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Review
Instituto de Investigacion en Discapacidades Neurologicas (IDINE), Departamento de Ciencias Medicas, Facultad de Medicina,
Universidad Castilla-La Mancha, Campus Biosanitario, C/Almansa 14, 02008 Albacete, Spain
2
Department of Pharmacology, University of Minnesota, 321 Church Street South East, Minneapolis, MN 55455, USA
Review
a2 Adrenergic
GABAB
Cholinergic
Cannabinoid
Reward
Motor activity
Natural rewards
Self-administration
Dependence/withdrawal
Learning/memory
Spatial learning/memory
Fear conditioning
Anxiety
Schizophrenia
Seizure/epilepsy
Energy homeostasis
Thermoregulation
Neurodevelopment
Girk gene(s)
Mutation
Phenotype
Refs
Girk1, Girk4
Girk1, Girk4
Girk4
GIRK1, GIRK4
GIRK4
Null
Null
Null
Multiple
Multiple
Resting tachycardia
Decreased chronotropic response
Decreased variability
Long QT, atrial fibrillation
Associated with aldosteronism
[86,87]
[86,87]
[86]
[8890]
[91,92]
Girk1, Girk2
Girk2
Girk2
Null
Null
Null
Hyperalgesia
Hyperalgesia
Hyperalgesia
[93,94]
[93]
[93]
Girk1, Girk2
Girk3
GIRK2
Girk2,Girk3
Girk2
Girk2
Girk2, Girk3
Null
Null
Polymorphism
Null
Null
Null
Null
Decreased analgesia
Decreased sensitivity
Increased dosing requirement
Decreased analgesia
Decreased analgesia
Decreased analgesia
Decreased sensitivity
[9397]
[98]
[99,100]
[93,95,98]
[95]
[95]
[95,98]
Girk1, Girk2
Girk2, Girk4
Girk2
Girk2, Girk3
Girk2
Girk2 & Girk3
Girk3
GIRK2
Null
Null
Triploid
Null
Null
Null
Null
Polymorphism
[101103]
[104,105]
[58]
[102]
[106]
[97]
[107]
[108]
Girk4
Girk2
Girk2
GIRK1
Girk2
Girk4
Girk2
Girk2
Null
Triploid
Null
Polymorphism
Null
Null
Null
weaver
Decreased recall
Decreased contextual recall
Anxiolysis
Genetic association
Increased spontaneous and PTZ-induced
Late-onset obesity
Decreased drug-induced hypothermia
Loss of granule and dopamine neurons
[109]
[58]
[104,110]
[111]
[74]
[105]
[112]
[113]
The table lists outcomes from behavioral studies involving mice harboring mutant Girk subunits (null/knockout, triploid, or weaver) or from human linkage studies (GIRK
genes in uppercase) that identified polymorphisms or mutations in GIRK genes.
Girk2/3, Girk2/4) and homomers (Girk2 and Girk4) display K+ selectivity, inward rectification, and G proteindependent gating [1,2]. Although it cannot form a functional homomer, Girk1 is an integral subunit of most
neuronal Girk channels and the cardiac Girk channel IKACh
[5,17]. Girk1 confers robust receptor-dependent activity to
Girk heteromers, attributable in part to unique residues
found in the pore and second transmembrane helix that
enhance single-channel conductance and opening probability [8,1820]. The intracellular C-terminal domain also
contributes to the potentiating influence of Girk1 on
GPCR-dependent heteromeric channel activity, likely
due to the presence of unique Gbg, Ga, and phosphatidylinositol 4,5-bisphosphate (PIP2) interaction domains and
phosphorylation sites [2026].
