Inhibition of voltage-dependent sodium currents by cannabidiol

Voltage-gated sodium channels initiate action potentials in excitable tissues. Altering these channels’ function can lead to many pathophysiological conditions. The family of voltage-gated sodium channel genes encodes 10 proteins (including Nav2.1) distributed throughout the central and peripheral nervous systems, cardiac and skeletal muscles. The SCN4A gene encodes the Nav1.4 channel, which is primarily responsible for depolarization of the skeletal muscle fibers. Many mutations in SCN4A are found and associated with the myotonic syndromes and periodic paralyses. These conditions are both considered gain-of-function and can be severely life-limiting with respect to performing everyday tasks. From a broader standpoint, hyperexcitability presents as a significant problem in other tissues besides skeletal muscles. Gain-of-function in sodium channels has been linked to a wide-range of pathophysiological conditions such as inherited erythromelalgia, epilepsy, and arrhythmias. Treating these types of pathologies requires an in-depth understanding of their underlying mechanisms. One way to gain this understanding is to investigate physiological triggers. There is also a dire need for novel ways of reducing the hyperexcitability associated with mutant sodium channels. One promising compound is the non-psychotropic component of the Cannabis sativa plant, cannabidiol. This compound has recently been shown to modulate some of the neuronal sodium channels. Although cannabidiol has shown efficacy in clinical trials, the underlying mechanism of action remains unknown. Sodium channels could be among the molecular targets for cannabidiol.In my doctoral research: 1) I studied how a single missense mutation, P1158S, in Nav1.4 causes various degrees of gain-of-function (myotonia and periodic paralysis) by using pH changes to probe P1158S gating modifications; 2) I studied the inhibitory effects of cannabidiol on voltage-dependent sodium currents; 3) I investigated the mechanism through which cannabidiol imparts inhibition. Overall, these data reveal novel insights into sodium channel hyperexcitability and pharmacologically targeting of this hyperexcitability using cannabidiol

Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3

Voltage-gated sodium channels are key contributors to membrane excitability. These channels are expressed in a tissue-specific manner. Mutations and modulation of these channels underlie various physiological and pathophysiological manifestations. The effects of changes in extracellular pH on channel gating have been studied on several sodium channel subtypes. Among these, Nav1.5 is the most pH-sensitive channel, with Nav1.2 and Nav1.4 being mostly pH-resistant channels. However, pH effects have not been characterized on other sodium channel subtypes. In this study, we sought to determine whether Nav1.1 and Nav1.3 display resistance or sensitivity to changes in extracellular pH. These two sodium channel subtypes are predominantly found in inhibitory neurons. The expression of these channels highly depends on age and the developmental stage of neurons, with Nav1.3 being found mostly in neonatal neurons, and Nav1.1 being found in adult neurons. Our present results indicate that, during extracellular acidosis, both channels show a depolarization in the voltage-dependence of activation and moderate reduction in current density. Voltage-dependence of steady-state fast inactivation and recovery from fast inactivation were unchanged. We conclude that Nav1.1 and Nav1.3 have similar pH-sensitivities

Dual-task motor performance with a tongue-operated assistive technology compared with hand operations

<p>Abstract</p> <p>Background</p> <p>To provide an alternative motor modality for control, navigation, and communication in individuals suffering from impairment or disability in hand functions, a Tongue Drive System (TDS) has been developed that allows for real time tracking of tongue motion in an unobtrusive, wireless, and wearable device that utilizes the magnetic field generated by a miniature disk shaped magnetic tracer attached to the tip of the tongue. The purpose of the study was to compare the influence of a concurrent motor or cognitive task on various aspects of simple movement control between hand and tongue using the TDS technology.</p> <p>Methods</p> <p>Thirteen young able-bodied adults performed rapid and slow goal-directed movements of hand and tongue (with TDS) with and without a concurrent motor (hand or tongue) or cognitive (arithmetic and memory) task. Changes in reaction time, completion time, speed, correctness, accuracy, variability of displacement, and variability of time due to the addition of a concurrent task were compared between hand and tongue.</p> <p>Results</p> <p>The influence of an additional concurrent task on motor performance was similar between the hand and tongue for slow movement in controlling their displacement. In rapid movement with a concurrent motor task, most aspects of motor performance were degraded in hand, while tongue speed during rapid continuous task was maintained. With a concurrent cognitive task, most aspects of motor performance were degraded in tongue, while hand accuracy during the rapid discrete task and hand speed during the rapid continuous task were maintained.</p> <p>Conclusion</p> <p>Rapid goal-directed hand and tongue movements were more consistently susceptible to interference from concurrent motor and cognitive tasks, respectively, compared with the other movement.</p

