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Explain how the kinetics of the Na and K ion channels in the membrane of an excitable cell contribute to the characteristic shape of the action potential. What would be the effect on the action potential of changing the various attributes of the potassium channel?
Our ability to perform any action in life relies on the rapid communication between neurons, in our body (Armstrong et al. 1998).This communication involves an electrical message in the form of an action potential, that occurs when the nerve is stimulated and the information is transmitted accurately without alteration over vast distances (Elmslie 2001). The kintetics of ions and the sequential opening and closing of voltage gated sodium and potassium channels play crucial roles in transmitiing the signal to its destination (Cooper et al 1999).
When a neuron is at rest there is a potential difference across the cell membrane. This is called the membrane potential (Vm).The inside of the cell is negative with respect to the outside of the cell, due to the movement of ions through specific ion channels and the action of sodium/potassium pumps(Ruben. 2001). The potential difference arises as the concentration of ions is different inside of the cell than it is in the extracellular fluid (see Table 1). For example there is a greater concentration of K+ ions inside the cell but the concentration of Na+ is higher on the outside (Elmslie 2001). These variations in ionic concentrations are caused by the Sodium/Potassium pump which transports ions in and out of the cell via active transport against their concentration gradient generating for each ion, an electrical and chemical imbalance (Ruben. 2001). This unequal distribution causes K+ to diffuse back out of the cell along the concentration gradient and through K+ specific protein channels in the cell membrane. An undistributed nerve cell is impermeable to Na+ so these remain outside the cell. This means that the diffusion of K+ out of the cell results in less positive ions in the cytoplasm than in the extracellular fluid, making the inside more negative. This means that the membrane is polarised and because of the steady movement of ions the potential difference remains constant. In an undisturbed neuron there is a membrane potential of approximately -60mV.The electrochemical gradient produces a force that most cells in the body apply to the movement of essential substances across the cell membrane. In excitable cells however, such as nerve and muscle cells it is use it for electrical signalling (Elmslie 2001).
Table 1: Concentrations of different ions inside and outside the mammalian neuron. A- represents represents organic anions that cannot cross the cell membrane, E.g.proteins, amino acids and phosphate ions (adapted from Elmslie 2001)
Outside (mmol L-1)
Inside (mmol L-1)
Both selective membrane permeability and specific concentration gradients are needed in order to initiate an action potential in excitable cells. Depolarisation of the membrane potential to a threshold level which is reached when the volume of Na+ entering the cell is greater than the resting efflux of K+ (Ruben. 2001) Temporal or spatial summation of synaptic inputs made largely on to the neurons dendritic tree leads to the initiation voltage activated Na+ channels (Stuart et al. 1997). When a neuron is stimulated depolarisation occurs across the stimulated region. This activates voltage gated Na+ channels which involves a conformational change in protein that results in a pore which ions can flow through (Ruben. 2001) (see Fig 1). Voltage gated channels are extremely sensitive to tiny changes membrane potential (Armstrong et al. 1998). The opening of the voltage dependent sodium channel and the initial inï¬‚ux of Na1into the cell is that drives the upstroke of the action potential (Elmslie. 2010). Due to the electrochemical gradient caused by the difference in charge inside and outside the cell, the opening of the Na channels causes a swift influx of Na ions into the cell. This means rapid depolarisation occurs in this segment of the axon. There is now more positive ions inside the cell so the transmembrane potential becomes positive, this is the peak of the action potential (see Fig 2). The original depolarizing stimulus is only sufficient to open a small proportion of the sodium channels in the membrane (Ruben. 2001), but the resulting in flux of positive ions into the cell (Na+) further depolarises the membrane causing activation of even more sodium channels (Elmslie. 2010). This is a positive feedback cycle, as more channels open more ions flow into the cell activating additional channels.
Fig 1: Diagram showing the functional regions (A) and the protein folding (B) of the voltage gated channels. When an ion channel is open, the ion can pass through the channel pore and will ï¬‚ow across the membrane.
