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 myocytes. Although pore-forming alpha-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells, 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 alpha-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 alpha-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.
An
W F
WF
Millennium Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
Bowlby
M R
MR
Betty
M
M
Cao
J
J
Ling
H P
HP
Mendoza
G
G
Hinson
J W
JW
Mattsson
K I
KI
Strassle
B W
BW
Trimmer
J S
JS
Rhodes
K J
KJ
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D018076:DNA, Complementary; D006801:Humans; D051605:Kv Channel-Interacting Proteins; D051379:Mice; D008969:Molecular Sequence Data; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D051672:Shal Potassium Channels; D020798:Two-Hybrid System Techniques; D014982:Xenopus laevis
D002135:Calcium-Binding Proteins; C496756:Csen protein, mouse; D018076:DNA, Complementary; C497021:KCND3 protein, human; C496750:KCNIP1 protein, human; C496752:KCNIP2 protein, human; C496749:KCNIP3 protein, human; C497022:Kcnd3 protein, mouse; C497023:Kcnd3 protein, rat; C496754:Kcnip1 protein, mouse; C496757:Kcnip1 protein, rat; C496755:Kcnip2 protein, mouse; C496758:Kcnip2 protein, rat; C496760:Kcnip3 protein, rat; D051605:Kv Channel-Interacting Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D012097:Repressor Proteins; D051672:Shal Potassium Channels