Interaction of Calcineurin and Type-A GABA Receptor γ<sub>2</sub>Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Wang, Jian; Liu, Shuhong; Haditsch, Ursula; Tu, Weihong; Cochrane, Kimberley; Ahmadian, Gholamreza; Tran, Linda; Paw, Jadine; Wang, YuTian; Mansuy, Isabelle M.; Salter, Michael; Lü, You

doi:10.1523/jneurosci.23-03-00826.2003

Cited by 130 publications

(115 citation statements)

References 54 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Our finding that ␣3 is the functionally dominant ␣ subunit in the adult brain is consistent with the reported lack of seizures in ␣1 or ␣2 heterozygous mice (21,24). Reduced ␣3-mediated Na ϩ transport in neurons might furthermore lead to a greater elevation in posttetanic intracellular Na ϩ with a concomitant reduction in Na ϩ /Ca 2ϩ exchanger-mediated calcium extrusion, and dysregulated calcium transients could lead to a rise of the intracellular Ca 2ϩ level with accumulation of glutamate in the synaptic cleft (6) and to over-activation of calcineurin and internalization of GABA receptors (25,26).…”

Section: Resultssupporting

confidence: 83%

Mutation I810N in the α3 isoform of Na ⁺ ,K ⁺ -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Clapcote

Duffy

Xie

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

170

View full text Add to dashboard Cite

In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/؉ mice carry a mutation (I810N) which renders the normally expressed Na ؉ ,K ؉ -ATPase ␣3 isoform inactive. Total Na ؉ ,K ؉ -ATPase activity was reduced by 42% in Myk/؉ brain. The epilepsy in Myk/؉ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na ؉ ,K ؉ -ATPase ␣3 by transgenesis, which also rescued Na ؉ ,K ؉ -ATPase activity. Our findings reveal the functional significance of the Na ؉ ,K ؉ -ATPase ␣3 isoform in the control of epileptiform activity and seizure behavior.alpha3 Na ϩ ,K ϩ ATPase ͉ BAC rescue ͉ epilepsy ͉ forward genetic screen ͉ mouse

show abstract

Section: Resultssupporting

confidence: 83%

Mutation I810N in the α3 isoform of Na ⁺ ,K ⁺ -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Clapcote

Duffy

Xie

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

170

View full text Add to dashboard Cite

show abstract

“…Indeed, a GABA A R activation-mediated but membrane depolarization-independent mechanism that leads to elevation of intracellular calcium has been described recently (Chavas et al, 2004). In addition, depolarization-and NMDA receptor-dependent calcium entry is also implicated in regulated trafficking and function of γ2 subunit-containing GABA A Rs (Marsden et al, 2007;Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABAA receptors

Yao

Norris

et al. 2008

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

Accumulation of GABA A receptors (GABA A Rs) at GABAergic synapses requires the cytoplasmic loop region and C-terminal transmembrane domain of the receptor γ2 subunit. We here report a novel interaction of γ2 with Calcium-Modulating cyclophilin Ligand (CAML), an integral membrane protein that regulates this mechanism. Interaction of GABA A Rs with CAML depends on both the cytoplasmic region and fourth transmembrane domain of the γ2 subunit, CAML immunoprecipitates with GABA A Rs from transfected cells and brain lysates and colocalizes with γ2 in ER vesicles in soma and dendrites of neurons. CAML shRNA treatment results in reduced expression of postsynaptic GABA A Rs, along with significant reductions in GABA-evoked whole-cell currents and GABAergic synaptic function, while glutamatergic transmission is unaffected. Reduced surface expression of GABA A Rs in CAML mutant neurons is associated with selective deficits in recycling of endocytosed GABA A Rs to the cell surface. Our results indicate a specific role of CAML in functional expression and endocytic recycling of postsynaptic GABA A Rs.

show abstract

“…With stronger stimuli, however, CaN appears to be activated in shafts to a level enabling it to dominate over CaMKIIα, in part by preventing translocation of the kinase. The ability of the phosphatase to bind to GABA A Rs (23) and localize at inhibitory synapses with the strong stimulus (Fig. S7) may enhance this competition, perhaps by competing for binding sites.…”

Section: Discussionmentioning

confidence: 99%

“…As mGFP-CaMKIIα transfection more than doubled the amount of immunocytochemically detected kinase (251 ± 36% of control levels), the introduced kinase may overwhelm an endogenous signaling pathway that regulates CaMKIIα translocation. Conditions that elevate CaMKIIα activity at excitatory synapses have been reported to induce CaN binding to GABA A Rs at inhibitory synapses, resulting in their dephosphorylation and depression of inhibition (22,23). Thus, we examined whether CaN also regulates CaMKIIα translocation to inhibitory synapses with glutamate treatment.…”

