Lee JH et al. (2014), Metergoline inhibits the neuronal Nav1.2 voltag...

XB-ART-49126

Acta Pharmacol Sin 2014 Jul 01;357:862-8. doi: 10.1038/aps.2014.30.

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Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na(+) channels expressed in Xenopus oocytes.

Lee JH , Liu J , Shin M , Hong M , Nah SY , Bae H .

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AIM: Metergoline is an ergot-derived psychoactive drug that acts as a ligand for serotonin and dopamine receptors. The aim of this study was to investigate the regulatory effects of metergoline on the neuronal Nav1.2 voltage-dependent Na(+) channels in vitro. METHODS: Xenopus oocytes were injected with cRNAs encoding rat brain Nav1.2 α and β1 subunits. Voltage-activated Na(+) currents were recorded using two-electrode voltage clamp technique. Drugs were applied though perfusion. RESULTS: Both metergoline and lidocaine reversibly and concentration-dependently inhibited the peak of Na(+) currents with IC50 values of 3.6 ± 4.2 and 916.9 ± 98.8 μmol/L, respectively. Metergoline (3 μmol/L) caused a 6.8 ± 1.2 mV depolarizing shift of the steady-state activation curve of the Na(+) currents, and did not alter the inactivation curve. In contrast, lidocaine (3 μmol/L) caused a 12.7 ± 1.2 mV hyperpolarizing shift of the inactivation curve of the Na(+) currents without changing the steady-state activation curve. Both metergoline and lidocaine produced tonic and use-dependent inhibition on the peak of Na(+) currents. CONCLUSION: Metergoline exerts potent inhibition on the activity of neuronal Nav1.2 channels, which may contribute to its actions on the central nervous system.

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Species referenced: Xenopus laevis
Genes referenced: nav1 scn1a scn2a scn4b

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	Figure 1. Effects of metergoline on neuronal Nav1.2 channel currents and the current-voltage relationship. (A–C) Oocytes were injected with wild-type Nav1.2 α- and β1-subunit cRNA and maintained for three to four days before Na+ currents were recorded in ND96 using the two-electrode voltage clamp technique. The traces are representative of six separate oocytes from three different frogs in the absence (Con) or presence of 10 μmol/L metergoline or washout. Metergoline showed substantial inhibition on the peak currents of Nav1.2. (D) The current-voltage relationship was obtained using voltage steps between −50 mV and +50 mV taken in 5-mV increments. Voltage steps were applied in the absence (•) or presence (○) of 10 μmol/L metergoline or after washout of metergoline (▾). The peaks of the evoked currents, normalized to the peak current evoked by the voltage step to −10 mV in the absence of metergoline, were used in the I–V plot. The data represent the mean±SEM (n=7–9/group).
	Figure 2. Tonic inhibition of Nav1.2 channel currents by metergoline and lidocaine. (A) The peak inward current amplitudes (○) elicited by 200-ms depolarizations to −10 mV from a holding potential of −100 mV, evoked every 5 s. Data were obtained in eight separate oocytes from three different frogs. Metergoline (10 μmol/L) or lidocaine (300 μmol/L) were applied during the period indicated by the solid bars. (B) Averaged traces of Nav1.2 channel currents taken at the time “a”, “b”, and “c” in (A). (C and D) Concentration-response curves of metergoline or lidocaine-mediated inhibition of the peak currents of the Nav1.2 channel. Metergoline inhibited the large inward peak currents of the Nav1.2 channel in a concentration-dependent manner. The solid lines were fit using the Hill equation, as described in the Materials and methods section. The data represent the mean±SEM (n=12–15/group).
	Figure 3. The effect of metergoline and lidocaine on the steady-state activation and inactivation of the Nav1.2 channel current. (A and C) Effect of metergoline or lidocaine on the steady-state activation and inactivation of Nav1.2 channel current was examined as described in a previous report15. In brief, the voltage-dependence of Na+ channel activation was calculated by measuring the peak current at test potentials ranging from −50 mV to +10 mV evoked in 5 mV increments. The voltage-dependence of conductance was compared in the absence (○) or presence (▪) of 10 μmol/L metergoline or 1 mmol/L lidocaine. The conductance curve in the presence of metergoline or lidocaine is scaled to the maximum conductance (•). Inactivation was measured using a two-pulse protocol in which oocytes were held at −100 mV and depolarized to potentials from −90 mV to −20 mV for 500 ms, followed by a test-pulse to −10 mV for 10 ms to determine channel availability. Inactivation curves are shown in the absence (○) or presence (▪) of 10 μmol/L metergoline or 1 mmol/L lidocaine. Inactivation curves in the presence of metergoline or lidocaine are scaled to the maximum (•). The data represent the mean±SEM (n= 8–10/group). The curves represent a two-state Boltzmann function as described in the Materials and methods section.
	Figure 4. Use-dependent blockade of the Nav1.2 channel current by metergoline or lidocaine. (A) and (B), Sixty 20-ms depolarizing pulses to −10 mV were applied from a holding potential of −100 mV at 10 Hz in the absence or presence of metergoline [1 μmol/L (○) and 3 μmol/L (▾) in panel A] or lidocaine [300 μmol/L (○) and 1000 μmol/L (▾) in panel B] in oocytes expressing neuronal Nav1.2 channels. The peak currents were normalized to the current during the first pulse in the presence of agents to compare control current. Treatment with metergoline and lidocaine induced use-dependent inhibition of the Nav1.2 channel. Data represent the mean±SEM (n=5–7/group).

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