Could tuning of the inhibitory tone involve graded changes in neuronal chloride transport?

Titz, Stefan; Sammler, Esther; Hormuzdi, Sheriar G.

doi:10.1016/j.neuropharm.2015.03.026

Cited by 29 publications

(43 citation statements)

References 54 publications

(74 reference statements)

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“…Dephosphorylation of KCC2 at these sites stimulates KCC2 activity (14, 15) to significantly higher levels, capable of eliciting hyperpolarizing GABA A responses even in neurons with an extremely negative resting membrane potentials (16). We examined the phosphorylation status (P) of NKCC1 Thr202/Thr207/Thr212 and KCC2 Thr906/Thr1007 in spinal cords from naïve and SNI-treated Wnk1 Δ Hsn2 /Δ Hsn2 and Wnk1 +/+ mice (Fig 2a and 2b).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition

et al. 2016

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WNK1/HSN2 kinase, mutated in a Mendelian form of congenital pain insensitivity, contributes to a maladaptive decrease in KCC2 cotransporter activity and a loss of GABA inhibition in the spared nerve injury (SNI) model of neuropathic pain by increasing KCC2 inhibitory phosphorylation at Thr906/Thr1007. Antagonizing WNK1/HSN2 signaling reduces SNI-induced cold allodynia and mechanical hyperalgesia, decreases up-regulated KCC2 Thr906/Thr1007 phosphorylation, and normalizes pathological GABA depolarizations of injured spinal cord lamina II neurons. These data collectively provide novel mechanistic insight into, and a compelling therapeutic target for, neuropathic pain after nerve injury.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition

et al. 2016

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“…As one possible implication of depolarization of E GABA , experiments in rodent epilepsy models have revealed that seizure-like events are preceded by surges in interneuron activity that depolarize E GABA , sparking a positive feedback loop that can result in runaway activity ( Lillis et al, 2012 ; Kaila et al, 2014 ). Interestingly, E GABA has been found to exhibit a strong sensitivity to changes in factors that can affect Cl − levels ( Kaila et al, 2014 ) some of which, such as KCC2-mediated Cl − extrusion ( Sivakumaran et al, 2015 ; Moore et al, 2017 ; Schulte et al, 2018 ; Titz et al, 2015 ), may be tunable by cellular signaling pathways ( Titz et al, 2015 ). According to our model, compromised KCC2 function would likely depolarize E GABA , slowing or even preventing decision-making.…”

Section: Discussionmentioning

confidence: 99%

A computational model explains and predicts substantia nigra pars reticulata responses to pallidal and striatal inputs

Phillips

Rosner

Gittis

et al. 2020

Preprint

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A computational model explains and 1 predicts substantia nigra pars 2 reticulata responses to pallidal and 3 striatal inputs 4 Abstract As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) 10 is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum 11 (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection 12 rely on these pathways' inhibitory actions. Yet, experimental results on SNr responses to these 13 inputs are limited and include excitatory e ects. Our study combines experimental and 14 computational work to characterize, explain, and make predictions about these pathways. We 15 observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including 16 biphasic and excitatory e ects, which our modeling shows can be explained by intracellular 17 chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating 18 mode, including its responses in decision-making scenarios, and GPe output may modulate 19 synchrony and low-frequency oscillations of SNr neurons, which we con rm using optogenetic 20 stimulation of GPe terminals within the SNr. 21 22 29 also receives converging GABA A -receptor mediated synaptic inputs associated with the two major 30 transmission channels through the BG, the direct and indirect pathways. Thus, the behavioral 31 in uence of the BG is ultimately regulated by how the SNr integrates these inputs. 32 Although dominant theories of action selection strongly rely on the inhibitory actions of these 33 pathways on SNr, the details of this integration process have not been thoroughly investigated 34 and remain poorly understood. Interestingly, the inputs to SNr from the two pathways feature 35 distinct characteristics. Indirect pathway GABAergic projections to SNr arise from the external 36 segment of the globus pallidus (GPe), which engages in tonic spiking activity; occur via basket-like 37 synapses around the soma of SNr neurons; and exhibit short-term depression. Direct pathway 38 inputs are delivered by striatal (Str) neurons, which spike much more sparsely; are located on distal 39 1 of 35 Manuscript submitted to eLife dendrites; and exhibit short-term facilitation (Smith and Bolam, 1991; Von Krosigk et al., 1992; 40 Connelly et al., 2010; Lavian and Korngreen, 2016). The complexity of how these aspects interact 41 may have hindered the study of the convergence of these inputs to the SNr, yet there may be an 42 additional, easily overlooked factor in uencing the process as well: GABA dynamics (Raimondo 43 et al., 2012; Doyon et al., 2011 Doyon et al., , 2016b. The ongoing activity of GPe neurons would likely induce a 44 large tonic chloride load on SNr neurons, potentially depolarizing the GABA reversal potential, E GABA . 45 Although striatal inputs are less frequent, their impacts would be a ected by chloride accumulation, 46 which could be exaggerated in smaller dendritic co...

