Three mechanisms underlie KCNQ2/3 heteromeric potassium M-channel potentiation.
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.
Instituto Cajal Consejo Superior de Investigaciones Científicas (CSIC), 28002 Madrid, Spain.
Ainhoa
A
Etxeberria
Irene
I
Santana-Castro
M Paz
MP
Regalado
Paloma
P
Aivar
Alvaro
A
Villarroel
D000818:Animals; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D008845:Microinjections; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; D011188:Potassium