Four mammalian Kv3 genes have been identified, each of which generates, by alternative splicing, multiple protein products differing in their C-terminal sequence. Products of the Kv3.1 and Kv3.2 genes express similar delayed-rectifier type currents in heterologous expression systems, while Kv3.3 and Kv3.4 proteins express A-type currents. All Kv3 currents activate relatively fast at voltages more positive than -10 mV, and deactivate very fast. The distribution of Kv3 mRNAs in the rodent CNS was studied by in situ hybridization, and the localization of Kv3.1 and Kv3.2 proteins has been studied by immunohistochemistry. Most Kv3.2 mRNAs (approximately 90%) are present in thalamic-relay neurons throughout the dorsal thalamus. The protein is expressed mainly in the axons and terminals of these neurons. Kv3.2 channels are thought to be important for thalamocortical signal transmission. Kv3.1 and Kv3.2 proteins are coexpressed in some neuronal populations such as in fast-spiking interneurons of the cortex and hippocampus, and neurons in the globus pallidus. Coprecipitation studies suggest that in these cells the two types of protein form heteromeric channels. Kv3 proteins appear to mediate, in native neurons, similar currents to those seen in heterologous expression systems. The activation voltage and fast deactivation rates are believed to allow these channels to help repolarize action potentials fast without affecting the threshold for action potential generation. The fast deactivating current generates a quickly recovering after hyperpolarization, thus maximizing the rate of recovery of Na+ channel inactivation without contributing to an increase in the duration of the refractory period. These properties are believed to contribute to the ability of neurons to fire at high frequencies and to help regulate the fidelity of synaptic transmission. Experimental evidence has now become available showing that Kv3.1-Kv3.2 channels play critical roles in the generation of fast-spiking properties in cortical GABAergic interneurons.
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 Kv1 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...
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