The functional relevance of Girk channel subunit composition is nicely illustrated in the ventral tegmental area
(VTA). VTA dopamine neurons express Girk2 and Girk3,
whereas VTA GABA neurons express Girk1, Girk2, and
Girk3 [27,28]. VTA dopamine neurons are significantly
less sensitive than VTA GABA neurons to direct GABAB
2
Review
Box 1. Cellular and subcellular diversity of Girk channels
Although Girk channel expression has been reported in neuroendocrine cells and more recently in some cancer cells (e.g., [114117]), the
expression and relevance of Girk channels is far better understood in
the heart and nervous system. Girk1/4 heteromers comprise the
muscarinic-gated atrial K+ channel IKACh, a crucial mediator of the
parasympathetic regulation of heart rate [5,86]. Although the prototypical neuronal Girk channel is thought to be the Girk1/2 heteromer,
multiple Girk channel subtypes are present in the rodent nervous
system. Indeed, Girk3 is expressed throughout the central nervous
system [9] and, although Girk4 expression is not prominent in the
brain, it is found in a few regions including the hypothalamus and
cerebellum [105,118]. Girk1, Girk2, and Girk3 are coexpressed in many
neuron populations, including hippocampal pyramidal neurons
[9,10]. By contrast, dopamine neurons of the VTA and substantia
nigra pars compacta (SNc) display Girk2/3 and Girk2a/c heteromers,
respectively [27,119]. The cerebellum exemplifies the molecular
diversity that can be achieved via differential subunit expression:
seven distinct Girk expression patterns were discerned within the
various neuronal subtypes in this brain region [118].
Girk channels are distributed mainly in the somato-dendritic
compartment of neurons (e.g., [10,96,118,120]). This distribution is
consistent with most studies showing that Girk channels selectively
mediate the postsynaptic inhibitory effects of neurotransmitters and
related drugs, while making little or no contribution to their
presynaptic inhibitory effects [121]. Some ultrastructural and
functional data, however, support the contention that Girk channels
contribute to presynaptic inhibition in some neurons [122124]. Girk
channels of distinct subunit composition can also exist within
specific subcellular compartments of the same neuron. For example, Girk1 and Girk2 show extensive colocalization across the
different dendritic layers of the hippocampus [120]. Their expression
levels vary among dendritic regions innervated by distinct synaptic
inputs in CA1 pyramidal cells, showing a significant increase from
proximal to distal dendrites. By contrast, Girk3 is more uniformly
distributed along the cell surface of pyramidal cells, including the
presynaptic terminal [10]. In addition, Girk2 and Girk3 are evenly
distributed along the postsynaptic density (PSD) of pyramidal cells
and Purkinje cells, whereas Girk1 is absent from excitatory synapses
and only observed at perisynaptic sites [10,96,120,123]. Finally, in
the subpopulation of parvalbumin-expressing interneurons consisting mainly of basket and chandelier cells, Girk1, Girk2, and Girk3
share the same localization at very similar densities [125]. Collectively, these data argue that distinct Girk channel subtypes exist in a
tissue/cell type- and subcellular compartment-dependent manner, a
scenario that enhances the prospects for selective and efficacious
therapeutic manipulation of Girk signaling.
Review
(A)
N-terminus
100
200
300
400
500
(B)
Girk1
Turret
C-terminus
Out
P 2 M2
Girk2A
Ser-9
M1 1
P 2 M2
Na+
In
VL
gg
TM
PIP2
ELETEEEE
Girk2C
M1 1
P 2 M2
Girk3
M1 1
P 2 M2
Girk4
M1 1
P 2 M2
ESKV
EAEKAEAEDHEEEE
G
N-term
CTD
G
N-term
TRENDS in Neurosciences
Figure 1. Structure of G protein-gated inwardly rectifying potassium (K+) Girk channels. (A) Linear depiction of Girk channel subunits, including two prevalent Girk2 splice
variants expressed in the mouse nervous system. The four Girk subunits exhibit a high degree of homology in the membrane-spanning (M1, M2), extracellular (1, 2), and
pore (P) domains, with most inter-subunit differences observed in the distal N- and C-terminal domains. The Girk2 splice variants and Girk4 contain endoplasmic reticulum
(ER) export signals (ELETEEEE and EAEKAEAEDHEEEE, respectively) not found in the other subunits [7]. Girk2 also exhibits an N-terminal internalization motif (VL), whose
influence on channel trafficking is precluded by phosphorylation of Girk2(Ser9) [71]. Girk2C and Girk3 possess identical C-terminal PDZ interaction motifs (ESKV). (B)
Structure of the GirkGbg complex from a side-view, with colors highlighting Girk2 (blue), Gb (red), Gg [green, with associated geranyl-geranyl (gg) lipid modification], PIP2
(yellow/orange sticks), Na+ ions (purple spheres), K+ ions (green spheres within the pore). Note that there are four Gbg binding sites per channel, and the Gbg facing the
viewer has been removed for clarity [16]. Other abbreviations: CTD, C-terminal domain; N-term, N-terminal domain; PIP2, phosphatidylinositol 4,5-bisphosphate; TM,
transmembrane domains.