After about a millisecond the membrane begins to repolarise (Ruben. 2001) This occurs due to the spontaneous inactivation of the Sodium channels, reducing the conductance of Na+ across the cell membrane. Inactivation gating of the channels occurs because a portion of the peptide channels located in the cytoplasm diffuses into the opening of the pore therefore blocking conduction of the ions (Armstrong et al. 1998). The decrease in membrane permeability to Na+ causes a decrease in the membrane potential towards the normal resting potential (Ruben. 200). It is the k+ channels to restore the membrane potential to rest (Armstrong et al 1998). K= concentrations are higher on the inside of the neuron than in the extracellular ï¬‚uid (Elmslie. 2010), but at threshold the driving force on potassium ions is small but due to the electrochemical gradient it increases near peak of action potential. To repolarize the membrane, the potassium eï¬„ux must exceed the sodium inï¬‚ux. The efflux is mediated by the activity of both voltage-independent and voltage-dependent potassium channels. Voltage-dependant K+ channels are activated, although much slower than the sodium channels, further increasing the conductance of K+, driving the membrane potential towards lower voltages, hence contributing to the falling phase of the action potential (see Fig 2) (Elmslie 2010).
Fig 2: Ionic basis of the action potential. The first trace shows the voltage recording during an action potential, showing threshold level the membrane potential (Vrest), the rising and falling phases and the refactory period. The other two traces shows the conductance of the Na+ and K+ across the cell membrane on the same time course of the action potential, The steeper more narrow peak on the Na+ trace indicates that the Na+ channels are activated and inactivated much more rapidly than the K+ channels. (Figure adapted from Ruben. 2001)
K+ channels are activated and inactivated much more slowly than the Na+ channels, this delay leads to hyperpolarisation of the membrane (Ruben. 2001) (see Fig 2) At this point there is little sodium permeability and the movement of Na+ ions returns to that of rest. This combined with the increased movement of K+ ions out of the cell means that the membrane potential is driven even lower than the resting level). This is the refactory period and is characterised by an increases in the threshold for action potential generation (Elmslie. 2010). As the K+ channels inactivate, the membrane potential returns to resting.. (Ruben. 2001)
Mutations of the potassium channels could interfere with the repolarising current of the K+ ions. (Zuberi et al 1999, cited in Rayan et al 2010) Waters et al (2005) investigated mutations in the KCNC3 gene that codes for voltage gated potassium channels. Two mutations they found resulted in changes in the amino acid sequences that code for the S4 and S5 subunits of the potassium channel (see Fig 3).They identified KCNC3 mutations as causative of phenotypes ranging from developmental disorders to late-onset neurodegenerative disease. (Waters et al 2006). A mutation of the channel could change the rate in which it activates and inactivates. If for example the channel activates more quickly the cell membrane could begin repolarising before the action potential has reached its peak. This would weaken the electrical signal and could reduce the likelihood of propagation. The mutation could also affect the voltage dependent activity of the channel or the number of function channels (Rayan et al 2010,). If the activity of potassium channels in the membrane of the neuron were to be reduced then repolarisation of the action potential would be delayed and the amount of excitation needed to reach threshold and produce an action potential would be lowered (Cooper et al 1999).
Fig 3: The structure of a voltage-gated potassium channel. Six transmembrane .Segments S1-S4 form the voltage sensor domain. Positively charged arginine residues in S4 detect changes in voltage. Segments S5 and S6 and the re-entrant loop form the ion-selective pore. S5 forms the pore outer helix and functions to couple voltage sensor conformational changes with pore opening and closing. (Figure adapted from Waters et al 2006)
Carrying out any cognitive or motor task requires the firing of action potentials (Stuart et al. 1997) and it's the strict regulation of the transmembrane movement of K= and Na+ and the critical timing involved in the activation and inactivation of their respective ion channels that shapes the action potential. Any mutation or disease affecting the attributes of the ion channels involved in the formation of the action potential could be catastrophic to humans and recent studies have linked channel mutations to ataxia and more recently, diseases such as epilepsy (Rayan et al 2010).