Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

Bähring, Robert

doi:10.1080/19336950.2018.1491243

Cited by 23 publications

(25 citation statements)

References 96 publications

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“…Phosphorylation of Kv4, including that elicited by PKA, PKC and MAP/ERK activated by G-protein signaling cascades and/or changes in intracellular calcium functionally regulates expression of and the biophysical properties of these channels 80,81 . Additionally, the existence of marked expression of mRNA encoding for members of the KChIP auxiliary subunits, acting as intracellular calcium sensors, in NGFCs provides an additional mechanism for Kv4 channel modulation 63,82 . Together, these possible cellular routes link neuronal activity to the modulation of subthreshold IKA conductances that ultimately dictate NGFC excitability.…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

Chittajallu

Auville

Mahadevan

et al. 2020

Preprint

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Spatiotemporal interactions between glutamatergic excitatory and GABAergic inhibitory neuronsunderly input-output transformations critical for complex brain functions. However, the extent of malleability in this interplay particularly that occuring via modifications in GABAergic interneuron recruitment and output is relatively unexplored in humans. We demonstrate that a specialized interneuron subtype collectively termed neurogliaform cells embedded in both mouse and human neural circuits are susceptible to remarkably similar activity-dependent modulation in their intrinsic properties including the previously characterized distal axonal phenomenon known as barrage firing. Interestingly, we reveal a parallel yet hitherto undescribed plasticity, occurring in the absence of barrage firing manifesting as an enhanced efficacy of excitatory depolarizing inputs to somatodendritic domains in eliciting action potential output. In principle, these evolutionary conserved plasticity routes tune the extent of inhibition mediated by neurogliaform cells constituting circuit mechanisms relevant for human cognitive processing and behavior.only in rodents but also in non-human primates and humans revealing both similar and divergent properties across these species 17,24,30, 36, 37 . However, only a few reports have described short and longterm plasticity impacting recruitment and activity of mouse NGFCs 38, 39 with a conspicuous lack of published evidence demonstrating any such mechanisms in their human counterparts 15 .In the current study we demonstrate that adult mouse and human NGFCs can undergo analogous forms of activity-dependent modulation of their intrinsic properties. In particular, we reveal a previously undescribed plasticity manifesting as a short-term enhancement in the ability of depolarizing inputs to evoke action potential output which, in mouse, is in part due to functional regulation of subthreshold, transient K + -conductance(s) (including those mediated by Kv4-containing channels).Although the underlying induction and expression mechanisms remain to be fully determined, this evolutionary retention demonstrates that the ability to modulate NGFC excitability represents canonical mechanisms stressing their importance. From a research perspective, this conservation also highlights the relevance of the mouse model as a predictive tool in basic science research aimed at further unravelling the behavioral correlates dependent on the tuning of NGFC mediated inhibition 40 under physiological and pathological contexts in humans. RESULTS Activity-dependent enhancement in intrinsic excitability of NGFCs manifested by barrage firing is evolutionary conserved.EGFP+ interneurons (INs) with soma located in the superficial portion of stratum lacunosummoleculare (SLM) of mid-ventral hippocampi and Layer I (LI) of cortex (lateral to mid-ventral hippocampi) interneurons in P35-P60 GAD65-EGFP or Htr3A-EGFP mice were targeted 41, 42, 43 . Using the approach outlined above our data was restricted to NGFCs derived from progenitors ...

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Section: Discussionmentioning

confidence: 99%

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

Chittajallu

Auville

Mahadevan

et al. 2020

Preprint

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“…However, how these interactions are regulated remains largely unknown. KChIP EF-hands can bind Mg 2+ and Ca 2+ , and there is evidence suggesting Ca 2+ binding to KChIP can influence its interaction with Kv4α (Morohashi et al, 2002; Chen et al, 2006; Pioletti et al, 2006; Lee et al, 2009; Gonzalez et al, 2014; Bähring, 2018). N-glycosylation of DPP10 controls its interaction with Kv4α, and its ability to modulate channel surface expression and biophysical properties (Cotella et al, 2010, 2012).…”

Section: Introductionmentioning

confidence: 99%

SUMOylating Two Distinct Sites on the A-type Potassium Channel, Kv4.2, Increases Surface Expression and Decreases Current Amplitude

Welch

Forster

Atlas

et al. 2019

Front. Mol. Neurosci.

