Requirement of subunit co-assembly and ankyrin-G for M-channel localization at the axon initial segment

Rasmussen, Hanne B.; Frøkjær-Jensen, Christian; Jensen, Camilla Stampe; Jensen, Henrik Sindal; Jørgensen, Nanna K.; Misonou, Hiroaki; Trimmer, James S.; Olesen, Søren‐Peter; Schmitt, Nicole

doi:10.1242/jcs.03396

Cited by 104 publications

(128 citation statements)

References 37 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…We next asked what the specific contribution of AIS Kv7 channels was to the suppression of spontaneous firing. For this, we designed a peptide (referred to ankyrin G-binding peptide, or ABP) that had an identical amino acid sequence (YIAEGES-DTD) to the Kv7.2/Kv7.3 ankyrin G-binding motif, which plays a significant role in axonal targeting (5,(7)(8)(9). A BLAST (National Institutes of Health Database) search using Swiss-Prot also revealed that this binding motif is unique to Kv7.2/Kv7.3 subunits.…”

Section: Ankyrin-binding Inhibition Results In Spontaneous Action Potmentioning

confidence: 99%

“…Recent immunohistochemical evidence has shown that the principal subunits forming native M channels, Kv7.2 and Kv7.3 (3,4), are concentrated at the axon initial segment (AIS) and nodes of Ranvier of central and peripheral principal neurons (5)(6)(7)(8)(9), where they colocalize with Na ϩ channels. Like Na ϩ channels, they contain an ankyrin G-binding motif that targets them to the AIS (5,8). They are also expressed at lower densities at the soma and possibly dendrites and synaptic terminals (4,6,7,10,11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons

Shah

Migliore

Valencia

et al. 2008

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

254

293

View full text Add to dashboard Cite

Members of the Kv7 family (Kv7.2-Kv7.5) generate a subthreshold K ؉ current, the M؊ current. This regulates the excitability of many peripheral and central neurons. Recent evidence shows that Kv7.2 and Kv7.3 subunits are targeted to the axon initial segment of hippocampal neurons by association with ankyrin G. Further, spontaneous mutations in these subunits that impair axonal targeting cause human neonatal epilepsy. However, the precise functional significance of their axonal location is unknown. Using electrophysiological techniques together with a peptide that selectively disrupts axonal Kv7 targeting (ankyrin G-binding peptide, or ABP) and other pharmacological tools, we show that axonal Kv7 channels are critically and uniquely required for determining the inherent spontaneous firing of hippocampal CA1 pyramids, independently of alterations in synaptic activity. This action was primarily because of modulation of action potential threshold and resting membrane potential (RMP), amplified by control of intrinsic axosomatic membrane properties. Computer simulations verified these data when the axonal Kv7 density was three to five times that at the soma. The increased firing caused by axosomatic Kv7 channel block backpropagated into distal dendrites affecting their activity, despite these structures having fewer functional Kv7 channels. These results indicate that axonal Kv7 channels, by controlling axonal RMP and action potential threshold, are fundamental for regulating the inherent firing properties of CA1 hippocampal neurons.axon initial segment ͉ CA1 pyramidal neurons ͉ M-current ͉ KCNQ channels N euronal Kv7 (KCNQ) channels form a noninactivating K ϩ current (also known as the MϪ current); this turns on at subthreshold potentials and regulates the excitability of a variety of peripheral and central neurons (1-3). Recent immunohistochemical evidence has shown that the principal subunits forming native M channels, Kv7.2 and Kv7.3 (3,4), are concentrated at the axon initial segment (AIS) and nodes of Ranvier of central and peripheral principal neurons (5-9), where they colocalize with Na ϩ channels. Like Na ϩ channels, they contain an ankyrin G-binding motif that targets them to the AIS (5, 8). They are also expressed at lower densities at the soma and possibly dendrites and synaptic terminals (4,6,7,10,11).Spontaneous mutations in Kv7 subunits cause epilepsy in humans (2) and mice (12). The hippocampus is strongly implicated in epilepsy (13) and accordingly, previous somatic recordings from these neurons have indicated that the Kv7 current is involved in determining several aspects of neuronal excitability, including the resting membrane potential (RMP), spike frequency adaptation, and burst suppression (e.g., refs. 14-16). However, the specific contribution made by Kv7 channels in the AIS to these or other manifestations of excitability has not been determined. This is important, because some human epileptogenic mutations impair axonal Kv7 subunit expression (7).We have used selective pharmacological and mol...

