Zhang Hongling, Katnik Christopher, Cuevas Javier
Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine 12901 Bruce B. Downs Blvd., Tampa, FL 33612 USA.
Int J Physiol Pathophysiol Pharmacol. 2009 Nov 15;2(1):1-11.
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 IC(50) 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.
已表明西格玛（σ）受体可调节心内神经节神经元中的多种离子通道类型，包括电压门控钙通道和钾通道。然而，仅抑制这些通道并不能完全解释先前报道的σ受体诱导的神经元兴奋性变化。在电流钳模式下，对新生大鼠分离的心内神经元进行全细胞膜片钳实验，以评估σ受体激活对这些细胞主动膜特性的影响。浴用泛选择性σ受体激动剂1,3-二邻甲苯基胍（DTG）和σ-1选择性激动剂（+）-喷他佐辛，可显著增加动作电位潜伏期，并在去极化电流斜坡刺激下降低动作电位超射，这表明电压门控钠通道受到抑制。全细胞电压钳实验表明，这些σ激动剂在所有测试电位下均可使这些细胞中去极化激活的Na(+)电流可逆性降低。膜去极化产生的峰值电流呈剂量依赖性降低，DTG和（+）-喷他佐辛的IC(50)值分别为32μM和49μM。σ-1受体选择性拮抗剂BD 1063（100 nM）可抑制DTG（30μM）对Na(+)电流的阻断约50%，表明这些效应是由σ-1受体激活介导的。DTG还将Na(+)通道的稳态失活曲线向更负的电位移动，在不存在和存在30μM DTG时，半激活膜电位分别从-49 mV变为-63 mV。综上所述，这些结果表明σ-1受体激活通过调节电压门控Na(+)通道降低心内神经节神经元的兴奋性。
