Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical WarfareFig. 19-7. Sodium channel proteins play an essential role in action potential generation and propagation in neurons andother excitable cell types. The resting membrane potential of a neuron remains around - 80 mV. When the neuron membranebecomes excited by the binding of neurotransmitters to their appropriate receptor molecules for example, the cell beginsto depolarize and these voltage-gated sodium channels are activated. In response to membrane depolarization, these channelsopen, increasing cell membrane conductance and a large influx of sodium ions travels down the sodium concentrationgradient. This large sodium current drives the membrane potential of the cell towards the reversal potential for sodium,approximately + 55 mV and is recognizable on electrophysiological recordings of neuron activity as the “spike” or actionpotential. Membrane potential is returned to resting by a combination of the termination of sodium influx due to loss ofdriving force on sodium, the eventual inactivation of the voltage-gated sodium channels, and the opening of potassiumchannels. The inactivated state is different from the closed channel state, with the inactivated-to-closed transition drivenby the slight hyperpolarization of the cell membrane, which occurs in response to potassium current. Only closed channelsare available to open.Voltage-gated sodium channels are protein complexes composed of a 260 kDa α-subunit and one or more smaller, auxiliaryβ-subunits (β1, β2, or β3). The variable combinations of the α-subunit with multiple β-subunits allow the creation ofa number of functionally distinct channels. The α-subunit illustrated here folds into four transmembrane domains (I–IV),colored green, blue, orange, and purple. The transmembrane domains are composed of six α-helical segments designatedS1 through S6 (see Figure 19-4).The use of biological agents against civilian populationsis a legitimate issue of concern; attacks usingbiological agents have already occurred in the UnitedStates and abroad. We must anticipate terrorist groupsemploying toxins or other agents that are not consideredclassical weapon agents. Understanding the realstrengths and weaknesses of toxins as weapons allowsan educated and realistic assessment of the threatposed by toxins and can guide the administration ofsurveillance programs and contingency plans.AcknowledgmentThe authors thank Lieutenant Colonel Charles Millard, Walter Reed Army Institute of Research, andDr Mark Poli, US Army Medical Research Institute of Infectious Diseases, for their insight and editorialcontributions.634