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“…The most prominent of which contained Sptan1 (65 peptides), Sptbn1 (36 peptides), Sptbn2 (15 peptides), Ank2 (8 peptides), Itpr1 (7 peptides), Acta2 (8 peptides), and Myh10 (10 peptides). There was a subnetwork containing Grm2/3/5 (9,11, and 15 peptides respectively), and Gabbr2 (8 Peptides). There was also a subnetwork containing C1qa/b/c (23,27, and 19 peptides respectively).…”

Section: Analyzing the Composition Of Stable Protein Complexes Of Kcc2mentioning

confidence: 99%

“…These changes in neuronal Clextrusion reflect a sustained increase in the expression levels of Kcc2 after birth, the mRNA levels of which do not reach their maximal levels in humans until 20-25 years of age (7). In addition to this, the appropriate developmental appearance of hyperpolarizing GABAAR currents is also in part determined by the phosphorylation status of Kcc2, a process that facilitates its membrane trafficking and activity (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of multi-protein complexes enriched in the K-Cl co-transporter 2 from brain plasma membranes

Smalley

Kontou

Choi

et al. 2020

Preprint

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Kcc2 plays a critical role in determining the efficacy of synaptic inhibition, however, the cellular mechanism neurons use to regulate its membrane trafficking, stability and activity are ill-defined. To address these issues, we used affinity purification to isolate stable multi-protein complexes of Kcc2 from the plasma membrane of murine forebrain. We resolved these using Blue-native polyacrylamide gel electrophoresis (BN-PAGE) coupled to LC-MS/MS. Purified Kcc2 migrated as distinct molecular species of 300, 600 and 800 kDa following BN-PAGE. In excess of 90% coverage of the soluble N and C-termini of Kcc2 was obtained. The 300kDa species largely contained Kcc2, which is consistent with a dimeric quaternary structure for this transporter. Intriguingly, lower levels of Kcc1 were also found in this species suggesting the existence of “mixed” Kcc2/Kcc1 heterodimers. The 600 and 800 kDa species represented stable multi-protein complexes of Kcc2. We identified a set of novel structural, ion transporting and signaling protein interactors, that are present at both excitatory and inhibitory synapses, consistent with the proposed association of Kcc2. These included spectrins, ankyrins, and the IP3 receptor. We also identified interactors more directly associated with phosphorylation; Akap5 and Lmtk3. Finally, we used LC-MS/MS on highly purified endogenous plasma membrane Kcc2 to detect phosphorylation sites. We detected 11 sites with high confidence, including known and novel sites. Collectively our experiments demonstrate that Kcc2 is associated with components of the neuronal cytoskeleton and signaling molecules that may act to regulate transporter membrane trafficking, stability, and activity.

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Could tuning of the inhibitory tone involve graded changes in neuronal chloride transport?

Cited by 29 publications

References 54 publications

Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition

Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition

A computational model explains and predicts substantia nigra pars reticulata responses to pallidal and striatal inputs

Isolation and characterization of multi-protein complexes enriched in the K-Cl co-transporter 2 from brain plasma membranes

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