressed at a lower density in AZG cells. Human AZG cells also express inwardly rectifying K+ current(s) (KIR) that include quasi-instantaneous and time-dependent components. This is the first report demonstrating the presence of KIR in whole cell recordings from AZG cells of any species. The time-dependent current was selectively inhibited by AngII, and ACTH, identifying it as a G protein-coupled (GIRK) channel, most likely KIR3.4 (KCNJ5). The quasi-instantaneous KIR current was not inhibited by AngII or ACTH, and may be a separate non-GIRK current. Finally, AZG cells express a voltage-gated, rapidly inactivating K+ current whose properties identified as KV1.4 (KCNA4), a conclusion confirmed by Northern blot. These findings demonstrate that human AZG cells express K2P and GIRK channels whose inhibition by AngII and ACTH are likely coupled to depolarization-dependent secretion. They further demonstrate that human AZG K+ channels differ fundamentally from the widely adopted rodent models for human aldosterone secretion.

scholarly journals Differential effects of inhibitory G protein isoforms on G protein-gated inwardly rectifying K+ currents in adult murine atria

2018 ◽  
Vol 314 (5) ◽  
pp. C616-C626 ◽  
Author(s):  
Muriel Nobles ◽  
David Montaigne ◽  
Sonia Sebastian ◽  
Lutz Birnbaumer ◽  
Andrew Tinker
Keyword(s):  
G Protein ◽  
Knockout Mice ◽  
Protein Isoforms ◽  
Girk Channels ◽  
Differential Effects ◽  
Girk Channel ◽  
Inhibitory G Protein ◽  
Genetic Deletion ◽  
The Right ◽  
Inwardly Rectifying

G protein-gated inwardly rectifying K+ (GIRK) channels are the major inwardly rectifying K+ currents in cardiac atrial myocytes and an important determinant of atrial electrophysiology. Inhibitory G protein α-subunits can both mediate activation via acetylcholine but can also suppress basal currents in the absence of agonist. We studied this phenomenon using whole cell patch clamping in murine atria from mice with global genetic deletion of Gαi2, combined deletion of Gαi1/Gαi3, and littermate controls. We found that mice with deletion of Gαi2 had increased basal and agonist-activated currents, particularly in the right atria while in contrast those with Gαi1/Gαi3 deletion had reduced currents. Mice with global genetic deletion of Gαi2 had decreased action potential duration. Tissue preparations of the left atria studied with a multielectrode array from Gαi2 knockout mice showed a shorter effective refractory period, with no change in conduction velocity, than littermate controls. Transcriptional studies revealed increased expression of GIRK channel subunit genes in Gαi2 knockout mice. Thus different G protein isoforms have differential effects on GIRK channel behavior and paradoxically Gαi2 act to increase basal and agonist-activated GIRK currents. Deletion of Gαi2 is potentially proarrhythmic in the atria.

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1335-1343 ◽  
Author(s):  
Haripriya Shankar ◽  
Swaminathan Murugappan ◽  
Soochong Kim ◽  
Jianguo Jin ◽  
Zhongren Ding ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
G Protein ◽  
Shape Change ◽  
Human Platelets ◽  
P2y12 Receptor ◽  
Functional Responses ◽  
Girk Channels ◽  
Girk Channel ◽  
Inwardly Rectifying

Abstract The role of the Gi-coupled platelet P2Y12 receptor in platelet function has been well established. However, the functional effector or effectors contributing directly to αIIbβ3 activation in human platelets has not been delineated. As the P2Y12 receptor has been shown to activate G protein–gated, inwardly rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any of the functional responses of the platelet P2Y12 receptor. Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4. In aspirin-treated and washed human platelets, 2 structurally distinct GIRK inhibitors, SCH23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(±)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), inhibited adenosine diphosphate (ADP)–, 2-methylthioADP (2-MeSADP)–, U46619-, and low-dose thrombin–mediated platelet aggregation. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y12-mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced Gq-mediated platelet shape change and intracellular calcium mobilization. Unlike AR-C 69931MX, a P2Y12 receptor–selective antagonist, the GIRK channel blockers did not affect the ADP-induced adenlylyl cyclase inhibition, indicating that they do not directly antagonize the P2Y12 receptor. We conclude that GIRK channels are important functional effectors of the P2Y12 receptor in human platelets.

scholarly journals G-protein–gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids

2016 ◽  
Vol 124 (3) ◽  
pp. 641-650 ◽  
Author(s):  
Gaspard Montandon ◽  
Jun Ren ◽  
Nicole C. Victoria ◽  
Hattie Liu ◽  
Kevin Wickman ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
G Protein ◽  
Respiratory Depression ◽  
Ventrolateral Medulla ◽  
Wild Type ◽  
Girk Channels ◽  
Systemic Injection ◽  
Baseline Rate ◽  
Girk Channel ◽  
Inwardly Rectifying

