Trafficking Mechanisms Underlying Neuronal Voltage-gated Ion Channel Localization at the Axon Initial Segment

Overview

Journal Epilepsia

Specialty Neurology

Date 2012 Dec 11

PMID 23216576

Citations 36

Authors

Helene Vacher

James S Trimmer

Affiliations

Soon will be listed here.

Abstract

Voltage-gated ion channels are diverse and fundamental determinants of neuronal intrinsic excitability. Voltage-gated K(+) (Kv) and Na(+) (Nav) channels play complex yet fundamentally important roles in determining intrinsic excitability. The Kv and Nav channels located at the axon initial segment (AIS) play a unique and especially important role in generating neuronal output in the form of anterograde axonal and backpropagating action potentials. Aberrant intrinsic excitability in individual neurons within networks contributes to synchronous neuronal activity leading to seizures. Mutations in ion channel genes give rise to a variety of seizure-related "channelopathies," and many of the ion channel subunits associated with epilepsy mutations are localized at the AIS, making this a hotspot for epileptogenesis. Here we review the cellular mechanisms that underlie the trafficking of Kv and Nav channels found at the AIS, and how Kv and Nav channel mutations associated with epilepsy can alter these processes.

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References

Sitia R, Braakman I . Quality control in the endoplasmic reticulum protein factory. Nature. 2003; 426(6968):891-4. DOI: 10.1038/nature02262. View

Xie G, Harrison J, Clapcote S, Huang Y, Zhang J, Wang L . A new Kv1.2 channelopathy underlying cerebellar ataxia. J Biol Chem. 2010; 285(42):32160-73. PMC: 2952217. DOI: 10.1074/jbc.M110.153676. View

Vacher H, Trimmer J . Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels. Pflugers Arch. 2011; 462(5):631-43. PMC: 3371647. DOI: 10.1007/s00424-011-1004-8. View

Shi G, Nakahira K, Hammond S, Rhodes K, Schechter L, Trimmer J . Beta subunits promote K+ channel surface expression through effects early in biosynthesis. Neuron. 1996; 16(4):843-52. DOI: 10.1016/s0896-6273(00)80104-x. View

Mantegazza M, Curia G, Biagini G, Ragsdale D, Avoli M . Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol. 2010; 9(4):413-24. DOI: 10.1016/S1474-4422(10)70059-4. View

OConnell K, Rolig A, Whitesell J, Tamkun M . Kv2.1 potassium channels are retained within dynamic cell surface microdomains that are defined by a perimeter fence. J Neurosci. 2006; 26(38):9609-18. PMC: 6674455. DOI: 10.1523/JNEUROSCI.1825-06.2006. View

Grubb M, Burrone J . Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature. 2010; 465(7301):1070-4. PMC: 3196626. DOI: 10.1038/nature09160. View

Krzemien D, Schaller K, Levinson S, Caldwell J . Immunolocalization of sodium channel isoform NaCh6 in the nervous system. J Comp Neurol. 2000; 420(1):70-83. View

Gomez-Posada J, Etxeberria A, Roura-Ferrer M, Areso P, Masin M, Murrell-Lagnado R . A pore residue of the KCNQ3 potassium M-channel subunit controls surface expression. J Neurosci. 2010; 30(27):9316-23. PMC: 6632484. DOI: 10.1523/JNEUROSCI.0851-10.2010. View

10.

Catterall W . From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000; 26(1):13-25. DOI: 10.1016/s0896-6273(00)81133-2. View

11.

Kole M, Stuart G . Signal processing in the axon initial segment. Neuron. 2012; 73(2):235-47. DOI: 10.1016/j.neuron.2012.01.007. View

12.

Caldwell J, Schaller K, Lasher R, Peles E, Levinson S . Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci U S A. 2000; 97(10):5616-20. PMC: 25877. DOI: 10.1073/pnas.090034797. View

13.

Hu W, Tian C, Li T, Yang M, Hou H, Shu Y . Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation. Nat Neurosci. 2009; 12(8):996-1002. DOI: 10.1038/nn.2359. View

14.

Rasband M . The axon initial segment and the maintenance of neuronal polarity. Nat Rev Neurosci. 2010; 11(8):552-62. DOI: 10.1038/nrn2852. View

15.

Duflocq A, Chareyre F, Giovannini M, Couraud F, Davenne M . Characterization of the axon initial segment (AIS) of motor neurons and identification of a para-AIS and a juxtapara-AIS, organized by protein 4.1B. BMC Biol. 2011; 9:66. PMC: 3198992. DOI: 10.1186/1741-7007-9-66. View

16.

Heeroma J, Henneberger C, Rajakulendran S, Hanna M, Schorge S, Kullmann D . Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release. Dis Model Mech. 2009; 2(11-12):612-9. PMC: 2773728. DOI: 10.1242/dmm.003582. View

17.

Redman P, He K, Hartnett K, Jefferson B, Hu L, Rosenberg P . Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1. Proc Natl Acad Sci U S A. 2007; 104(9):3568-73. PMC: 1805571. DOI: 10.1073/pnas.0610159104. View

18.

Shapira S, McCaskill C, Northrup H, Spikes A, Elder F, Sutton V . Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet. 1997; 61(3):642-50. PMC: 1715949. DOI: 10.1086/515520. View

19.

Wimmer V, Reid C, So E, Berkovic S, Petrou S . Axon initial segment dysfunction in epilepsy. J Physiol. 2010; 588(Pt 11):1829-40. PMC: 2901971. DOI: 10.1113/jphysiol.2010.188417. View

20.

Maljevic S, Wuttke T, Seebohm G, Lerche H . KV7 channelopathies. Pflugers Arch. 2010; 460(2):277-88. DOI: 10.1007/s00424-010-0831-3. View