Action Potentials PDF

Medical Neurosciences ACTION POTENTIALS KEY WORDS AND CONCEPTS: 1. The action potential (AP) and the ionic mechanisms involved; how Na+ and K+ contribute to the AP 2. The membrane viewed as an “equivalent circuit” 3. How the passive membrane properties EMF, R and C contribute to AP production and...

Medical Neurosciences ACTION POTENTIALS KEY WORDS AND CONCEPTS: 1. The action potential (AP) and the ionic mechanisms involved; how Na+ and K+ contribute to the AP 2. The membrane viewed as an “equivalent circuit” 3. How the passive membrane properties EMF, R and C contribute to AP production and characteristics 4. How the characteristics of voltage-gated Na+ and K+ channels influence the shape of the AP 5. The ionic basis and significance of threshold and accommodation and their role in excitability 6. To understand the refractory period and the transient period of hyperpolarization after the AP IONIC BASIS OF THE ACTION POTENTIAL A typical AP recorded from a neuron by an intracellular microelectrode measuring transmembrane voltage is shown in PPT 2-2 and 2-3 (red traces). APs are initiated when the depolarizing stimulus brings the membrane potential to a special value referred to as threshold (#3 in PPT 2-3). Depolarizing stimuli which do not depolarize the membrane to threshold will not evoke an AP. Stimuli greater than threshold strength do not produce additional increases in AP amplitude; i.e. the AP is an "all or none" phenomenon. Depolarizing stimuli include propagating APs, neurotransmitter-induced depolarization (an excitatory post-synaptic potential), or a sensory potential in response to some stimulus (e.g. mechanical, electrical, osmotic, temperature change). The regenerating portion of the AP begins after threshold (#4 in 2-3). After the depolarization phase is a repolarization phase (#6 in PPT 2-3) that returns the transmembrane voltage to the resting membrane potential, near EK. Typically, the depolarization phase lasts less than 1 msec and the repolarization phase 1-2 msec. A slight hyperpolarization beyond resting membrane potential is typical of many neurons (#8 in PPT 2-3). A sudden, sequential increase in membrane permeability to Na+ and then to K+ ions underlies the AP. Depolarizing stimuli cause the membrane to become more permeable to Na+ (voltage sensitive Na+ channels open) leading to Na+ influx. This causes the depolarization phase of the AP. However, the influence of ENa+ lasts for a very short time (less than 1 msec) because 1) the enhanced permeability of the membrane to Na+ is very transient and 2) the permeability of the membrane to K+ increases as the slower-to-respond K+-channels open and allow K+ to leave. The latter re-establishes the dominance of EK in determining membrane potential and repolarizes the cell to its resting level. Thus, the membrane depolarizes towards ENa+ and then a short time later it repolarizes towards EK+. Threshold (Vth) is the membrane potential at which the inward Na+ current (increased by the depolarization) just exceeds the outward K+ current (primarily through passive channels). When Na+ ions cross the membrane unbalanced by K+ ions going out, net positive charge is deposited on the inside of the membrane and the membrane is additionally depolarized. This slight depolarization stimulates more Na+ channels to open. This leads to more inward Na+ current, more depolarization, more open Na+ channels, more inward current, more depolarization, etc. in a rapid regenerative cycle that drives the membrane potential towards ENa+. Note from PPT 2-2 that the increase in Na+ current lasts for only a very short period of time, it actually begins to decline at or before the peak of the AP (Vpeak). What accounts for this decrease in Na+ current? Recall that channel type C (the Na+ channel) has an inactivation gate that shifts into an occluding position across the pore a short time after the channel opens. Thus the Na+ channels only stay open for a short period of time and, therefore, the enhanced permeability of the membrane to Na+ is only transient. Note in particular the evidence presented for the involvement of voltage-dependent Na+ and K+ channels using the toxins TTX (tetrodotoxin) and TEA (tetraethylammonium) that specifically block the Na+ (TTX) and K+ (TEA) channels. Given that Cl- channels are open at the resting potential (in most cells) and during the AP. Will Cl- ions have any effect on the AP, and if so, what would the effect be? Hint: remember that ECl is at the resting membrane potential in many neurons because this ion distributes passively in most cells. PASSIVE MEMBRANE PROPERTIES AND THE EQUIVALENT CIRCUIT PPT 2-4 shows the membrane as an equivalent circuit, illustrating the passive membrane properties of electromotive force (EMF), resistance (R) and capacitance (C), using the traditional symbols in circuit design. In this case the EMF is shown as batteries in opposite directions representing the electrochemical driving forces on Na+ (inward) and K+ (outward), with in-line resistors representing the total membrane resistance for each ion species. We can use the equivalent circuit to describe an action potential as first a transient decrease in resistance in the Na+ arm of the parallel circuits followed by a transient decrease in resistance of the K+ arm of the circuit. The membrane acts as a capacitor and stores charge to be “given back” following each change in membrane potential (see PPT 2-8). THRESHOLD, ACCOMMODATION, AND REFRACTORY PERIOD PPTs 2-7 to 2-12 provide a series of examples to illustrate threshold and accommodation. In each example, charge (current) is being injected into a neuron via a glass micropipette that has been inserted through the membrane. The glass pipette is like having an insulated wire pushed through the membrane; it can accurately measure the potential difference across the membrane (comparing the inside to the outside of the cell) and can allow the introduction of charge or current into the cell. PPT 2-7 shows the basic set-up that will be used in the other slides, and PPT 2-8 shows what happens when current is injected into a cell, including a change in membrane potential and storage of charge on the membrane acting as a capacitor. Threshold potential is not a fixed, unchanging value. Since threshold occurs at the voltage when inward Na+ current just overcomes the outward K+ current, the threshold voltage is affected by anything that alters the magnitudes of these currents. For example, threshold is moved toward resting membrane potential in cases of Ca2+-deficiency because Na+ channels become more sensitive to voltage changes (we don’t really understand why, we just know that they do). More channels will open for a given depolarizing stimulus, the Na+ current will be larger and it will be easier to overcome the resting K+ current. In contrast, if the depolarization towards threshold is slow, it gives the voltage sensitive K+ channels an opportunity to open and counteract the increasing Na+ current. Thus, the threshold potential is increased (less negative) and a greater change in voltage (depolarization) is required to generate an action potential. This comes about, at least in part, by the fact that the slow depolarization results in some Na+ channels entering, and remaining in the inactivated state. If the depolarization is very slow, it can prevent the Na+ current from ever overcoming the K+ current and an AP will not fire. These two examples involve a process referred to as accommodation. It arises when significant numbers of Na+ channels become inactivated and the overall sensitivity of the neuron to depolarization (its excitability) is decreased. By definition, this also means that the threshold has changed, as shown in PPTs 2-11 and 2-12. The refractory period (PPT 4-16) is the time following an AP during which a neuron will not fire another AP. During the absolute (effective) refractory period a neuron will not fire an AP regardless of the stimulation strength because there has not yet been sufficient time for reactivation of Na+ channels so little inward current can be produced. During the relative refractory period an AP may be evoked (some of the Na+ channels have reactivated), however, a stimulus of increased strength is required because the permeability of the membrane to K+ is still high and more depolarization is required to activate the increased number of Na+ channels required in the face of the enhanced K+ current.