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The Kv4 A-type potassium currents contribute to controlling the frequency of slow repetitive firing and back-propagation of action potentials in neurons and shape the action potential in heart. Kv4 currents exhibit rapid activation and inactivation and are specifically modulated by K-channel interacting proteins (KChIPs). Here we report the discovery and functional characterization of a modular K-channel inactivation suppressor (KIS) domain located in the first 34 aa of an additional KChIP (KChIP4a T he Kv4 subfamily of voltage-gated potassium channels underlie somatodendritic A-currents in several types of neurons (1-3) and I to in cardiac myocytes (4-7). Operating at subthreshold membrane potentials, they contribute to controlling the frequency of slow repetitive firing in these excitable cells. The dendritic A-type K ϩ current in hippocampal neurons helps to integrate the back-propagating action potentials and excitatory postsynaptic potentials or inhibitory postsynaptic potentials, providing a rapid electric signal to initiate associative events such as long-term potentiation (LTP) and long-term depression (LDP) (8-12). In heart, I to impacts on the early phase of repolarization of the action potential (13,14).We recently identified K-channel interacting protein 1-3 (KChIP1-3) that specifically modulate Kv4 currents (15). KChIP1-3 increase total Kv4 current, moderately slow channel inactivation, and considerably accelerate recovery from inactivation (15). They are EF-hand Ca 2ϩ -binding proteins that belong to the recoverin͞neuronal calcium sensor-1 (NCS-1) family. KChIP1 and KChIP 3 are predominantly expressed in neuronal tissues, whereas KChIP2 is predominantly expressed in heart and brain (15).Here we report an unexpected, distinct modulation of Kv4 currents by a K-channel inactivation suppressor (KIS) domain present in an additional KChIP, KChIP4a. We show that by eliminating fast inactivation in conjunction with changes in other kinetic parameters, the KIS domain effectively converts the fast inactivating A-type current to a slowly inactivating delayed rectifier type of currents. Also, we present evidence that KChIPs with and without the KIS domain modulate Kv4 currents in a combinatorial manner. The KIS domain acts oppositely to the Kv␤1 ball domain (16-19) and the ball-like domains of maxi-K ␤2, ␤3 subunits (20-22). These observations indicate that auxiliary subunits provide diverse mechanisms to control activity of potassium channels. Materials and MethodsElectrophysiology. Unitary potassium currents were recorded from cell-attached patches in the presence of 2 mM KCl in the recording pipette as described (23, 24). Macroscopic potassium currents were recorded by applying the two-electrode voltage clamp method in Xenopus oocytes and the tight-seal whole-cell method in Chinese hamster ovary cells and cerebellar granule neurons essentially as described (25), except noted as follows. To examine the kinetics of the macroscopic rising phase, the currents were evoked from a holding potential of Ϫ100 mV by 3...