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A769662: a Novel Voltage-Gated Sodium Channel Blocker Marina N

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A769662: a Novel Voltage-Gated Sodium Channel Blocker Marina N A769662: A novel voltage-gated sodium channel blocker Marina N. Asiedu, Theodore J. Price and Greg Dussor Department of Pharmacology, The University of Arizona Health Science Center, Tucson, AZ 460.02/WW21 Abstract Acute A769662 application suppresses action potential A769662 produces a significant hyperpolarizing shift in sodium channel inactivation Voltage-gated sodium channels regulate neuronal excitability and the generation and firing in sensory neurons propagation of action potentials. Recent studies in our laboratory have revealed that AMPK activators decrease sensory neuron excitability, potentially by preventing Na+ channel phosphorylation from kinases such as ERK. However, whether the decrease in excitability may also be due to direct block of sodium channels is unknown. Patch-clamp For activation, whole-cell Na+ electrophysiology was used to measure the direct effect of A769662, a positive allosteric currents are elicited by 50 ms test modulator of AMPK, on sodium channel function in sensory neurons. Using current- pulses to potentials between -80 clamp recordings, A769662 inhibited action potential firing stimulated by a 1s and +40mV in steps of 5mV from depolarizing ramp current injection. In voltage-clamp recordings, application of A769662 a holding potential of -120V reduced the amplitudes of Na+ currents induced by a voltage step protocol. Since (N=10). For steady-state fast A769662 was applied acutely (for durations as short as 5 sec) in both current- and inactivation, currents are elicited voltage-clamp recordings, these finding suggest a direct channel blocking effect. The with 50ms test pulses to -10mV block of Na+ currents by A769662 was dose-dependent with approximately 50% block at after 500ms conditioning pulses 10 µM. In addition, acute application of A769662 produced a significant hyperpolarizing from -100 to -10mV (N=9). For shift in the inactivation curve of Na+ currents suggesting that A769662 has an effect on activation, k = 6.16mV for control ;k = 10.37mV for the voltage dependence of Na+ channel activity. Further, A769662 decreased the + An action potential is A769662 amplitude of Na currents in Nav1.7-transfected HEK cells and produced a significant defined as a spike that hyperpolarizing shift in the voltage dependence of Nav1.7 current inactivation. These data + indicate that in addition to AMPK activation, A769662 acts as a direct blocker/modulator crosses 0mV and has an A769662 decreases Na current amplitude and produces a significant amplitude > 40mV. of TTX-sensitive and TTX-resistant channels, an additional effect that may enhance hyperpolarizing shift in the voltage dependence of Nav 1.7 current efficacy of this compound as a pain therapeutic. Slow ramp currents from 0.1 to 0.7nA with a Δ of activation and inactivation curve 0.2nA are injected over a 1 sec period to generate A step from a hyperpolarizing repetitive firing. N=5 potential (-80 mV) to a Methods depolarizing potential (0 mV) Animals: Adult male Sprague-Dawley rats (225-250g) were used for the patch for 25 ms from a holding potential of -80mV. electrophysiology studies. ICR mice (25g) were used for the behavioral studies. + Cell culture: TG neurons were dissociated enzymatically using papain and collagenase Acute application of A769662 reduces Na current followed by mechanical dissociation. For patch-clamp experiments, cells were cultured in L- 15 media supplemented with 10% fetal calf serum and kept in normal air at room temperature amplitude in a dose-dependent manner for < 24 hrs. Nav1.7-transfected HEK cells were plated at low passage numbers (<20) and kept at 37°C for < 24 hrs. For activation, whole-cell Na+ currents are elicited by 50 ms Electrophysiology: Whole cell patch-clamp experiments were performed on isolated rat TG test pulses to potentials between -80 and +40mV in steps of neurons in vitro using a MultiClamp 700B (Axon Instruments) patch-clamp amplifier and 5mV from a holding potential of -120V (N=7). For steady- PClamp 9 acquisition software (Axon Instruments). Recordings were sampled at 5kHz and state fast inactivation, currents are elicited with 50ms test filtered at 1 kHz (Digidata 1322A, Axon Instrumrnts). Pipettes (OD: 1.5mm, ID: 0.86mm, pulses to -10mV after 500ms conditioning pulses from -100 Sutter Instrument) were pulled using a P-97 puller (Sutter Instrument) and heat polished to to -10mV (N=7). 1.5-4 MΩ resistance using a microforge (MF-83, Narishige). Series resistance was typically < 7 MΩ and was compensated 60-80%. Data were analyzed using Clampfit 10 (Molecular Devices and Origin 8 (OriginLab). Statistics: All data are presented as mean ± sem. Significant difference between groups for Conclusions current amplitude was assessed by a paired t-test. Measures of dose by time were done by two-way ANOVA with Bonferroni post-hoc test. Dose-response curve was analyzed by 1. A769662 inhibits action potential firing in sensory neurons. variable slope nonlinear regression using GraphPad Prism 5.0 ( GraphPad, San Diego, CA). 2. Acute application of A769662 dose-dependently reduces Na+ current amplitude. 3. A769662 produces a significant hyperpolarizing shift in the sodium channel inactivation curve. 4. In Nav1.7 transfected HEK cells, A769662 reduces Na+ current amplitude and FUNDING SUPPORT produces a significant hyperpolarizing shift in Nav1.7 channel activation and fast The University of Arizona Foundation, The American Pain Society, inactivation curve. and The NIH/NINDS (NS072204). A step from a hyperpolarizing potential (-80 mV) to a depolarizing potential (0 mV) for 25 These findings indicate that A769662 acts as a direct Na+ channel blocker ms from a holding potential of -60mV. /modulator in addition to its AMPK activation effects. .
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