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J Physiol Volume 586, Number 8, 2093-2106, April 15, 2008 DOI: 10.1113/jphysiol.2007.150540
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NEUROSCIENCE

Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons

 Yimy Amarillo1, Jose A. De Santiago-Castillo2, Kevin Dougherty2, Jonathon Maffie1, Elaine Kwon1, Manuel Covarrubias2 and Bernardo Rudy1

1 Department of Physiology & Neuroscience and Department of Biochemistry, Smilow Neuroscience Program, New York University School of Medicine, Smilow Research Center, 522 First Avenue, 6th Floor, New York, NY 10016, USA
2 Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College of Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA

Kv4 channels mediate most of the somatodendritic subthreshold operating A-type current (ISA) in neurons. This current plays essential roles in the regulation of spike timing, repetitive firing, dendritic integration and plasticity. Neuronal Kv4 channels are thought to be ternary complexes of Kv4 pore-forming subunits and two types of accessory proteins, Kv channel interacting proteins (KChIPs) and the dipeptidyl-peptidase-like proteins (DPPLs) DPPX (DPP6) and DPP10. In heterologous cells, ternary Kv4 channels exhibit inactivation that slows down with increasing depolarization. Here, we compared the voltage dependence of the inactivation rate of channels expressed in heterologous mammalian cells by Kv4.2 proteins with that of channels containing Kv4.2 and KChIP1, Kv4.2 and DPPX-S, or Kv4.2, KChIP1 and DPPX-S, and found that the relation between inactivation rate and membrane potential is distinct for these four conditions. Moreover, recordings from native neurons showed that the inactivation kinetics of the ISA in cerebellar granule neurons has voltage dependence that is remarkably similar to that of ternary Kv4 channels containing KChIP1 and DPPX-S proteins in heterologous cells. The fact that this complex and unique behaviour (among A-type K+ currents) is observed in both the native current and the current expressed in heterologous cells by the ternary complex containing Kv4, DPPX and KChIP proteins supports the hypothesis that somatically recorded native Kv4 channels in neurons include both types of accessory protein. Furthermore, quantitative global kinetic modelling showed that preferential closed-state inactivation and a weakly voltage-dependent opening step can explain the slowing of the inactivation rate with increasing depolarization. Therefore, it is likely that preferential closed-state inactivation is the physiological mechanism that regulates the activity of both ternary Kv4 channel complexes and native ISA-mediating channels.

(Received 26 December 2007; accepted after revision 12 February 2008; first published online 14 February 2008)
Corresponding author B. Rudy: Smilow Neuroscience Program, Smilow Research Center, New York University School of Medicine, 522 First Avenue, 6th Floor, New York, NY 10016, USA. Email: rudyb01{at}med.nyu.edu

This paper has online supplemental material.






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