Article

A-type K+ channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons.

Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8103, St Louis, MO 63110, USA.
The Journal of Physiology (Impact Factor: 4.38). 05/2012; 590(Pt 16):3877-90. DOI: 10.1113/jphysiol.2012.229013
Source: PubMed

ABSTRACT Rapidly activating and rapidly inactivating voltage-gated A-type K+ currents, IA, are key determinants of neuronal excitability and several studies suggest a critical role for the Kv4.2 pore-forming α subunit in the generation of IA channels in hippocampal and cortical pyramidal neurons. The experiments here demonstrate that Kv4.2, Kv4.3 and Kv1.4 all contribute to the generation of IA channels in mature cortical pyramidal (CP) neurons and that Kv4.2-, Kv4.3- and Kv1.4-encoded IA channels play distinct roles in regulating the intrinsic excitability and the firing properties of mature CP neurons. In vivo loss of Kv4.2, for example, alters the input resistances, current thresholds for action potential generation and action potential repolarization of mature CP neurons. Elimination of Kv4.3 also prolongs action potential duration, whereas the input resistances and the current thresholds for action potential generation in Kv4.3−/− and WT CP neurons are indistinguishable. In addition, although increased repetitive firing was observed in both Kv4.2−/− and Kv4.3−/− CP neurons, the increases in Kv4.2−/− CP neurons were observed in response to small, but not large, amplitude depolarizing current injections, whereas firing rates were higher in Kv4.3−/− CP neurons only with large amplitude current injections. In vivo loss of Kv1.4, in contrast, had minimal effects on the intrinsic excitability and the firing properties of mature CP neurons. Comparison of the effects of pharmacological blockade of Kv4-encoded currents in Kv1.4−/− and WT CP neurons, however, revealed that Kv1.4-encoded IA channels do contribute to controlling resting membrane potentials, the regulation of current thresholds for action potential generation and repetitive firing rates in mature CP neurons.

0 Bookmarks
 · 
218 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cerebellum receives sensory information by mossy fiber input from a multitude of sources that require differential signal processing. A compartmentalization of function begins with the segregation of mossy fibers across 10 distinct lobules over the rostrocaudal axis, with tactile receptor afferents prevalent in anterior lobules and vestibular input in caudal lobules. However, it is unclear how these unique signals might be differentially processed at the circuit level across the cerebellum. As granule cells receive mossy fiber input, they represent a key stage at which postsynaptic mechanisms could influence signal processing. Granule cells express an A-type current mediated by Kv4 potassium channels that modify the latency and frequency of spike output. The current study examined the potential for a Cav3 calcium-Kv4 channel complex to regulate the response of granule cells to mossy fiber input in lobules 2 and 9 of the rat cerebellum. Similar A-type currents were recorded in both regions, but the Cav3 calcium current was expressed at a substantially higher density in lobule 9 cells, acting to increase A-type current availability through its influence on Kv4 voltage for inactivation. The difference in excitability imparted by Cav3-Kv4 interactions proves to allow lobule 2 granule cells to respond more effectively to tactile stimulus-like burst input and lobule 9 cells to slow shifts in input frequency characteristic of vestibular input. The expression pattern of Cav3 channels and its control of Kv4 availability thus provides a novel means of processing widely different forms of sensory input across cerebellar lobules.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2014; 34(26):8800-12. DOI:10.1523/JNEUROSCI.0981-14.2014 · 6.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The intrinsic excitability of neurons is known to be dynamically regulated by activity-dependent plasticity and homeostatic mechanisms. Such processes are commonly analyzed in the context of input-output functions that describe how neurons fire in response to constant levels of current. However, it is not well understood how changes of excitability as observed under static inputs translate to the function of the same neurons in their natural synaptic environment. Here we performed a computational study and hybrid experiments on rat bed nucleus of stria terminalis neurons to compare the two scenarios. The inward rectifying Kir-current (IKir) and the hyperpolarization-activated cation current (Ih) were found to be considerably more effective in regulating the firing under synaptic inputs than under static stimuli. This prediction was experimentally confirmed by dynamic clamp insertion of a synthetic inwardly rectifying Kir-current into the biological neurons. At the same time, ionic currents that activate with depolarization were more effective regulating the firing under static inputs. When two intrinsic currents are concurrently altered such as those under homeostatic regulation, the effects in firing responses under static versus dynamic inputs can be even more contrasting. Our results show that plastic or homeostatic changes of intrinsic membrane currents can shape the current step responses of neurons and their firing under synaptic inputs in a differential manner.
    Journal of Neurophysiology 10/2014; 113(1). DOI:10.1152/jn.00226.2014 · 3.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In order to investigate the effect of sodium ferulate (SF) on voltage-activated K(+) channels, the delayed rectifier K(+) current (Ik) in PC12 rat pheochromocytoma cells was recorded using the automated patch-clamp method. The results indicated that following the application of SF, the Ik in PC12 cells was significantly decreased in a concentration-dependent manner. The analysis of activation kinetic curves and inactivation kinetic curves of Ik showed that SF had an effect on the activation and inactivation kinetics. Following the application of 15.3 μM SF, the activation curve of the Ik of PC12 cells was shifted to positive potentials and the inactivation curve of the Ik of PC12 cells was shifted to negative potentials. This study revealed that the delayed rectifier K(+) currents of PC12 cells were inhibited following SF treatment in a concentration-dependent manner. The mechanism may be associated with the delayed activation and enhanced inactivation of Ik-associated channels.
    Experimental and therapeutic medicine 09/2014; 8(3):983-987. DOI:10.3892/etm.2014.1806 · 0.94 Impact Factor
    This article is viewable in ResearchGate's enriched format

Preview

Download
0 Downloads