Review
RE
RE
LE-Ly
LE-Ly
EE
Key:
Girk2
Girk2
Girk2
Girk1
EE
Girk2
Girk3
Girk1
Girk3
SNX27
TRENDS in Neurosciences
Figure 2. Subunit-dependent regulation of Girk channel trafficking by sorting nexin 27 (SNX27). Neuronal Girk channels are thought to internalize into early endosomes
(EE), at which point they can be recycled back to the cell surface via recycling endosomes (RE) or diverted to late endosomes/lysosomes (LE-Ly) for degradation. Via a
selective physical and functional association with Girk3, SNX27 enhances the trafficking of Girk3-containing channels to early endosomes, leading ultimately to increased
lysosomal degradation and consequently, reduced numbers of Girk channels on the cell surface (right side of schematic). By contrast, SNX27 does not influence the
trafficking of Girk2 homomers or Girk1/2 heteromers (left side of schematic).
Review
(A)
(B)
Cocaine
(C)
Baclofen
Excitatory
imput
Saline
DA dendrite
DA dendrite
Excitatory
imput
Cocaine
Excitatory
imput
Control
(E)
(D)
Cocaine
(F)
Axon
terminal
Saline
Spine
Spine
Dendrite
Dendrite
Cocaine
Key:
Girk
GABABR
NMDA
AMPA
Intracellular
compartment
TRENDS in Neurosciences
Figure 3. Plasticity of neuronal Girk signaling. Cocaine-induced suppression of Girk signaling in the ventral tegmental area (VTA) (AC) and medial prefrontal cortex (mPFC)
(DF). (A) A single cocaine injection reduced baclofen-induced (GABAB receptor-dependent) Girk currents in VTA dopamine neurons, an adaptation that persisted for up to 5
days, required activation of D2 dopamine receptors, and correlated with a redistribution of Girk2-containing channels (but not of GABAB receptors) from the cell surface to
intracellular sites (B,C) [53]. (D) Repeated cocaine administration suppressed baclofen-induced Girk currents in layer 5/6 pyramidal neurons, an adaptation that persisted for
more than 1 month, required activation of D1 dopamine receptors, and correlated with a phosphorylation-dependent redistribution of Girk2-containing channels and GABAB
receptors from the cell surface to intracellular sites (D,F) [55]. The blue line in the current traces shows that the baclofen-induced current was reversed by a GABAB receptor
antagonist.
Review
dopamine receptor-dependent. Moreover, GABABGirk
signaling (but not somatodendritic inhibitory signaling
via D2 dopamine or a2 adrenergic receptors, or somatodendritic GABAB-dependent signaling that did not involve
Girk channels) was suppressed by repeated cocaine in
layer 5/6 mPFC pyramidal neurons, whereas Girk signaling via both the GABAB and D2 dopamine receptor was
suppressed by acute cocaine in VTA dopamine neurons.
These observations are reminiscent of the selective enhancement by neuronal activity of Girk signaling via the
A1 adenosine (but not GABAB) receptor [69], and suggest
that some forms of Girk signaling plasticity are compartmentalized within neurons, and are presumably driven by
the GPCR or other proteins within the signaling macrocomplex.
