MOLECULAR AND FUNCTIONAL CHANGES IN ... - Semantic Scholar
Neuroscience 119 (2003) 323–333
MOLECULAR AND FUNCTIONAL CHANGES IN VOLTAGE-DEPENDENT Naⴙ CHANNELS FOLLOWING PILOCARPINE-INDUCED STATUS EPILEPTICUS IN RAT DENTATE GRANULE CELLS R. K. ELLERKMANN,a,b1 S. REMY,a,b1 J. CHEN,a,c D. SOCHIVKO,a C. E. ELGER,a B. W. URBAN,b A. BECKERc AND H. BECKa*
tion of -subunit expression may contribute to the depolarizing shift in the inactivation curve following S.E. © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.
a Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany
Key words: Na channel ␣ subunit, Na channel  subunit, hippocampus, epilepsy, expression alteration, window current.
b
Department of Anaesthesiology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany c
Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany
Voltage-dependent Na⫹ channels are composed of a pore-forming ␣ subunit associated with two auxiliary subunits, 1 and 2. These channels are ubiquitous membrane proteins in excitable cells (Catterall, 1992) and are responsible for the initiation and propagation of action potentials. The generation of action potentials appears to be due to Na⫹ currents located within the axon, near the axon initial segment (Colbert and Johnston, 1996; Colbert and Pan, 2002). Na⫹ channels with distinct properties are present in dendrites of CNS neurons, and confer active properties to these compartments (Golding and Spruston, 1998; Jung et al., 1997; Stuart et al., 1997; Stuart and Sakmann, 1994). The regional and cellular localization of different Na⫹ channel subtypes suggests that they subserve specialized tasks that are likely to be of importance in maintaining the functional heterogeneity of CNS neurons (Whitaker et al., 2000). Thus, altered density or biophysical properties of Na⫹ channels may have important consequences for neuronal excitability and may be important in CNS diseases associated with altered excitability, such as chronic epilepsy. The importance of Na⫹ channels in chronic epilepsy is further underscored by the fact that several anti-epileptic drugs act predominantly via a usedependent inhibition of Na⫹ channels (Clare et al., 2000; Ragsdale et al., 1991). These considerations prompted a series of investigations aimed at determining molecular and functional changes in Na⫹ channels in experimental and human epilepsy. On a functional level, altered Na⫹ channel properties have been described in CA1 neurons at the chronic stages following kindling epileptogenesis. The changes consisted of a modest shift of the fast voltage-dependent steadystate inactivation curve in the depolarizing direction together with a modest increase in current amplitude by 20% (Vreugdenhil et al., 1998). Similar analyses were carried out in the limbic status model (Ketelaars et al., 2001), in which damage to the hippocampus and the occurrence of spontaneous seizures can be observed. In CA1 neurons, a significant shift in the steady-state inactivation curve was not observed, but the voltage dependence of activation
Abstract—Status epilepticus (S.E.) is known to lead to a large number of changes in the expression of voltage-dependent ion channels and neurotransmitter receptors. In the present study, we examined whether an episode of S.E. induced by pilocarpine in vivo alters functional properties and expression of voltage-gated Naⴙ channels in dentate granule cells (DGCs) of the rat hippocampus. Using patch-clamp recordings in isolated DGCs, we show that the voltage-dependent inactivation curve is significantly shifted toward depolarizing potentials following S.E. (halfmaximal inactivation at ⴚ43.2ⴞ0.6 mV) when compared with control rats (ⴚ48.2ⴞ0.8 mV, P
MOLECULAR AND FUNCTIONAL CHANGES IN VOLTAGE-DEPENDENT Naⴙ CHANNELS FOLLOWING PILOCARPINE-INDUCED STATUS EPILEPTICUS IN RAT DENTATE GRANULE CELLS R. K. ELLERKMANN,a,b1 S. REMY,a,b1 J. CHEN,a,c D. SOCHIVKO,a C. E. ELGER,a B. W. URBAN,b A. BECKERc AND H. BECKa*
tion of -subunit expression may contribute to the depolarizing shift in the inactivation curve following S.E. © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.
a Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany
Key words: Na channel ␣ subunit, Na channel  subunit, hippocampus, epilepsy, expression alteration, window current.
b
Department of Anaesthesiology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany c
Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany
Voltage-dependent Na⫹ channels are composed of a pore-forming ␣ subunit associated with two auxiliary subunits, 1 and 2. These channels are ubiquitous membrane proteins in excitable cells (Catterall, 1992) and are responsible for the initiation and propagation of action potentials. The generation of action potentials appears to be due to Na⫹ currents located within the axon, near the axon initial segment (Colbert and Johnston, 1996; Colbert and Pan, 2002). Na⫹ channels with distinct properties are present in dendrites of CNS neurons, and confer active properties to these compartments (Golding and Spruston, 1998; Jung et al., 1997; Stuart et al., 1997; Stuart and Sakmann, 1994). The regional and cellular localization of different Na⫹ channel subtypes suggests that they subserve specialized tasks that are likely to be of importance in maintaining the functional heterogeneity of CNS neurons (Whitaker et al., 2000). Thus, altered density or biophysical properties of Na⫹ channels may have important consequences for neuronal excitability and may be important in CNS diseases associated with altered excitability, such as chronic epilepsy. The importance of Na⫹ channels in chronic epilepsy is further underscored by the fact that several anti-epileptic drugs act predominantly via a usedependent inhibition of Na⫹ channels (Clare et al., 2000; Ragsdale et al., 1991). These considerations prompted a series of investigations aimed at determining molecular and functional changes in Na⫹ channels in experimental and human epilepsy. On a functional level, altered Na⫹ channel properties have been described in CA1 neurons at the chronic stages following kindling epileptogenesis. The changes consisted of a modest shift of the fast voltage-dependent steadystate inactivation curve in the depolarizing direction together with a modest increase in current amplitude by 20% (Vreugdenhil et al., 1998). Similar analyses were carried out in the limbic status model (Ketelaars et al., 2001), in which damage to the hippocampus and the occurrence of spontaneous seizures can be observed. In CA1 neurons, a significant shift in the steady-state inactivation curve was not observed, but the voltage dependence of activation
Abstract—Status epilepticus (S.E.) is known to lead to a large number of changes in the expression of voltage-dependent ion channels and neurotransmitter receptors. In the present study, we examined whether an episode of S.E. induced by pilocarpine in vivo alters functional properties and expression of voltage-gated Naⴙ channels in dentate granule cells (DGCs) of the rat hippocampus. Using patch-clamp recordings in isolated DGCs, we show that the voltage-dependent inactivation curve is significantly shifted toward depolarizing potentials following S.E. (halfmaximal inactivation at ⴚ43.2ⴞ0.6 mV) when compared with control rats (ⴚ48.2ⴞ0.8 mV, P