Section: Camkiiα Selectively Localizes To Inhibitory Synapses Followingmentioning

confidence: 99%

Selective translocation of Ca ²⁺ /calmodulin protein kinase IIα (CaMKIIα) to inhibitory synapses

Marsden

Shemesh

Bayer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

133

151

View full text Add to dashboard Cite

Ca 2+ /Calmodulin protein kinase IIα (CaMKIIα) has a central role in regulating neuronal excitability. It is well established that CaMKIIα translocates to excitatory synapses following strong glutamatergic stimuli that induce NMDA-receptor (NMDAR)-dependent longterm potentiation in CA1 hippocampal neurons. We now show that CaMKIIα translocates to inhibitory but not excitatory synapses in response to more moderate NMDAR-activating stimuli that trigger GABA A -receptor (GABA A R) insertion and enhance inhibitory transmission. Such moderate NMDAR activation causes Thr286 autophosphorylation of CaMKIIα, which our results demonstrate is necessary and sufficient, under basal conditions, to localize CaMKIIα at inhibitory synapses and enhance surface GABA A R expression. Although stronger glutamatergic stimulation coupled to AMPA receptor insertion also elicits Thr286 autophosphorylation, accumulation of CaMKIIα at inhibitory synapses is prevented under these conditions by the phosphatase calcineurin. This preferential targeting of CaMKIIα to glutamatergic or GABAergic synapses provides neurons with a mechanism whereby activity can selectively potentiate excitation or inhibition through a single kinase mediator.C a 2+ /Calmodulin protein kinase IIα (CaMKIIα) is essential for NMDA receptor (NMDAR)-dependent potentiation of many excitatory synapses (1, 2). However, CaMKIIα also directly phosphorylates the inhibitory GABA A receptor (GABA A R) α1, β2, β3, and γ2 subunits (3-5). CaMKIIα activation increases GABA A Rs in synaptosomal preparations (6), and potentiates GABA A R-mediated currents in neurons of the spinal cord dorsal horn (7), cortex (8), cerebellum (9, 10), and hippocampus (7, 11). We recently reported that hippocampal inhibitory synapses are potentiated upon activation of NMDARs through a CaMKIIα-dependent insertion of GABA A Rs into the membrane (12). The similar role of CaMKIIα in NMDAR-dependent excitatory and inhibitory potentiation raises the question of how specificity in the modulation of excitatory or inhibitory synapses is maintained.CaMKIIα translocates to excitatory synapses on dendritic spines following long-term potentiation (LTP) induction (13,14), glutamate receptor activation (15-17), or sensory stimulation in vivo (18). However, it is not known whether CaMKIIα must similarly translocate to inhibitory synapses on dendritic shafts to modulate GABAergic transmission. If so, an understanding of the differential regulation of CaMKIIα targeting to inhibitory and excitatory synapses would provide important insight into the control of neuronal excitability.Here we show that although strong activation of NMDARs induces translocation of CaMKIIα to excitatory synapses and enhances surface AMPAR levels, a weaker activation of NMDARs localizes CaMKIIα to inhibitory synapses. This differential translocation of CaMKIIα is dependent on the activation of calcineurin (CaN), which prevents CaMKIIα targeting to inhibitory synapses in response to strong stimuli. Analysis of CaMKIIα mutants further reveals that whe...

show abstract

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Cited by 130 publications

References 54 publications

Mutation I810N in the α3 isoform of Na ⁺ ,K ⁺ -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Mutation I810N in the α3 isoform of Na ⁺ ,K ⁺ -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABAA receptors

Selective translocation of Ca ²⁺ /calmodulin protein kinase IIα (CaMKIIα) to inhibitory synapses

Contact Info

Product

Resources

About

Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Cited by 130 publications

References 54 publications

Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABAA receptors

Selective translocation of Ca 2+ /calmodulin protein kinase IIα (CaMKIIα) to inhibitory synapses

Contact Info

Product

Resources

About

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Mutation I810N in the α3 isoform of Na ⁺ ,K ⁺ -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Mutation I810N in the α3 isoform of Na ⁺ ,K ⁺ -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Selective translocation of Ca ²⁺ /calmodulin protein kinase IIα (CaMKIIα) to inhibitory synapses