GIRK2 splice variants and neuronal G protein-gated K channels: implications for channel function and behavior.

paper Cited Public

Authors: Marron Fernandez de Velasco, Ezequiel; Zhang, Lei; N Vo, Baovi; Tipps, Megan; Farris, Shannon; Xia, Zhilian; Anderson, Allison; Carlblom, Nicholas; Weaver, C David; Dudek, Serena M; Wickman, Kevin
Year: 2017
Journal: Scientific reports
PMID: 28487514
DOI: 10.1038/s41598-017-01820-2
PMCID: PMC5431628

Figure 1

Functional comparison of GIRK2a and GIRK2c in HEK cells. (A) Whole-cell currents (Vhold = −70 mV) evoked by baclofen (100 μM) in HEK cells expressing GABABR, GIRK1, and either GIRK2a (red) or GIRK2c (blue). No current was evoked by baclofen in cells expressing only GABABR (control, black). Scale: 500 pA/10 s. (B) Summary of baclofen-induced, steady-state current densities (Ibaclofen, pA/pF) in HEK cells expressing GIRK1/GIRK2a or GIRK1/GIRK2c (t 19 = 1.1, P = 0.29; n = 10–11/group). Individual data points are represented as small squares overlapping the relevant bar in the plot. (C,D) Activation (t 19 = 1.5, P = 0.16) and deactivation (t 16 = 0.4, P = 0.72) kinetics for baclofen-induced currents in HEK cells expressing GIRK1/GIRK2a or GIRK1/GIRK2c (n = 9–11/group). (E) Representative concentration-response experiment for a HEK cell expressing GABABR and GIRK1/GIRK2c. Scale: 500 pA/10 s. (F,G) Summary of concentration-response experiments for baclofen-induced currents in HEK cells expressing GIRK1/GIRK2a or GIRK1/GIRK2c (t 17 = 1.0, P = 0.32; n = 9–10/group). Currents were normalized to the response evoked by 100 μM baclofen in each experiment.

Figure 2

GIRK2 expression in the mouse hippocampus. (A) Girk2a and Girk2c mRNA levels as assessed by RNA-Seq in CA1 cell body and neuropil samples, taken from 3 adult mice. Main effects of isoform (F1,8 = 14.3, P < 0.01) and compartment (F1,8 = 27.1, P < 0.001) were observed, but there was no interaction between isoform and compartment (F1,8 = 0.07, P = 0.80). Symbols: *P < 0.05 vs. GIRK2a (within compartment); +,++ P < 0.05 and 0.01, respectively, vs. cell body (within isoform). (B) Representative GIRK2 immunoblots (from 3 independent experiments) of adult hippocampus and neonatal hippocampal culture (10–12 DIV) from wild-type (WT) and Girk2 −/− mice, probed with pan-GIRK2 or GIRK2c antibodies (upper blots), as well as a β-actin antibody (lower blots). (C,D) Representative images showing GIRK2 immunolabeling (as revealed with the pan-GIRK2 antibody) in cultured hippocampal neurons from wild-type (C) and Girk2 −/− (D) mice. Neurons were co-stained with a MAP2 antibody to highlight neuronal morphology and dendritic processes. Scale bar: 50 microns.

Figure 3

Subcellular distribution of GIRK2a and GIRK2c in Girk2 −/− pyramidal neurons. (A,B) Representative images showing GIRK2 (red) and MAP2 (green) immunolabeling, and their overlay, in Girk2 −/− hippocampal pyramidal neurons expressing either GIRK2a (A) or GIRK2c (B). Scale bars: 50 microns. The insets highlight different densities of GIRK2a and GIRK2c puncta along proximal/primary (Ai,Bi) and distal/secondary (Aii,Bii) dendritic segments. Scale bars: 5 microns. (C) Quantification of GIRK2a and GIRK2c labeling in dendrites from infected Girk2 −/− pyramidal neurons. GIRK2 fluorescence intensity was measured in 2–3 primary (t 27 = 1.4, P = 0.17), secondary (t 29 = 2.1, *P < 0.05), and tertiary (t 27 = 5.2, ***P < 0.001) dendritic segments from 5 different neurons expressing each subunit. Fluorescence intensity is expressed as arbitrary units (AU) normalized to segment length. Only GIRK2 labeling that overlapped directly with the dendritic segment (identified by MAP2 labeling) was quantified in this analysis.

