A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions

Lerche, Holger; Biervert, Christian; Alekov, Alexi K.; Schleithoff, Lothar; Lindner, Martin; Klingler, Werner; Bretschneider, Frank; Mitrović, Nenad; Jurkat‐Rott, Karin; Bode, Harald; Lehmann‐Horn, Frank; Steinlein, Ortrud K.

doi:10.1002/1531-8249(199909)46:3<305::aid-ana5>3.0.co;2-5

Cited by 133 publications

(85 citation statements)

References 33 publications

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“…The C-terminal frameshift mutations of KCNQ2 (P681-FS and G838-FS) caused by 1-bp deletion replace the distal Cterminal sequences with unrelated amino acid sequences starting from residue P681 (31) or G838 (32). Whereas both frameshift mutations had no effect on the total protein expression in axons, the P681-FS, but not the G838-FS, mutation abolished axonal surface expression and slightly elevated the dendritic total protein level of HA-KCNQ3͞KCNQ2 (Fig.…”

Section: Effect Of Bfnc Mutations On Surface Expression Of Kcnq Channmentioning

confidence: 62%

Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains

Chung

Jan

2006

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

175

214

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The M channels, important regulators of neuronal excitability, are voltage-gated potassium channels composed of KCNQ2-5 subunits. Mutations in KCNQ2 and KCNQ3 cause benign familial neonatal convulsions (BFNC), dominantly inherited epilepsy and myokymia. Crucial for their functions in controlling neuronal excitability, the M channels must be placed at specific regions of the neuronal membrane. However, the precise distribution of surface KCNQ channels is not known. Here, we show that KCNQ2͞KCNQ3 channels are preferentially localized to the surface of axons both at the axonal initial segment and more distally. Whereas axonal initial segment targeting of surface KCNQ channels is mediated by ankyrin-G binding motifs of KCNQ2 and KCNQ3, sequences mediating targeting to more distal portion of the axon reside in the membrane proximal and A domains of the KCNQ2 C-terminal tail. We further show that several BFNC mutations of KCNQ2 and KCNQ3 disrupt surface expression or polarized surface distribution of KCNQ channels, thereby revealing impaired targeting of KCNQ channels to axonal surfaces as a BFNC etiology.axon initial segment ͉ axon targeting ͉ epilepsy ͉ KCNQ potassium channel N euronal KCNQ channels, voltage-dependent potassium channels that activate slowly but show no inactivation, correspond to the M channels that exert crucial influence over neuronal excitability (1). Inhibition of M channels by muscarinic agonist (hence the name) and other neurotransmitters enhances action potential firing in central and autonomic neurons (2). M channels are mostly heterotetramers composed of KCNQ2 and KCNQ3 (3,4). The overlapping expression patterns of KCNQ2 and KCNQ3 include brain areas implicated in seizure development, such as hippocampus, neocortex, and thalamus (3, 5, 6). The critical involvement of KCNQ channels in controlling neuronal excitability is underscored further by the fact that benign familial neonatal convulsions (BFNC) mutations in KCNQ2 and KCNQ3 cause epilepsy (7,8) and myokymia (9). Consistently, retigabine, a potent KCNQ channel opener (10) can suppress seizures in a number of animal models (11-13) and attenuate neuropathic pain (14, 15), whereas linopirdine and XE991, developed as ''cognitive enhancer'' drugs for treatment of Alzheimer disease and other memory disorders, are potent blockers of KCNQ channels (10).KCNQ channels contribute to the neuronal resting membrane potentials (16), hippocampal theta oscillation (17, 18), spike frequency adaptation (16,(18)(19)(20), spike after depolarization (16, 21), and after hyperpolarization (18,20). Consistent with reports of the ability of KCNQ channels to modulate motor axon excitability (9, 22) and transmitter release (23), KCNQ2 and KCNQ3 proteins have been detected in axons (5,6,24,25), the axonal initial segment (AIS) and nodes of Ranvier (26,27). It remains possible, however, that the neuronal soma and dendrites express functional KCNQ channels, given the transmitter modulation of KCNQ channels (2) and strong somatodendritic KCNQ2 and KCNQ3 immunoreactivi...

