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Modulation of A-type potassium channels by a family of calcium sensors


In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes1,2. Although pore-forming α-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells3, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 α-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 α-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.

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Figure 1: YTH interaction and tissue expression of KChIPs1–3.
Figure 2: Sequence alignment of human KChIPs with members of the recoverin family of Ca2+-sensing proteins.
Figure 3: Immunolocalization of Kv4 and KChIP1 in COS-1 cells and rat brain. a–c, COS-1 cells were transiently transfected with KChIP1 cDNA alone (a), Kv4.2 alone (b) or KChIP1 and Kv4.2 (c).
Figure 4: KChIPs co-associate with Fu4 α-subunits.
Figure 5: KChIP1 alters the density and kinetics of Kv4.2 currents in CHO cells.


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We thank P. Chanda and W. Edris for generation and purification of the recombinant KChIP proteins; J. Wardwell-Swanson and S. Nawoschik for generating mammalian and oocyte expression constructs; L. Buchwalder for preparation of the anti-KChIP and anti-Kv4 mouse monoclonal antibodies; J. Tang, K. Maden and S. Dembski for help with the yeast two-hybrid screen; K. Young, Q. Wang, Y. M. Xie, T. Novak, C. Gimeno and P. Errada for technical advice; and J. Moyer, J. Barrett, M. Cockett, P. McGonigle, J. Lillie, R. Breitbart, K. Willis and P. DiStefano for support and encouragement.

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Correspondence to Kenneth J. Rhodes.

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An, W., Bowlby, M., Betty, M. et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature 403, 553–556 (2000).

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