Figure 4

Overlap of GIRK2a and GIRK2c with PSD-95 in pyramidal neurons. (A,B) Representative images showing GIRK2 (red) and PSD-95 (green) immunolabeling, and their overlay, in a Girk2 −/− hippocampal pyramidal neuron expressing GIRK2a (A) or GIRK2c (B). Scale bars: 50 microns. The inset (Bi) highlights the limited overlap between PSD-95 and GIRK2, as demonstrated with GIRK2c. Scale bars: 20 microns. (C) Quantification of overlap between PSD-95 and GIRK2a or GIRK2c, under control conditions and following morphine treatment (n = 8 per isoform and treatment condition). Main effects of isoform (F1,28 = 9.2, P < 0.01) and treatment (F1,28 = 22.1, P < 0.001) were observed, but there was no interaction between isoform and treatment (F1,28 = 0.3, P = 0.60). Symbols: *P < 0.05 vs. GIRK2a (within treatment); +,++ P < 0.05 and 0.01, respectively, vs. control (within isoform).

Figure 5

GPCR-GIRK currents in Girk2 −/− pyramidal neurons expressing GIRK2a or GIRK2c. (A) Whole-cell currents (Vhold = −70 mV) evoked by baclofen (100 μM) in a wild-type pyramidal neuron expressing EGFP (WT, black), as well as Girk2 −/− pyramidal neurons expressing EGFP (Girk2 −/−, gray), GIRK2a (red), or GIRK2c (blue). Scale: 1 nA/5 s. (B) Summary of baclofen-induced, steady-state current densities (pA/pF) in wild-type control and Girk2 −/− pyramidal neurons expressing EGFP, GIRK2a, or GIRK2c (F3,53 = 44.8, P < 0.001; n = 11–16/group). Symbols: ***P < 0.001 vs. WT. (C,D) Summary of activation (C; F2,35 = 19.2, P < 0.001) and deactivation (D) F2,33 = 2.76, P = 0.08) kinetics for baclofen-induced currents in infected wild-type and Girk2 −/− pyramidal neurons. Symbols: ***P < 0.001 vs. WT (n = 11–15 per group). (E) EC50 values for baclofen-induced currents in infected wild-type and Girk2 −/− pyramidal neurons expressing GIRK2a or GIRK2c (F2,17 = 8.84, P < 0.01; n = 6–8/group). Symbols: *,**P < 0.05 and 0.01, respectively, vs. WT. (F) Whole-cell currents evoked by adenosine (10 μM) in a wild-type pyramidal neuron expressing EGFP, as well as Girk2 −/− pyramidal neurons expressing EGFP, GIRK2a, or GIRK2c (Vhold = −70 mV). Scale: 500 pA/5 s. (G) Summary of adenosine-induced, steady-state current densities (Iadenosine, pA/pF) in wild-type control and Girk2 −/− pyramidal neurons expressing EGFP, GIRK2a, or GIRK2c (F3,36 = 32.1, P < 0.001; n = 9–13/group). Symbols: ***P < 0.001 vs. WT. (H) Whole-cell currents evoked by 8-OH-DPAT (10 μM) in a wild-type pyramidal neuron expressing EGFP, as well as Girk2 −/− pyramidal neurons expressing EGFP, GIRK2a, or GIRK2c (Vhold = −70 mV). As currents evoked by 8-OH-DPAT persisted following bath washout, the 5HT1AR-selective antagonist WAY100635 (WAY, 2 μM) was used to demonstrate reversibility of the 8-OH-DAT response. Scale: 500 pA/5 s. (I) Summary of 8-OH-DPAT-induced, steady-state current densities (I8-OH-DPAT, pA/pF) in wild-type control and Girk2 −/− pyramidal neurons expressing EGFP, GIRK2a, or GIRK2c (F3,30 = 7.92, P < 0.001; n = 5–11/group). Symbols: *P < 0.05 vs. WT. (J) Summary of current densities (pA/pF) evoked by 10 μM ML297 (IML297) in wild-type control and Girk2 −/− pyramidal neurons expressing EGFP, GIRK2a, or GIRK2c (F2,12 = 2.0, P = 0.16; n = 5–8/group).