show abstract

Section: Ankyrin-binding Inhibition Results In Spontaneous Action Potmentioning

confidence: 99%

mentioning

confidence: 99%

Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons

Shah

Migliore

Valencia

et al. 2008

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

254

293

View full text Add to dashboard Cite

show abstract

“…These constructs have a point mutation in their selectivity filter, rendering them nonconductive, and were previously shown to inhibit the ImAHP in neurons (6, 13). We co-transfected KCNQ2GS and KCNQ3GS because previous work demonstrated that both are required for robust surface expression in pyramidal neurons (14). As shown in Fig.…”

Section: Contribution Of Kcnq2 To Imahp In Hippocampusmentioning

confidence: 99%

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents

Tzingounis

Nicoll

2008

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

122

143

View full text Add to dashboard Cite

Benign familial neonatal convulsion (BNFC) is a neurological disorder caused by mutations in the potassium channel genes KCNQ2 and KCNQ3, which are thought to contribute to the medium afterhyperpolarization (mAHP). Despite their importance in normal brain function, it is unknown whether they invariably function as heteromeric complexes. Here, we examined the contribution of KCNQ3 and KCNQ2 in mediating the apamin-insensitive mAHP current (ImAHP) in hippocampus. The ImAHP was not impaired in CA1 pyramidal neurons from mice genetically deficient for either KCNQ3 or KCNQ2 but was reduced Ϸ50% in dentate granule cells. While recording from KCNQ-deficient mice, we observed that the calcium-activated slow afterhyperpolarization current (IsAHP) was also reduced in dentate granule cells, suggesting that KCNQ channels might also contribute to this potassium current whose molecular identity is unknown. Further pharmacological and molecular experiments manipulating KCNQ channels provided evidence in support of this possibility. Together our data suggest that multiple KCNQ subunit compositions can mediate the ImAHP, and that the very same subunits may also contribute to the IsAHP. We also present data suggesting that the neuronal calcium sensor protein hippocalcin may allow for these dual signaling processes.Epilepsy ͉ KCNQ ͉ M-current ͉ Retigabine ͉ sAHP

show abstract

“…From an evolutionary perspective, KCNQ2 and KCNQ3 were the last KCNQ subunits to emerge, coincident with the apparition of myelin (Hill et al, 2008). The KCNQ2/3 subunits acquired an ankyrin G-binding motif, that allows them to concentrate at the nodes of Ranvier and the axonal initial segment (AIS) (Pan et al, 2006;Rasmussen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Expression of KCNQ2 and KCNQ3 yields only small currents, whereas their coexpression yields heteromeric currents 10-fold larger (Wang et al, 1998). KCNQ3 is a major determinant of M-channels location to the AIS (Rasmussen et al, 2007) and displays a predominant intracellular distribution, whereas its combination with KCNQ2 leads to a large increase in axonal surface expression (Chung et al, 2006). KCNQ3 is unusual because it has an alanine in the inner vestibule, three residues upstream of the signature GYG (see Fig.…”

Section: Introductionmentioning

confidence: 99%

A Pore Residue of the KCNQ3 Potassium M-Channel Subunit Controls Surface Expression

Gómez-Posada¹,

Etxeberría²,

Roura-Ferrer³

et al. 2010

Journal of Neuroscience

View full text Add to dashboard Cite

KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are the principal subunits underlying the potassium M-current, which exerts a strong control on neuronal excitability. KCNQ3 subunits coassemble with KCNQ2 to form functional heteromeric channels that are specifically transported to the axonal initial segment and nodes of Ranvier. In contrast, there is no evidence for functional homomeric KCNQ3 channels in neurons, and it appears that these are inefficiently trafficked to the plasma membrane. Among eukaryotic potassium channels, the KCNQ3 subunit is unusual because it has an alanine in place of a threonine at the pore inner vestibule, three residues upstream of the GYG signature sequence of the selectivity filter. This residue is critical for the potentiation of the current after heteromerization, but the mechanism is unknown. We report that the presence of this uncommon residue at position 315 has a strong impact on the stability of the homotetramers and on channel trafficking. Wild-type KCNQ3 expressed alone is retained within the endoplasmic reticulum, and this mechanism is overcome by the substitution of threonine for Ala315. KCNQ3 subunits require assembly with KCNQ2 to exit this compartment, whereas KCNQ3-A315T is no longer dependent on KCNQ2 to form channels that are efficiently trafficked to the plasma membrane. The presence of this alanine, therefore, plays an important role in regulating the subunit composition of functional M-channels expressed at the surface of neurons.

show abstract

Requirement of subunit co-assembly and ankyrin-G for M-channel localization at the axon initial segment

Cited by 104 publications

References 37 publications

Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons

Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents

A Pore Residue of the KCNQ3 Potassium M-Channel Subunit Controls Surface Expression

Contact Info

Product

Resources

About