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Section: Effect Of Bfnc Mutations On Surface Expression Of Kcnq Channmentioning

confidence: 62%

Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains

Chung

Jan

2006

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

175

214

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“…In the C terminus, there are four regions with high probability of forming an ␣ helix (helices A-D) (Yus-Najera et al, 2002). Clusters of positively charged residues reminiscent of retention/retrieval signals (Teasdale and Jackson, 1996;Ma and Jan, 2002) are present at the end (Lerche et al, 1999) and close to helix C. This is intriguing because helix C makes up the assembly domain (Maljevic et al, 2003;Schwake et al, 2003), and it could easily be envisaged that putative retention signals close to this helix could be concealed after channel assembly. Surface expression appears to be also regulated by other regions, because all chimeras were less efficient than Q2 at promoting Q3 traffic to the membrane (Fig.…”

Section: Discussionmentioning

confidence: 99%

Three Mechanisms Underlie KCNQ2/3 Heteromeric Potassium M-Channel Potentiation

Etxeberría¹,

Santana-Castro²,

Regalado³

et al. 2004

J. Neurosci.

117

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The non-inactivating potassium M-current exerts a strong influence on neuronal excitability. The channels responsible for this current are made up of KCNQ subunits, and mutations in most of these produce human pathologies. Notably, in terms of excitation, mutations in either KCNQ2 or KCNQ3 lead to benign neonatal familial convulsions. Although a mere reduction of 25% in KCNQ2/3 function can increase excitability to epileptogenic levels, the potentiation of these subunits has anti-epileptogenic effects. After KCNQ2/3 heteromerization, current levels can augment as much as 10-fold, and we have discovered that there are three processes underlying this potentiation. First, there is an increase in the number of channels inserted in the membrane after heteromerization of the C-terminal region. Second, the N-terminal domain from KCNQ2 exerts a negative influence on the current level. Finally, Ala 315 of KCNQ3, a residue located in the inner vestibule after the selectivity filter, plays a critical role in preventing current flow in KCNQ3 homomeric channels, whereas it is permissive in heteromers in combination with Thr at the equivalent 276 position of KCNQ2.

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“…In addition, in a benign familial neonatal convulsions pedigree, a 56-amino acid extension in the length of the KCNQ2 C-terminal tail caused by a frameshift mutation at the 3Ј-end of the open reading frame, lowers current amplitudes drastically when expressed in Xenopus oocytes. In contrast, truncation of the last seven natural amino acids increases channel activity 2-fold (30). Together, these results stress the functional importance of the C-terminal region in the KCNQ proteins.…”

Section: Cloning and Tissue Distribution Of Kcnq5-a Search Of The Genmentioning

confidence: 99%

Molecular Cloning and Functional Expression of KCNQ5, a Potassium Channel Subunit That May Contribute to Neuronal M-current Diversity

Lerche¹,

Scherer²,

Seebohm³

et al. 2000

Journal of Biological Chemistry

250

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We have isolated KCNQ5, a novel human member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. When expressed in Xenopus oocytes, KCNQ5 generated voltage-dependent, slowly activating K ؉ -selective currents that displayed a marked inward rectification at positive membrane voltages. KCNQ5 currents were insensitive to the K ؉ channel blocker tetraethylammonium but were strongly inhibited by the selective M-current blocker linopirdine. Upon coexpression with the structurally related KCNQ3 channel subunit, current amplitudes increased 4 -5-fold. Compared with homomeric KCNQ5 currents, KCNQ3/KCNQ5 currents also displayed slower activation kinetics and less inward rectification, indicating that KCNQ5 combined with KCNQ3 to form functional heteromeric channel proteins. This functional interaction between KCNQ5 and KCNQ3, a component of the M-channel, suggests that KCNQ5 may contribute to a diversity of heteromeric channels underlying native neuronal M-currents.

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A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions

Cited by 133 publications

References 33 publications

Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains

Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains

Three Mechanisms Underlie KCNQ2/3 Heteromeric Potassium M-Channel Potentiation

Molecular Cloning and Functional Expression of KCNQ5, a Potassium Channel Subunit That May Contribute to Neuronal M-current Diversity

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