Pathological biomechanical stresses cause cardiac hypertrophy, which is associated with QT prolongation and arrhythmias. Previous studies have demonstrated that repolarizing K + current densities are decreased in pressure overload-induced left ventricular hypertrophy, resulting in action potential and QT prolongation. Cardiac hypertrophy also occurs with exercise training, but this physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk, suggesting that repolarizing K + currents are upregulated, in parallel with the increase in myocyte size, to maintain normal cardiac function. To explore this hypothesis directly, electrophysiological recordings were obtained from ventricular myocytes isolated from two mouse models of physiological hypertrophy, one produced by swim-training of wild-type mice and the other by cardiac-specific expression of constitutively active phosphoinositide-3-kinase-p110α (caPI3Kα). Whole-cell voltage-clamp recordings revealed that repolarizing K + current amplitudes were higher in ventricular myocytes isolated from swim-trained and caPI3Kα, compared with wild-type, animals. The increases in K + current amplitudes paralleled the observed cellular hypertrophy, resulting in normalized or increased K + current densities. Electrocardiographic parameters, including QT intervals, as well as ventricular action potential waveforms in swim-trained animals/myocytes were indistinguishable from controls, demonstrating preserved electrical function. Additional experiments revealed that inward Ca 2+ current amplitudes/densities were also increased in caPI3Kα, compared with WT, left ventricular myocytes. The expression of transcripts encoding K + , Ca 2+ and other ion channel subunits was increased in swim-trained and caPI3Kα ventricles, in parallel with the increase in myocyte size and with the global increases in total cellular RNA expression. In contrast to pathological hypertrophy, therefore, the functional expression of repolarizing K + (and depolarizing Ca 2+ ) channels is increased with physiological hypertrophy, reflecting upregulation of the underlying ion channel subunit transcripts and resulting in increased current amplitudes and the normalization of current densities and action potential waveforms. Taken together, these results suggest that activation of PI3Kα signalling preserves normal myocardial electrical functioning and could be protective against the increased risk of arrhythmias and sudden death that are prevalent in pathological cardiac hypertrophy.

The rapidly activating and inactivating voltage-dependent outward K ϩ (Kv) current, I A , is widely expressed in central and peripheral neurons. I A has long been recognized to play important roles in determining neuronal firing properties and regulating neuronal excitability. Previous work demonstrated that Kv4.2 and Kv4.3 ␣-subunits are the primary determinants of I A in mouse cortical pyramidal neurons. Accumulating evidence indicates that native neuronal Kv4 channels function in macromolecular protein complexes that contain accessory subunits and other regulatory molecules. The K ϩ channel interacting proteins (KChIPs) are among the identified Kv4 channel accessory subunits and are thought to be important for the formation and functioning of neuronal Kv4 channel complexes. Molecular genetic, biochemical, and electrophysiological approaches were exploited in the experiments described here to examine directly the roles of KChIPs in the generation of functional Kv4-encoded I A channels. These combined experiments revealed that KChIP2, KChIP3, and KChIP4 are robustly expressed in adult mouse posterior (visual) cortex and that all three proteins coimmunoprecipitate with Kv4.2. In addition, in cortical pyramidal neurons from mice lacking KChIP3 (KChIP3 Ϫ/Ϫ ), mean I A densities were reduced modestly, whereas in mean I A densities in KChIP2 Ϫ/Ϫ and WT neurons were not significantly different. Interestingly, in both KChIP3 Ϫ/Ϫ and KChIP2 Ϫ/Ϫ cortices, the expression levels of the other KChIPs (KChIP2 and 4 or KChIP3 and 4, respectively) were increased. In neurons expressing constructs to mediate simultaneous RNA interference-induced reductions in the expression of KChIP2, 3, and 4, I A densities were markedly reduced and Kv current remodeling was evident.

Female patients presenting with their first trigger finger have the highest rate of long-term treatment success after a single corticosteroid injection. Patients who continue to experience symptom relief two years after injection are likely to maintain long-term success.

