A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon.
KCNQ (KV7) 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 (NaV) 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 NaV alpha subunits that serves these functions. All identified NaV and KCNQ genes of worms, insects, and molluscs lack the ankyrin-G binding motif. In contrast, vertebrate orthologs of NaV alpha subunits, KCNQ2, and KCNQ3 (including from bony fish, birds, and mammals) all possess the motif. Thus, concerted ankyrin-G interaction with KCNQ and NaV 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.
Pan
Zongming
Z
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kao
Tingching
T
Horvath
Zsolt
Z
Lemos
Julia
J
Sul
Jai-Yoon
JY
Cranstoun
Stephen D
SD
Bennett
Vann
V
Scherer
Steven S
SS
Cooper
Edward C
EC
D000595:Amino Acid Sequence; D000818:Animals; D017487:Ankyrins / Q000172:deficiency / Q000502:physiology*; D001369:Axons / Q000502:physiology*; D005075:Biological Evolution; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles; D051658:KCNQ2 Potassium Channel / Q000276:immunology / Q000502:physiology*; D051659:KCNQ3 Potassium Channel / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008958:Models, Molecular; D008967:Molecular Biology / Q000379:methods; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D010455:Peptides / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011901:Ranvier's Nodes / Q000378:metabolism; D051381:Rats; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods
C094681:Ank3 protein, mouse; D017487:Ankyrins; D007211:Indoles; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D010455:Peptides; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; C007293:DAPI