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The Journal of Neuroscience, October 13, 2004, 24(41):9146-9152; doi:10.1523/JNEUROSCI.3194-04.2004

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Cellular/Molecular
Three Mechanisms Underlie KCNQ2/3 Heteromeric Potassium M-Channel Potentiation

Ainhoa Etxeberria,¹ Irene Santana-Castro,¹ M. Paz Regalado,¹ Paloma Aivar,² and Alvaro Villarroel²

¹Instituto Cajal Consejo Superior de Investigaciones Científicas (CSIC), 28002 Madrid, Spain, and ²Unidad de Biofísica, CSIC-Universidad del País Vasco (UPV)/Euskal Herriko Unibersitatea, UPV, 48940 Leioa, Spain

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.

Key words: Kv7; KCNQ; M-current; epilepsy; pore; surface expression

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Received June 29, 2004; accepted August 31, 2004.

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