Kv4 Accessory Protein DPPX (DPP6) is a Critical Regulator of Membrane Excitability in Hippocampal CA1 Pyramidal Neurons

• Published in: Journal of neurophysiology Vol. 100; no. 4; pp. 1835 - 1847
• Main Authors: Kim, Jinhyun, Nadal, Marcela S, Clemens, Ann M, Baron, Matthew, Jung, Sung-Cherl, Misumi, Yoshio, Rudy, Bernardo, Hoffman, Dax A
• Format: Journal Article
• Language: English
• Published: United States Am Phys Soc 01.10.2008; American Physiological Society
• Subjects: Action Potentials - genetics; Action Potentials - physiology; Animals; CHO Cells; Computer Simulation; Cricetinae; Cricetulus; Data Interpretation, Statistical; Electrophysiology; Hippocampus - cytology; Hippocampus - physiology; Organ Culture Techniques; Patch-Clamp Techniques; Pyramidal Cells - physiology; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Shal Potassium Channels - physiology; Sindbis Virus - genetics; Synaptic Membranes - physiology
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.90261.2008

1 Molecular Neurophysiology and Biophysics Unit, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; 2 Department of Physiology and Neuroscience Smilow Neuroscience Program, New York University School of Medicine, New York City, New York; and 3 Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan Submitted 11 February 2008; accepted in final form 23 July 2008 A-type K + currents have unique kinetic and voltage-dependent properties that allow them to finely tune synaptic integration, action potential (AP) shape and firing patterns. In hippocampal CA1 pyramidal neurons, Kv4 channels make up the majority of the somatodendritic A-type current. Studies in heterologous expression systems have shown that Kv4 channels interact with transmembrane dipeptidyl-peptidase-like proteins (DPPLs) to regulate the surface trafficking and biophysical properties of Kv4 channels. To investigate the influence of DPPLs in a native system, we conducted voltage-clamp experiments in patches from CA1 pyramidal neurons expressing short-interfering RNA (siRNA) targeting the DPPL variant known to be expressed in hippocampal pyramidal neurons, DPPX (siDPPX). In accordance with heterologous studies, we found that DPPX downregulation in neurons resulted in depolarizing shifts of the steady-state inactivation and activation curves, a shallower conductance-voltage slope, slowed inactivation, and a delayed recovery from inactivation for A-type currents. We carried out current-clamp experiments to determine the physiological effect of the A-type current modifications by DPPX. Neurons expressing siDPPX exhibited a surprisingly large reduction in subthreshold excitability as measured by a decrease in input resistance, delayed time to AP onset, and an increased AP threshold. Suprathreshold DPPX downregulation resulted in slower AP rise and weaker repolarization. Computer simulations supported our experimental results and demonstrated how DPPX remodeling of A-channel properties can result in opposing sub- and suprathreshold effects on excitability. The Kv4 auxiliary subunit DPPX thus acts to increase neuronal responsiveness and enhance signal precision by advancing AP initiation and accelerating both the rise and repolarization of APs. Address for reprint requests and other correspondence: D. A. Hoffman, Molecular Neurophysiology and Biophysics Unit, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Dr., Rm. 3C-905, Bethesda, MD 20892-3715 (E-mail: hoffmand{at}mail.nih.gov )