CSB332 Lecture 8 Notes

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Cell and Systems Biology
Course Code
Francis Bambico

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CSB332 Lecture 8 Slide 2 - An action potential is brought about by the opening of voltage-gated Na+ channels and the opening and closing of K+ channels. An action potential is regenerative because it produces a chain reaction. When a voltage-gated Na+ channel is opened by changes in membrane potential, Na+ ions moves in. As more Na+ ions move into the neuron, the more the neuron gets depolarized. Greater depolarization would eventually open up some more voltage-gated Na+ channels that are sensitive to the depolarization value. - An action potential has four phases. o Initiation is when a threshold membrane potential is achieved Slide 3 - Voltage-gated calcium channel doesn’t do much in a typical mammalian neuron, but it is important in heart functions. - Voltage-gated sodium channel o The pore forming region of the ion channel is formed between S5 and S6. The P-loop is the pore formation region of the ion channel. - Voltage-gated potassium channel o The K+ channel signature sequence is a sequence of amino acids that is different from the sequence in the Na+ channel. Slide 4 - The S4 helix moves/changes/behaves in accordance to changes in membrane potential. It is sensitive to the membrane potential because its amino acid residues are positively charged. The S4 helix is contained in a crevice or orifice in the 3D structure. This provides movement for the S4 helix. If you depolarize the neuron, then the S4 helix would move outwards and closer to the external environment, which results in changes in the conformation of the ion channel. - S4 is connected to the S6 segment. The movement of S4 would change the conformation of the S5 segment, which results in the opening of the gate. - There is a similar arrangement in a voltage-gated sodium channel. Slide 7 - During initiation, the membrane reaches the threshold of excitation and produces an action potential. - The afterhyperpolarization phase is the downward offshoot of membrane potential. During this phase, you will not be able to stimulate the neuron to fire again, called the refractory period. This phase is caused by Ca2+-activated K+ channels. Upon depolarization, Ca2+ influx results in an increase of Ca2+ concentration inside the neuron, which activates K+ channels. - The action potential is a regenerative process because slight changes in the membrane potential will result in the opening of voltage-gated Na+ channels, leading to inward conductance, leading to a progressive increase of membrane potential, leading to more openings of voltage-gated Na+ channels. The more positive the membrane potential, then the more voltage-gated Na+ channels open. Slide 8 - Hodgkin and Huxley discovered the different ionic currents that are responsible for the generation of the action potential using a voltage clamp recording. - Assume that you do not know what currents are responsible for the generation of the action potential. The change in membrane potential that characterizes an action potential is produced by ionic flow. Assume that you do not know what the identities of the ions are that contribute to the characteristic shape of the action potential. - The problem with intracellular recording is that when you stimulate/depolarize the neuron, the current is really fast, so you won’t be able to catch the different currents that contribute to the generation of the action potential. - You have to have a tool to maintain the changes in membrane potential for long periods of time. You have to stabilize the membrane potential of neuron and observe the resulting current because it is difficult to pinpoint which currents are being changed by a certain depolarization step since the action potential is regenerative. o The membrane potential changes according to changes in current flow. You won’t be able to hold a stable membrane potential and examine the current with intracellular recording. You have to clamp/hold the membrane potential for long periods of time to observe the inward and outward flow of current. - The voltage is clamped or held at a certain potential to readily observe the inward and outward flow of current. The command voltage is the voltage that you want to analyze and hold for long periods of time. The amplifier will inject an external current that maintains or clamps the voltage. The current being injected to achieve command voltage is the current that is associated with the command voltage. The injected current is called the compensatory current, which is the current that are you interested in measuring and is associated with Vc. Slide 9 - Hodgkin and Huxley used different pharmacological agents to block different ions in and out of the neuron to identify which current is responsible for which part of the action potential, in combination with voltage clamp recording techniques. - TTX blocks Na+ channels - Saxitoxin blocks Na+ channels - TEA blocks K+ channels - Cocaine blocks Na+ channels (and K+ channel blocker) o Higher affinity for Na+ o Lower affinity for K+ Slide 10 - (B) o The early outward current is transient and very brief. The outward flow is called a capacitive current associated with depolarization. - (C) o Applied TEA, which is a blocker for K+ channels, and prevents inward and outward flow of K+. Observed a change in current. Retained the inward current. Abolished the late current. This tells you that the late current is blocked by a K+ antagonist; therefore the outward current produced in response to depolarization is K+ ions going out of the neuron. - (D) o Added TTX, which is a blocker for Na+ channels. Applied a depolarization step. Abolished the early inward curr
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