A Conserved Domain in Axonal Targeting of Kv1 (Shaker) Voltage-Gated Potassium Channels

Gu, Chen; Jan, Yuh Nung

doi:10.1126/science.1086998

Cited by 146 publications

(192 citation statements)

References 24 publications

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“…Grayscaleinverted images and camera lucida drawing were generated in PHOTOSHOP (Adobe Systems, San Jose) as described in ref. 50 (see Fig. 7 legend).…”

Section: Methodsmentioning

confidence: 99%

“…Immunostaining of surface CD4 fusion proteins or endogenous KCNQ2 and KCNQ3 proteins with rabbit anti-KCNQ2 and KCNQ3 antibodies (1:200 dilution) was performed as described in ref. 50.…”

Section: Methodsmentioning

confidence: 99%

“…Primary hippocampal cultures from 18-day embryonic rats were prepared and transfected at 7 days in vitro (DIV) as described in ref. 50. Surface immunostaining for HA-KCNQ channels at 10 DIV was performed as described in ref.…”

Section: Methodsmentioning

confidence: 99%

“…Surface immunostaining for HA-KCNQ channels at 10 DIV was performed as described in ref. 50 with the following modifications: Surface HA-KCNQ proteins were labeled with mouse anti-HA antibody (1:500 dilution) at 4°C overnight and visualized with biotinconjugated secondary antibodies for 2 h, followed by Alexa 660-conjugated strepavidin. Neurons were then permeabilized and incubated with rat anti-HA antibody to label total HA-KCNQ proteins (1:1,000 dilution) and rabbit anti-MAP2 antibody (1:1,000 dilution), followed by Alexa488-and Alexa350-conjugated secondary antibodies, respectively.…”

Section: Methodsmentioning

confidence: 99%

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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.

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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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“…Grayscaleinverted images and camera lucida drawing were generated in PHOTOSHOP (Adobe Systems, San Jose) as described in ref. 50 (see Fig. 7 legend).…”

Section: Methodsmentioning

confidence: 99%

“…Immunostaining of surface CD4 fusion proteins or endogenous KCNQ2 and KCNQ3 proteins with rabbit anti-KCNQ2 and KCNQ3 antibodies (1:200 dilution) was performed as described in ref. 50.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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.

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178

214

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“…Attaining a detailed understanding of axonal function will also require manipulation of the expression of specific ion channels at precise locations in the axon. The use of recently developed molecular tools to target defined channel subunits to specific axonal compartments could help to determine their role in axonal propagation 123,124 . For instance, the controlled expression of sodium or potassium channels at a high density at branch points would help us understand branch point failures.…”

Section: Axo-axonal Coupling and Fast Synchronizationmentioning

confidence: 99%

Information processing in the axon

2004

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mTOR referees memory and disease through mRNA repression and competition

Raab‐Graham

Niere

2017

FEBS Letters

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Mammalian target of rapamycin (mTOR) activity is required for memory and is dysregulated in disease. Activation of mTOR promotes protein synthesis; however, new studies are demonstrating that mTOR activity also represses the translation of mRNAs. Almost three decades ago, Kandel and colleagues hypothesised that memory was due to the induction of positive regulators and removal of negative constraints. Are these negative constraints repressed mRNAs that code for proteins that block memory formation? Herein, we will discuss the mRNAs coded by putative memory suppressors, how activation/inactivation of mTOR repress protein expression at the synapse, how mTOR activity regulates RNA binding proteins, mRNA stability, and translation, and what the possible implications of mRNA repression are to memory and neurodegenerative disorders.

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A Conserved Domain in Axonal Targeting of Kv1 (Shaker) Voltage-Gated Potassium Channels

Cited by 146 publications

References 24 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

Information processing in the axon

mTOR referees memory and disease through mRNA repression and competition

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