Nature 403, 553-556). We cloned a KChIP2 splice variant (KChIP2.2) from human ventricle. In comparison with KChIP2.1, coexpression of KChIP2.2 with human Kv4 channels in mammalian cells slowed the onset of Kv4 current inactivation (2-3-fold), accelerated the recovery from inactivation (5-7-fold), and shifted Kv4 steady-state inactivation curves by 8-29 mV to more positive potentials. The features of Kv4.2/KChIP2.2 currents closely resemble those of cardiac rapidly inactivating transient outward currents. KChIP2.2 stimulated the Kv4 current density in Chinese hamster ovary cells by ϳ55-fold. This correlated with a redistribution of immunoreactivity from perinuclear areas to the plasma membrane. Increased Kv4 cell-surface expression and current density were also obtained in the absence of KChIP2.2 when the highly conserved proximal Kv4 N terminus was deleted. The same domain is required for association of KChIP2.2 with Kv4 ␣-subunits. We propose that an efficient transport of Kv4 channels to the cell surface depends on KChIP binding to the Kv4 N-terminal domain. Our data suggest that the binding is necessary, but not sufficient, for the functional activity of KChIPs.Voltage-gated potassium (Kv) channels related to the Shal (Kv4) gene family (2-5) mediate rapidly inactivating outward currents related to neuronal subthreshold A-type currents (4) as well as transient outward currents (I to ) in cardiac myocytes (6). Kv4 channel subunits have been localized immunocytochemically to somatodendritic areas in rat brain neurons (7). The high abundance of neuronal Kv4 channels in neuronal soma and dendrites suggests that Kv4 channels play an important role in postsynaptic signal integration. In fact, Kv4 channel activity may prevent action potential back-propagation into dendrites, thereby controlling potentiation of dendritic excitability (8) and acting as "dendritic shock-absorbers" (9). Conversely, inactivation of Kv4 channels below the action potential firing threshold leads to increased postsynaptic neuronal excitability (10, 11).Recently, small Ca 2ϩ -binding and Kv channel-interacting proteins (KChIPs) 1 were discovered (1). They are encoded in three different genes (KChIP1, KChIP2, and KChIP3) (1) and are members of the recoverin superfamily of Ca 2ϩ -binding proteins (12), being closely related to frequenin (13). KChIPs are associated with Kv4 channels as shown by immunocytochemical colocalization and co-immunoprecipitation studies (1). Since KChIPs are prominently expressed in brain, neuronal Kv4 channels most likely contain KChIPs as an integral subunit component.Kv4 channels are also expressed in cardiac tissue, where they mediate I to . This current contributes to the early phase of cardiac action potential repolarization (14). We considered the possibility that, like neuronal Kv4 channels, cardiac Kv4 channels might be associated with KChIPs. Accordingly, we searched human cardiac mRNA for KChIP mRNA. In this work, we report the cloning of a human cardiac KChIP cDNA, KChIP2.2, which represents a splice variant...
Voltage-gated potassium channels (Kv) of the Shaker-related superfamily are assembled from membrane-integrated alpha subunits and auxiliary beta subunits. The beta subunits may increase Kv channel surface expression and/or confer A-type behavior to noninactivating Kv channels in heterologous expression systems. The interaction of Kv alpha and Kv beta subunits depends on the presence or absence of several domains including the amino-terminal N-type inactivating and NIP domains and the Kv alpha and Kv beta binding domains. Loss of function of Kv beta 1.1 subunits leads to a reduction of A-type Kv channel activity in hippocampal and striatal neurons of knock-out mice. This reduction may be correlated with altered cognition and motor control in the knock-out mice.
Shaker-related voltage-gated potassium (Kv) channels may be heterooligomers consisting of membrane-integral ␣-subunits associated with auxiliary cytoplasmic -subunits. In this study we have cloned the human Kv3.1 subunit and the corresponding KCNA3B gene.
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