Effects of Amiodarone and N-desethylamiodarone on Cardiac Voltage-Gated Sodium Channels

Amiodarone (AMD) is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (INa,P and INa,L) and determine whether these effects change as AMD is metabolized into N-Desethylamiodarone (DES). We hypothesized that AMD and DES block both INa,P and INa,L with similar profiles due to structural similarities. Given the inherent small amounts of INa,L in NaV1.5, we screened AMD and DES against the Long QT-3-causing mutation, ∆KPQ, to better detect any drug-mediated effect on INa,L. Our results show that AMD and DES do not affect WT or ∆KPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block ∆KPQ peak conductance compared to WT. Both compounds significantly increase INa,L and window currents. We conclude that both compounds have pro-arrhythmic effects on NaV1.5, especially ∆KPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD

A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the “skeletal muscle”, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results suggest that, unlike in WT-Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger the noted phenotypes in P1158S patients

Time-division multiplexing for cable reduction in ultrasound imaging catheters

In ultrasound imaging catheter applications, gathering the data from multi-element transducer arrays is difficult as there is a restriction on cable count due to the diameter of the catheter. In such applications, CMUT-on-CMOS technology allows for 2D arrays with many elements to be designed and bonded directly onto CMOS circuitry. This allows for complex electronics to be placed at the tip of the catheter which leads to the possibility to include electronic multiplexing techniques to greatly reduce the cable count required for a large element array. Current approaches to cable reduction tend to rely on area and power hungry circuits to function, making them unsuitable for use in catheters. Furthermore the length requirement for catheters and lack of power available to on-chip cable drivers leads to limited signal strength at the receiver end. In this paper an alternative approach using Analogue Time Division Multiplexing (TDM) is presented, which addresses the cable restrictions of the catheter and, using a novel digital demultiplexing technique, allows for a reduction in the number of analogue signal processing stages required

Direct Digital Demultiplexing of Analog TDM Signals for Cable Reduction in Ultrasound Imaging Catheters.

In real-time catheter based 3D ultrasound imaging applications, gathering data from the transducer arrays is difficult as there is a restriction on cable count due to the diameter of the catheter. Although area and power hungry multiplexing circuits integrated at the catheter tip are used in some applications, these are unsuitable for use in small sized catheters for applications like intracardiac imaging. Furthermore, the length requirement for catheters and limited power available to on-chip cable drivers leads to limited signal strength at the receiver end. In this paper an alternative approach using Analog Time Division Multiplexing (TDM) is presented which addresses the cable restrictions of ultrasound catheters. A novel digital demultiplexing technique is also described which allows for a reduction in the number of analog signal processing stages required. The TDM and digital demultiplexing schemes are demonstrated for an intracardiac imaging system that would operate in the 4 MHz to 11 MHz range. A TDM integrated circuit (IC) with 8:1 multiplexer is interfaced with a fast ADC through a micro-coaxial catheter cable bundle, and processed with an FPGA RTL simulation. Input signals to the TDM IC are recovered with -40 dB crosstalk between channels on the same micro-coax, showing the feasibility of this system for ultrasound imaging applications

Cannabidiol interactions with voltage-gated sodium channels

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels

Cannabidiol interactions with voltage-gated sodium channels

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high-resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels