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The Journal of Neuroscience, March 8, 2006, 26(10):2599-2613; doi:10.1523/JNEUROSCI.4314-05.2006

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Cellular/Molecular
A Common Ankyrin-G-Based Mechanism Retains KCNQ and Na_V Channels at Electrically Active Domains of the Axon

Zongming Pan,¹ Tingching Kao,¹ Zsolt Horvath,¹ Julia Lemos,¹ Jai-Yoon Sul,² Stephen D. Cranstoun,³ Vann Bennett,⁶ Steven S. Scherer,^1,4 and Edward C. Cooper^1,4,5

Departments of ¹Neurology, ²Neuroscience, and ³Bioengineering and Institutes of ⁴Neurological Sciences and ⁵Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and ⁶Department of Cell Biology and Howard Hughes Medical Institute, Duke University, Durham, North Carolina 27710

Correspondence should be addressed to Dr. Edward C. Cooper, Department of Neurology, University of Pennsylvania, 409 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6060. Email: edc{at}mail.med.upenn.edu

KCNQ (K_V7) potassium channels underlie subthreshold M-currents that stabilize the neuronal resting potential and prevent repetitive firing of action potentials. Here, antibodies against four different KCNQ2 and KCNQ3 polypeptide epitopes show these subunits concentrated at the axonal initial segment (AIS) and node of Ranvier. AIS concentration of KCNQ2 and KCNQ3, like that of voltage-gated sodium (Na_V) channels, is abolished in ankyrin-G knock-out mice. A short motif, common to KCNQ2 and KCNQ3, mediates both in vivo ankyrin-G interaction and retention of the subunits at the AIS. This KCNQ2/KCNQ3 motif is nearly identical to the sequence on Na_V subunits that serves these functions. All identified Na_V and KCNQ genes of worms, insects, and molluscs lack the ankyrin-G binding motif. In contrast, vertebrate orthologs of Na_V subunits, KCNQ2, and KCNQ3 (including from bony fish, birds, and mammals) all possess the motif. Thus, concerted ankyrin-G interaction with KCNQ and Na_V channels appears to have arisen through convergent molecular evolution, after the division between invertebrate and vertebrate lineages, but before the appearance of the last common jawed vertebrate ancestor. This includes the historical period when myelin also evolved.

Key words: action potential; axon initial segment; node of Ranvier; neuromodulation; epilepsy; M-current

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Received Oct. 10, 2005; revised Jan. 13, 2006; accepted Jan. 23, 2006.

Correspondence should be addressed to Dr. Edward C. Cooper, Department of Neurology, University of Pennsylvania, 409 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6060. Email: edc{at}mail.med.upenn.edu

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