Channel-anchored Protein Kinase CK2 and Protein Phosphatase 1 Reciprocally Regulate KCNQ2-containing M-channels via Phosphorylation of Calmodulin

Kang, Seungwoo; Xu, Mingxuan; Cooper, Edward C.; Hoshi, Naoto

doi:10.1074/jbc.m113.528497

Cited by 38 publications

(57 citation statements)

References 34 publications

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“…This molecular complex provides a tonic regulation of the phosphorylation of calmoduline (CaM) in the vicinity of KCNQ2 subunits. CK2-mediated phosphorylation of CaM regulates the M-current by facilitating CaM binding to KCNQ2 [19]. Thus, it appears that the existence of CK2 in target protein complexes, like ion channels, could be a fundamental mechanism to regulate CK2 specific activity at the AIS.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is likely that early Nav1-anchored CK2 regulates the probability of interaction with ankG via the phosphorylation of ABM to enhance Nav1 axonal transport and/or controls its specific transport to the AIS to promote its activity in this subcellular compartment. Similarly, KCNQ2 (Kv7.2) channels, which are clustered at the AIS, anchor CK2 and phosphatase PP1 [19]. This molecular complex provides a tonic regulation of the phosphorylation of calmoduline (CaM) in the vicinity of KCNQ2 subunits.…”

Section: Discussionmentioning

confidence: 99%

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CK2 accumulation at the axon initial segment depends on sodium channel Nav1

et al. 2014

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Edited by Maurice Montal Keywords:Protein kinase CK2 Nav1 Phosphorylation Phosphospecific antibody Dominant negative Axon initial segment a b s t r a c t Accumulation of voltage-gated sodium channel Nav1 at the axon initial segment (AIS), results from a direct interaction with ankyrin G. This interaction is regulated in vitro by the protein kinase CK2, which is also highly enriched at the AIS. Here, using phosphospecific antibodies and inhibition/ depletion approaches, we showed that Nav1 channels are phosphorylated in vivo in their ankyrinbinding motif. Moreover, we observed that CK2 accumulation at the AIS depends on expression of Nav1 channels, with which CK2 forms tight complexes. Thus, the CK2-Nav1 interaction is likely to initiate an important regulatory mechanism to finely control Nav1 phosphorylation and, consequently, neuronal excitability.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CK2 accumulation at the axon initial segment depends on sodium channel Nav1

et al. 2014

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“…CaM affects not only PIP 2 sensitivity [7,8], but also influences voltage sensitivity [7,9,10], regulation of the stability of the distal tetramerization domain [11], functional connection between this distal coiled-coil tetramerization domain and PIP 2 modulation [12] and plays a role in the suppression of Kv7.2/Kv7.3 currents mediated by bradykinin [13,14]. Furthermore, CaM plays a crucial role in Kv7.2 channel trafficking [15], therefore regulating polarized axonal surface expression [16,17] and the intracellular transport of Kv7.2 proteins to the plasma membrane [18].…”

Section: Introductionmentioning

confidence: 99%

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants

et al. 2018

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Heteromers of Kv7.2/Kv7.3 subunits constitute the main substrate of the neuronal M-current that limits neuronal hyper-excitability and firing frequency. Calmodulin (CaM) binding is essential for surface expression of Kv7 channels, and disruption of this interaction leads to diseases ranging from mild epilepsy to early onset encephalopathy. In this study, we addressed the impact of a charge neutralizing mutation located at the periphery of helix B (K526N). We found that, CaM binding and surface expression was impaired, although current amplitude was not altered. Currents were reduced at a faster rate after activation of a voltage-dependent phosphatase, suggesting that phosphatidylinositol-4,5-bisphosphate (PIP2) binding was weaker. In contrast, a charge neutralizing mutation located at the periphery of helix A (R333Q) did not affect CaM binding, but impaired trafficking and led to a reduction in current amplitude. Taken together, these results suggest that disruption of CaM-dependent or CaM-independent trafficking of Kv7.2/Kv7.3 channels can lead to pathology regardless of the consequences on the macroscopic ionic flow through the channel.

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“…The involvement of VGSCs to the mAHP might explain the discrepancy between the large M-current reduction (measured in the presence of TTX, a VGSC blocker) and the persistence of the mAHP in Kcnq2-and Kcnq3-null neurons. Additionally, as KCNQ2 channels bind to CK2, 8 a kinase required for the proper localization of VGSC to the AIS, KCNQ2 loss might also change the local concentration of CK2, leading to mislocalization of VGSCs in the AIS and a change in action potential properties. Future work combining Kcnq2, Kcnq3 and sodium channel knockout mice might clarify these questions.…”

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confidence: 99%