Figure 6

Synaptic GIRK currents in Girk2 −/− neurons expressing GIRK2a and GIRK2c. (A) Image showing EGFP expression in the CA1 region of an organotypic hippocampal slice, taken 7 d after infection with AAV8-hSyn-GIRK2a-IRES-EGFP. The dotted white line highlights key features of slice morphology. Scale bar: 500 microns (inset: 50 microns). (B) Summary of peak baclofen-induced somatodendritic current amplitudes (Ibaclofen) in dorsal CA1 pyramidal neurons, measured 7 d after CA1 infusion of control virus (con) to wild-type (WT) organotypic slices, or GIRK2 expression viruses (2a, 2c) to Girk2 −/− organotypic slices (F2,17 = 1.2, P < 0.01; n = 6–7/group). Symbols *,**P < 0.05 and 0.01, respectively, vs. WT. (C) Slow IPSCs evoked via stimulation of proximal (Schaffer collateral/SC) or distal (perforant path, PP) dendritic fields, in wild-type and Girk2 −/− CA1 pyramidal neurons expressing EGFP, as well as Girk2 −/− CA1 pyramidal neurons expressing GIRK2a or GIRK2c. The stimulus artifact and residual GABAAR-dependent responses were removed for clarity, and the triangles below the traces denote stimulation times. Scale: 100 pA/1 s. (D) Summary plot comparing the ratios of slow IPSC maximal amplitudes evoked by SC and PP stimulation in wild-type CA1 pyramidal neurons expressing EGFP, as well as Girk2 −/− CA1 pyramidal neurons expressing GIRK2a or GIRK2c (F2,37 = 51.9; P < 0.001; n = 6–8/group). Maximal responses evoked by stimulation of SC and PP fields were measured in each neuron, in counterbalanced fashion. Symbols: ***P < 0.001 vs. WT (control) and Girk2 −/− (GIRK2c).

Figure 7

Fear learning in CaMKIICre(+):Girk2 fl/fl mice expressing GIRK2a or GIRK2c. (A) EGFP expression in the dorsal CA1 of a CaMKIICre(+):Girk2 fl/fl mouse, 2 wk after infusion of the AAV8-CaMKIIα-DIO-GIRK2a-IRES-EGFP virus. Scale bar: 500 microns. (B) Representative somato-dendritic currents (Vhold = −60 mV) evoked by baclofen (200 μM) and reversed by the GABABR antagonist CGP54626 (2 μM) in dorsal CA1 pyramidal neurons from CaMKIICre(+):Girk2 fl/fl mice, 2 wk after infusion of Cre-dependent control (con, mCherry), GIRK2a, or GIRK2c virus. Scale: 100 pA/100 s. (C) Summary of baclofen-induced currents in dorsal CA1 pyramidal neurons from CaMKIICre(+):Girk2 fl/fl mice, 2 wk after infusion of Cre-dependent control (con, mCherry), GIRK2a, or GIRK2c virus (F2,11 = 24.3, P < 0.001; n = 4–5/group). Symbols: ***P < 0.001 vs. control. (D) Contextual fear learning in untreated CaMKIICre(−):Girk2 fl/fl mice and CaMKIICre(+):Girk2 fl/fl mice, and in CaMKIICre(+):Girk2 fl/fl mice following infusion of Cre-dependent control (con, mCherry), GIRK2a, or GIRK2c virus in the dorsal CA1 (F4,55 = 14.7, P < 0.001; n = 6–23/group). Symbols: *,***P < 0.05 and 0.001, respectively, vs. Cre(−). (E) Cue fear learning in untreated CaMKIICre(−):Girk2 fl/fl mice and CaMKIICre(+):Girk2 fl/fl mice, and in CaMKIICre(+):Girk2 fl/fl mice following infusion of Cre-dependent control (con, mCherry), GIRK2a, or GIRK2c virus in the dorsal CA1 (F4,55 = 4.0, P < 0.01; n = 6–23/group). Symbols: **P < 0.01 vs. Cre(−).

