In cortical neurons, pore-forming ␣-subunits of the Kv4 subfamily underlie the fast transient outward K ϩ current (I A ). Considerable evidence has accumulated demonstrating specific roles for I A channels in the generation of individual action potentials and in the regulation of repetitive firing. Although I A channels are thought to play a role in synaptic processing, little is known about the cell typeand synapse-specific distribution of these channels in cortical circuits. Here, we used immunolabeling with specific antibodies against Kv4.2 and Kv4.3, in combination with GABA immunogold staining, to determine the cellular, subcellular, and synaptic localization of Kv4 channels in the primary visual cortex of mice, in which subsets of pyramidal cells express yellow fluorescent protein. The results show that both Kv4.2 and Kv4.3 are concentrated in layer 1, the bottom of layer 2/3, and in layers 4 and 5/6. In all layers, clusters of Kv4.2 and Kv4.3 immunoreactivity are evident in the membranes of the somata, dendrites, and spines of pyramidal cells and GABAergic interneurons. Electron microscopic analyses revealed that Kv4.2 and Kv4.3 clusters in pyramidal cells and interneurons are excluded from putative excitatory synapses, whereas postsynaptic membranes at GABAergic synapses often contain Kv4.2 and Kv4.3. The presence of Kv4 channels at GABAergic synapses would be expected to weaken inhibition during dendritic depolarization by backpropagating action potentials. The extrasynaptic localization of Kv4 channels near excitatory synapses, in contrast, should stabilize synaptic excitation during dendritic depolarization. Thus, the synapse-specific distribution of Kv4 channels functions to optimize dendritic excitation and the association between presynaptic and postsynaptic activity.

The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against β agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure.

Rapidly activating and inactivating A-type K+ currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significantly (p < 0.0001) increased mean ± SEM repetitive firing rates in SCN neurons during the day (6.4 ± 0.5 Hz) and at night (4.3 ± 0.6 Hz), compared with nontargeted shRNA-expressing SCN neurons (day: 3.1 ± 0.5 Hz; night: 1.6 ± 0.3 Hz). IA was also significantly (p < 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 ± 11.8 pA/pF; night: 55.3 ± 7.7 pA/pF), compared with nontargeted shRNA-expressing (day: 121.7 ± 10.2 pA/pF; night: 120.6 ± 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and IA was larger at night. In addition, Kv4.1-targeted shRNA expression significantly (p < 0.001) increased mean ± SEM nighttime input resistance (Rin; 2256 ± 166 MΩ), compared to nontargeted shRNA-expressing SCN neurons (1143 ± 93 MΩ). Additional experiments revealed that acute knockdown of Kv4.1 significantly (p < 0.01) shortened, by ∼0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded IA channels in regulating circadian rhythms in neuronal excitability and behavior.

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

No abstract