Abstract Background Drugs acting on μ-opioid receptors (MORs) are widely used as analgesics but present side effects including life-threatening respiratory depression. MORs are G-protein–coupled receptors inhibiting neuronal activity through calcium channels, adenylyl cyclase, and/or G-protein–gated inwardly rectifying potassium (GIRK) channels. The pathways underlying MOR-dependent inhibition of rhythmic breathing are unknown. Methods By using a combination of genetic, pharmacological, and physiological tools in rodents in vivo, the authors aimed to identify the role of GIRK channels in MOR-mediated inhibition of respiratory circuits. Results GIRK channels were expressed in the ventrolateral medulla, a neuronal population regulating rhythmic breathing, and GIRK channel activation with flupirtine reduced respiratory rate in rats (percentage of baseline rate in mean ± SD: 79.4 ± 7.4%, n = 7), wild-type mice (82.6 ± 3.8%, n = 3), but not in mice lacking the GIRK2 subunit, an integral subunit of neuronal GIRK channels (GIRK2−/−, 101.0 ± 1.9%, n = 3). Application of the MOR agonist [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to the ventrolateral medulla depressed respiratory rate, an effect partially reversed by the GIRK channel blocker Tertiapin-Q (baseline: 42.1 ± 7.4 breath/min, DAMGO: 26.1 ± 13.4 breath/min, Tertiapin-Q + DAMGO: 33.9 ± 9.8 breath/min, n = 4). Importantly, DAMGO applied to the ventrolateral medulla failed to reduce rhythmic breathing in GIRK2−/− mice (percentage of baseline rate: 103.2 ± 12.1%, n = 4), whereas it considerably reduced rate in wild-type mice (62.5 ± 17.7% of baseline, n = 4). Respiratory rate depression by systemic injection of the opioid analgesic fentanyl was markedly reduced in GIRK2−/− (percentage of baseline: 12.8 ± 15.8%, n = 5) compared with wild-type mice (72.9 ± 27.3%). Conclusions Overall, these results identify that GIRK channels contribute to respiratory inhibition by MOR, an essential step toward understanding respiratory depression by opioids.

scholarly journals Dynamic role of the tether helix in PIP2-dependent gating of a G protein–gated potassium channel

2017 ◽  
Vol 149 (8) ◽  
pp. 799-811 ◽  
Author(s):  
Emre Lacin ◽  
Prafulla Aryal ◽  
Ian W. Glaaser ◽  
Karthik Bodhinathan ◽  
Eric Tsai ◽  
...  
Keyword(s):  
G Protein ◽  
Neuronal Excitability ◽  
Neurological Diseases ◽  
Dynamic Interaction ◽  
Open Probability ◽  
Dynamic Simulations ◽  
Anionic Phospholipid ◽  
Girk Channels ◽  
Functional Studies ◽  
Girk Channel

G protein–gated inwardly rectifying potassium (GIRK) channels control neuronal excitability in the brain and are implicated in several different neurological diseases. The anionic phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) is an essential cofactor for GIRK channel gating, but the precise mechanism by which PIP2 opens GIRK channels remains poorly understood. Previous structural studies have revealed several highly conserved, positively charged residues in the “tether helix” (C-linker) that interact with the negatively charged PIP2. However, these crystal structures of neuronal GIRK channels in complex with PIP2 provide only snapshots of PIP2’s interaction with the channel and thus lack details about the gating transitions triggered by PIP2 binding. Here, our functional studies reveal that one of these conserved basic residues in GIRK2, Lys200 (6′K), supports a complex and dynamic interaction with PIP2. When Lys200 is mutated to an uncharged amino acid, it activates the channel by enhancing the interaction with PIP2. Atomistic molecular dynamic simulations of neuronal GIRK2 with the same 6′ substitution reveal an open GIRK2 channel with PIP2 molecules adopting novel positions. This dynamic interaction with PIP2 may explain the intrinsic low open probability of GIRK channels and the mechanism underlying activation by G protein Gβγ subunits and ethanol.

Involvement of G-protein-activated inwardly rectifying K+ (GIRK) channels in opioid-induced analgesia

2000 ◽  
Vol 38 (1) ◽  
pp. 113-116 ◽  
Author(s):  
Kazutaka Ikeda ◽  
Toru Kobayashi ◽  
Toshiro Kumanishi ◽  
Hiroaki Niki ◽  
Ryoji Yano
Keyword(s):  
G Protein ◽  
Girk Channels ◽  
Inwardly Rectifying

scholarly journals Forepaw Sensorimotor Deprivation in Early Life Leads to the Impairments on Spatial Memory and Synaptic Plasticity in Rats

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Yuanyuan Zhang ◽  
Fei Li ◽  
Xiaohua Cao ◽  
Xingming Jin ◽  
Chonghuai Yan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Spatial Memory ◽  
Learning And Memory ◽  
Early Life ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Perforant Path ◽  
Sprague Dawley ◽  
Cellular Mechanisms ◽  
Spatial Reference

To investigate the influence of forepaw sensorimotor deprivation on memory and synaptic plasticity, Sprague-Dawley rats were divided into two groups: a sham-operated group and a group deprived of forepaw sensorimotor function by microsurgical operation at postnatal day 13 (PN13). Behavioral and electrophysiological studies were performed at PN25, PN35, PN45, and PN60. Open field test was used to assess the spontaneous locomotor activity. Morris water maze was used to evaluate spatial reference learning and memory. The long-term potentiation (LTP) in the medial perforant path—dentate gyrus (MPP-DG) pathway was examined with hippocampal slices. We found that forepaw sensorimotor deprivation did not affect spontaneous activity of the rats. However, spatial reference learning and memory were significantly impaired in their early life (PN25, PN35, and PN45). In accordance with the behavior results, LTP in MPP-DG pathway was significantly suppressed in their early life. These data demonstrated that forepaw sensorimotor deprivation led to the impairments on spatial memory via inducing pronounced deficits in the MPP-DG pathway to exhibit LTP, one of the major cellular mechanisms underlying learning and memory.

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