#	Section	Preview
0	Introduction	G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate the G protein-dependent,…
1	Introduction	GIRK channels are homo- and heterotetrameric complexes formed by 4 subunits (GIRK1/Kir3.1,…
2	Introduction	The diversity of neuronal GIRK channels is enhanced by alternative splicing which, in the case of…
3	Introduction	The impact of alternative splicing of the Girk2 (Kcnj6) gene on GIRK channel trafficking and…
4	Results — Comparison of GIRK2a and GIRK2c-containing channels in transfected mammalian cells	We began by comparing the functional properties of GIRK2a and GIRK2c expressed in mammalian (HEK)…
5	Results — GIRK2a and GIRK2c expression in the mouse hippocampus	HEK cells may lack factors that support GIRK2 isoform-specific contributions to channel trafficking…
6	Results — GIRK2a and GIRK2c expression in the mouse hippocampus	suggesting that an active RNA trafficking mechanism exists for both isoforms (Fig. 2A). Higher…
7	Results — GIRK2a and GIRK2c expression in the mouse hippocampus	We next assessed whether GIRK2a and GIRK2c proteins are present in mouse hippocampus and cultured…
8	Results — Subcellular distribution of GIRK2a and GIRK2c in Girk2−/− pyramidal neurons	While GIRK2a and GIRK2c exhibited comparable labeling patterns when expressed in cultured rat…
9	Results — Subcellular distribution of GIRK2a and GIRK2c in Girk2−/− pyramidal neurons	Consistent with a previous report35, the pan-GIRK2 antibody yielded a punctate labeling pattern in…
10	Results — Subcellular distribution of GIRK2a and GIRK2c in Girk2−/− pyramidal neurons	GIRK3 has been shown to mediate interactions between GIRK channels and proteins that can regulate…
11	Results — Overlap between PSD-95 and GIRK2 splice isoforms in Girk2−/− pyramidal neurons	GIRK2-containing channels are enriched near excitatory synapses15, 39, and some overlap between…
12	Results — GIRK currents measured in Girk2−/− pyramidal neurons expressing GIRK2a or GIRK2c	We next asked whether GIRK2a and GIRK2c conferred unique functionality to GIRK channels in cultured…
13	Results — GIRK currents measured in Girk2−/− pyramidal neurons expressing GIRK2a or GIRK2c	GIRK channels in hippocampal pyramidal neurons are also activated by adenosine and serotonin10, 40,…
14	Results — GIRK currents measured in Girk2−/− pyramidal neurons expressing GIRK2a or GIRK2c	We also probed for differences in the interaction between the GIRK2 isoforms and endogenous GIRK1 in…
15	Results — Synaptic GIRK currents in Girk2−/− pyramidal neurons expressing GIRK2a or GIRK2c	The lack of natural connectivity and normal afferent inputs to cultured neurons complicates efforts…
16	Results — Synaptic GIRK currents in Girk2−/− pyramidal neurons expressing GIRK2a or GIRK2c	Slow inhibitory postsynaptic currents (slow IPSCs) in dorsal CA1 pyramidal neurons were evoked by…
17	Results — Fear conditioning in CaMKIICre(+):Girk2fl/fl mice following GIRK2a or GIRK2c reconstitution	Recently, we reported that mice lacking GIRK2 in forebrain pyramidal neurons (CaMKIICre(+):Girk2…
18	Results — Fear conditioning in CaMKIICre(+):Girk2fl/fl mice following GIRK2a or GIRK2c reconstitution	reported previously for untreated CaMKIICre(+):Girk2 fl/fl mice6. Dorsal CA1 pyramidal neurons from…
19	Results — Fear conditioning in CaMKIICre(+):Girk2fl/fl mice following GIRK2a or GIRK2c reconstitution	We utilized a trace fear conditioning protocol to assess the impact of viral treatment on fear…

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In this knowledge base

Title	Year	PMID
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.	2023	36207584

External

Title	Authors	Journal	Year	Link
Live-cell quantitative monitoring reveals distinct, high-affinity Gβγ regulations of GIRK2 and GIRK1/2 channels.	Handklo-Jamal R et al.	—	2025	→
Machine learning identifies lactate metabolism biomarkers and deciphers immune infiltration landscapes in Parkinson's disease.	Lv H et al.	—	2025	→
Amyloid-β oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice.	Luo H et al.	—	2024	→
Domain-selective and sex-dependent regulation of learning and memory in mice by GIRK channel activity in CA1 pyramidal neurons of the dorsal hippocampus.	Luo H et al.	—	2024	→
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.	Popova D et al.	—	2023	→
Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits.	Kleschevnikov AM	—	2022	→
GIRK2 Channels in Down Syndrome and Alzheimer's Disease.	Kleschevnikov A	—	2022	→
Neuronal G protein-gated K<sup>+</sup> channels.	Luo H et al.	—	2022	→
Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APP<sub>Sw,Ind</sub> J9 Alzheimer's Disease Mouse Model.	Temprano-Carazo S et al.	—	2022	→
Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.	Weaver CD et al.	—	2021	→
Spatiotemporal Regulation of Transcript Isoform Expression in the Hippocampus.	Park J et al.	—	2021	→
GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells.	Anderson A et al.	—	2020	→
The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release.	Johnson CM et al.	—	2020	→
Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms	Goswamee P et al.	—	2019	—
Acetylcholine Release Inhibits Distinct Excitatory Inputs Onto Hippocampal CA1 Pyramidal Neurons via Different Cellular and Network Mechanisms.	Goswamee P et al.	—	2019	→
Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep.	Zou B et al.	—	2019	→
VU0810464, a non-urea G protein-gated inwardly rectifying K<sup>+</sup> (K<sub>ir</sub> 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K<sub>ir</sub> 3 channels and reduces stress-induced hyperthermia in mice.	Vo BN et al.	—	2019	→
Nociceptin/Orphanin-FQ Inhibits Gonadotropin-Releasing Hormone Neurons via G-Protein-Gated Inwardly Rectifying Potassium Channels.	Constantin S et al.	—	2018	→