The trafficking of Girk channels and GPCRGirk complexes to and from the cell surface that underlies the forms
of plasticity described above appears to be regulated by
phosphorylation. For example, the potentiation of synaptic
GABABGirk signaling triggered in parallel with LTP of
glutamatergic neurotransmission was dependent on Ca2+/
calmodulin-dependent protein kinase (CaMKII) activity
[70]. In addition, in cultured hippocampal neurons, CaMKII activation (via prolonged morphine treatment, activation of metabotropic glutamate receptors, or a
constitutively active CaMKII mutant) shifted the distribution of Girk2 from dendritic shafts to spines, leading to
enhanced Girk signaling via 5-HT receptors and decreased
GABABGirk signaling [73]. Although the direct molecular
target of CaMKII was not determined in these studies,
Girk2(Ser9) is a reasonable candidate. Phosphorylation of
Girk2(Ser9), which sits upstream of a unique internalization motif (VL) [7], suppresses surface trafficking of Girk2containing channels [71]. Conversely, dephosphorylation
of Girk2(Ser9) via protein phosphatase 1 (PP1) promotes
surface trafficking of Girk2-containing channels from recycling endosomes, explaining the activity-dependent potentiation of Girk signaling linked to the depotentiation of
LTP [69,71]. Although dephosphorylation of Girk2(Ser9)
promotes enhanced surface distribution of Girk channels,
psychostimulant-induced suppression of GABABGirk signaling in VTA GABA and layer 5/6 mPFC neurons is more
likely related to the phosphorylation status of the GABAB
receptor [54,55]. Surprisingly, despite the durable nature
of the drug-induced suppression of GABABGirk signaling
in these pyramidal neurons, acute intracellular treatment
with okadaic acid, an inhibitor of protein phosphatases
PP1/PP2a, restored normal Girk signaling.
Pharmacologic manipulation of Girk channels
Given the broad distributions and roles of Girk channels in
the nervous system, and their contributions to cardiac and
endocrine physiology, global and direct pharmacologic
manipulation of Girk signaling should evoke an array of
consequences, many undesirable (Table 1). Indeed, global
constitutive ablation of Girk2 triggers an array of phenotypes, most notably a shortened lifespan due to spontaneous lethal seizures [74]. Although constitutive ablation of
other Girk subunits correlates with less-severe phenotypes, the full therapeutic potential associated with inhibiting or enhancing Girk signaling will likely not be
Review
Girk1-containing heteromers, and was efficacious in mice
in delaying seizure onset in a maximal electroshock model
of epilepsy, and was able to prevent convulsions and
lethality in a chemically induced epilepsy model [84].
Accordingly, this family of compounds and derivatives
should afford an excellent opportunity to investigate the
potential therapeutic benefits associated with direct activation or inhibition of Girk1-containing channels, and may
serve as a platform for the identification of compounds that
can discriminate between a wide range of channel subtypes.
Concluding remarks
Although several outstanding questions remain (Box 2),
efforts by many research groups over the last two decades
have revealed key functional, structural, and regulatory
features of Girk channels. This body of evidence, combined
with our evolving understanding of Girk channel contributions to physiology and disease, and a continually improving capacity for pharmacologic manipulation, set the stage
for an exciting future of investigations into the therapeutic
potential of this interesting and important channel class.
Such efforts hold the promise of yielding novel therapeutic
approaches to the treatment of many forms of neurological,
cardiovascular, and neuroendocrine disorders.
Acknowledgments
This work was supported by National Institutes of Health (NIH) grants to
K.W. (MH061933, HL105550, and DA034696) and by the Spanish
Ministry of Science and Innovation BFU2012-38348 and CONSOLIDER-Ingenio CSD2008-0000 (to R.L.). The authors thank members of the
Wickman and Lujan laboratories for their suggestions for the manuscript.
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