Key points• The cytosolic K + channel accessory subunit, K + channel interacting protein 2 (KChIP2), was previously suggested to be critical in the generation of cardiac fast transient outward current (I to,f ) channels.• The experiments presented here revealed the novel finding that targeted deletion of KChIP2 results in the complete loss of the Kv4.2 protein, although Kcnd2 (Kv4.2) transcript expression is not decreased in KChIP2 −/− ventricles.• In contrast, the slow transient outward current, I to,s , is increased in KChIP2 −/− left ventricular apex myocytes and ventricular action potential waveforms in KChIP2 −/− and WT mice are not significantly different.• These results demonstrate the critical role of KChIP2 in the stabilization of native Kv4 proteins and that the loss of the Kv4.2 protein underlies the elimination of I to,f in KChIP2 −/− myocytes.• Taken together, the results here demonstrate that electrical remodelling compensates for the elimination of I to,f , maintaining physiological action potential repolarization in mouse myocardium.Abstract The fast transient outward K + current (I to,f ) underlies the early phase of myocardial action potential repolarization, contributing importantly to the coordinated propagation of activity in the heart and to the generation of normal cardiac rhythms. Native I to,f channels reflect the tetrameric assembly of Kv4 pore-forming (α) subunits, and previous studies suggest roles for accessory and regulatory proteins in controlling the cell surface expression and the biophysical properties of Kv4-encoded I to,f channels. Here, we demonstrate that the targeted deletion of the cytosolic accessory subunit, K + channel interacting protein 2 (KChIP2), results in the complete loss of the Kv4.2 protein, the α subunit critical for the generation of mouse ventricular I to,f . Expression of the Kcnd2 (Kv4.2) transcript in KChIP2 −/− ventricles, however, is unaffected. The loss of the Kv4.2 protein results in the elimination of I to,f in KChIP2 −/− ventricular myocytes. In parallel with the elimination of I to,f , the slow transient outward K + current (I to,s ) is upregulated and voltage-gated Ca 2+ currents (I Ca,L ) are decreased. In addition, surface electrocardiograms and ventricular action potential waveforms in KChIP2 −/− and wild-type mice are not significantly different, suggesting that the upregulation of I to,s and the reduction in I Ca,L compensate for the loss of I to,f . Additional experiments revealed that I to,f is not 'rescued' by adenovirus-mediated expression of KChIP2 in KChIP2 −/− myocytes, although I Ca,L densities are increased. Taken together, these results demonstrate that association with KChIP2 early in the biosynthetic pathway

Members of the KMembers of the Shal subfamily of voltage-gated K ϩ (Kv) channel pore-forming (␣) subunits encode rapidly activating and inactivating Kv channels that also recover rapidly from inactivation and are important in the generation of I A channels in neurons (1-4) and I to channels in cardiac myocytes (5, 6). Accumulating evidence suggests that functional Kv4 channels reflect the assembly of Kv4 ␣ subunits with one or more Kv channel accessory subunits and other regulatory proteins that influence channel cell surface expression and/or biophysical properties (7). The K ϩ channel-interacting proteins (KChIP), 4 members of the Neuronal Calcium Sensor superfamily (8, 9), for example, are cytosolic accessory subunits that were initially identified in a yeast two-hybrid screen using the N terminus of Kv4.2 as bait (10). Heterologous co-expression with accessory KChIP subunits increases Kv4.2 current densities, as well as altering the timeand voltage-dependent properties of currents (10 -14). Truncation of the first 40 amino acids in the Kv4.2 N terminus results in the loss of KChIP-mediated current modulation but a paradoxical increase in Kv4.2 current densities (11,14). Progressive truncation of the N terminus (up to 40 amino acids) was reported to result in progressively greater increases in current densities, although it was not determined whether the observed increase reflected increased total and/or cell surface Kv4.2 protein expression. Previous mutagenesis studies have been interpreted as suggesting that the major binding site for KChIP2 on the Kv4.2 N terminus is between residues 11 and 23 (15). Structural analysis of the N terminus of Kv4.3, crystallized in complex with the core region (conserved across all family members) of KChIP1 (16,17), however, revealed that KChIPs bind the distal 20 N-terminal residues of Kv4 ␣ subunits in a hydrophobic binding pocket.The KChIP-mediated increases in Kv4.2 current densities have been ascribed to increased trafficking of channels from the endoplasmic reticulum (ER) to the surface membrane (10,11,18), although a precise motif that regulates ER retention has yet to be identified. The amino acid motif Arg-Xaa-Arg (RXR) has been shown to play a role in ER retention of inwardly rectifying K ϩ channels (Kir) (19). For example, ATP-sensitive K ϩ channels (K ATP ) formed by the co-assembly of Kir6 ␣ subunits and sulfonylurea receptor accessory subunits are retained in the ER when either subunit is expressed alone. Subunit co-assembly, however, masks RXR retention motifs, promoting forward trafficking to the cell surface of channel complexes (20). Although the Kv4.2 N terminus contains (at positions 35-37) an RKR sequence, previous studies suggest that this sequence does not function as an ER retention motif (18). It has also been suggested that Kv4.2 alone traffics out of the ER but fails to progress beyond the Golgi complex in the absence of KChIPs (21 4 The abbreviations used are: KChIP, K ϩ channel-interacting protein; ER, endoplasmic reticulum; HP, holding potentia...