IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2010;2(1):1-11.

Original Article
Sigma receptor activation inhibits voltage-gated sodium channels in rat intracardiac
ganglion neurons

Hongling Zhang, Christopher Katnik, Javier Cuevas

From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B.
Downs Blvd., Tampa, FL  33612 USA.

Received September 18, 2009; accepted November 13, 2009; available online November 15, 2009

Abstract: Sigma (σ) receptors have been shown to regulate multiple ion channel types in intracardiac ganglion neurons, including
voltage-gated calcium and potassium channels.  However, the inhibition of these channels alone cannot fully account for σ receptor-
induced changes in neuronal excitability previously reported.  Whole-cell patch clamp experiments were conducted under current-
clamp mode in isolated intracardiac neurons from neonatal rats to assess the effects of σ receptor activation on the active membrane
properties of these cells.  Bath application of the pan-selective σ receptor agonist, 1,3-Di-o-tolylguanidine (DTG), and the σ-1-selective
agonist, (+)-pentazocine, significantly increased the action potential latency and decreased action potential overshoot in response to
depolarizing current ramps, which suggests inhibition of voltage-gated sodium channels.  Whole-cell voltage clamp experiments
showed that these σ agonists reversibly decrease depolarization-activated Na+ currents in these cells at all potentials tested. The peak
currents generated by membrane depolarizations were decreased in a dose dependent manner with IC50 values for DTG and (+)-
pentazocine of 32 µM and 49 µM, respectively.  The σ-1 receptor-selective antagonist, BD 1063 (100 nM), inhibited DTG (30 µM) block of
Na+ currents by ~ 50%, suggesting that the effects are mediated by activation of σ-1 receptors. DTG also shifted the steady-state
inactivation curve of Na+ channels to more negative potentials, with the membrane potential of half-activation shifting from -49 mV to
-63 mV in the absence and presence of 30 µM DTG, respectively. Taken together, these results suggest that σ-1 receptor activation
decreases intracardiac ganglion neuron excitability by modulating voltage-gated Na+ channels. (IJPPP909002).

Key words: Sigma-1 receptor, sodium channel, intracardiac neurons, action potential, parasympathetic

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Address all correspondence to:
Javier Cuevas, PhD
Department of Molecular Pharmacology and Physiology
University of South Florida College of Medicine
12901 Bruce B. Downs Blvd.
Tampa, FL  33612 USA.