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Post-translational conjugation of S mall U biquitin-like Mo difier (SUMO) peptides to lysine (K) residues on target proteins alters their interactions. SUMOylation of a target protein can either promote its interaction with other proteins that possess SUMO binding domains, or it can prevent target protein interactions that normally occur in the absence of SUMOylation. One subclass of voltage-gated potassium channels that mediates an A-type current, I A , exists as a ternary complex comprising Kv4 pore-forming subunits, Kv channel interacting proteins (KChIP) and transmembrane dipeptidyl peptidase like proteins (DPPL). SUMOylation could potentially regulate intra- and/or intermolecular interactions within the complex. This study began to test this hypothesis and showed that Kv4.2 channels were SUMOylated in the rat brain and in human embryonic kidney (HEK) cells expressing a GFP-tagged mouse Kv4.2 channel (Kv4.2g). Prediction software identified two putative SUMOylation sites in the Kv4.2 C-terminus at K437 and K579. These sites were conserved across mouse, rat, and human Kv4.2 channels and across mouse Kv4 isoforms. Increasing Kv4.2g SUMOylation at each site by ~30% produced a significant ~22%–50% decrease in I A G max , and a ~70%–95% increase in channel surface expression. Site-directed mutagenesis of Kv4.2g showed that K437 SUMOylation regulated channel surface expression, while K579 SUMOylation controlled I A G max . The K579R mutation mimicked and occluded the SUMOylation-mediated decrease in I A G max , suggesting that SUMOylation at K579 blocked an intra- or inter-protein interaction involving K579. The K437R mutation did not obviously alter channel surface expression or biophysical properties, but it did block the SUMOylation-mediated increase in channel surface expression. Interestingly, enhancing K437 SUMOylation in the K579R mutant roughly doubled channel surface expression, but produced no change in I A G max , suggesting that the newly inserted channels were electrically silent. This is the first report that Kv4.2 channels are SUMOylated and that SUMOylation can independently regulate Kv4.2 surface expression and I A G max in opposing directions. The next step will be to determine if/how SUMOylation affects Kv4 interactions within the ternary complex.

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“…The Downstream Regulatory Element Antagonist Modulator (DREAM; Carrion et al, 1999), also known as KChIP3 (An et al, 2000) or calsenilin (Buxbaum et al, 1998), is a member of the K V channel interacting proteins (KChIPs) belonging to the neuronal calcium sensor (NCS) family (Burgoyne, 2007). DREAM is a 29 kDa protein with four EF-hand motif (EF1–4), conserved among other NCS members, in which the EF2 mediates low affinity Ca 2+ binding and is occupied by Mg 2+ under physiological conditions, whereas EF3 and EF4 mediate high affinity Ca 2+ binding (Bahring, 2018). The physiological roles of DREAM have been gradually revealed.…”

Section: Introductionmentioning

confidence: 99%

Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

Peraza

Cercós

Miaja

et al. 2019

Front. Mol. Neurosci.

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Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin is a neuronal calcium sensor (NCS) with multiple functions, including the regulation of A-type outward potassium currents (IA). This effect is mediated by the interaction between DREAM and KV4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (IA) is responsible of the fast repolarization of neuron action potentials and frequency of firing. Using surface plasmon resonance (SPR) assays and electrophysiological recordings of KV4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the KV4.3/DREAM current in a concentration-, voltage-, and time-dependent-manner. By decreasing the peak current and slowing the inactivation kinetics, IQM-266 led to an increase in the transmembrane charge (QKV4.3/DREAM) at a certain range of concentrations. The slowing of the recovery process and the increase of the inactivation from the closed-state inactivation degree are consistent with a preferential binding of IQM-266 to a pre-activated closed state of KV4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of IA. Overall, the results presented here identify IQM-266 as a new chemical tool that might allow a better understanding of DREAM physiological role as well as modulation of neuronal IA in pathological processes.

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Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

Cited by 23 publications

References 96 publications

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

SUMOylating Two Distinct Sites on the A-type Potassium Channel, Kv4.2, Increases Surface Expression and Decreases Current Amplitude

Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

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