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USC BISC 307L - Muscle Figs
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BISC 307L 2nd Edition Lecture 12 Current LectureExcitation – Contraction CouplingIn the top right of the figure below in blue is the smooth ER of the muscle fiber, known as the sarcoplasmic reticulum(SR). Organelles in a skeletal muscle fiber have the sarco prefix – in a skeletal muscle fiber the sarcoplasm is the cytoplasm, and the sarcolemma is the plasma membrane. Also shown are the yellow transverse tubule rings that circle where the Z disks are. And the SR wraps the myofibril in between the t-tubules. This structure repeats down the length of the muscle fiber.An action potential going down themuscle fiber works and spreads thesame way as a typicalunmyelinated axon, but with onedifference - it spreads down bothdirections but it also spreads INTOthe fiber through the t-tubulesystem.The t-tubules, which branchthrough the whole fiber and formring-like membranous structuretubules, are continuous with the ECF. They are transversely oriented, regularly spaced (one per sarcomere), and they extend in a ring around the myofibril. If you magnified it, you would see the picture on the bottom left. Flanking the t-tubule on either side are the membranous sacks ofthe SR. An action potential that is going down the muscle fiber is able to spread into the t-tubular system because around the opening of each t-tubule are high concentrations of voltage gated Na channels, which act as current amplifiers that allow Na into the tubule, depolarizing it. If we zoom in even further on the connection between the t-tubule and the SR, we get the box on the right hand side. Recognize that a membrane potential exists across the membrane of the t-tubule - because the lumen is continuous with the outside, the membrane is polarized with the membrane potential, so the inside is negative with respect to the outside.In the t-tubular membrane there is a protein called the dihydropyridine receptor (called this because dihydropyridine is the class of drugs that is used to block this system). This receptor is avoltage sensing protein, but not a channel. This receptor is connected to a Ca releasing channel(called the ryanodine receptor) through the dotted line, which are proteins that serve asmechanical linkages between the voltage sensing dihydropyridine receptor on the left, and the Ca channel on the right. It undergoes a conformational change when the t-tubular membrane is depolarized, and the links pull and push and cause the Ca channel on the right to open. Becausethis channel is gated by mechanical forces transmitted by links from the voltage sensitive dihydropyridine receptor, it is said to be mechanically(not voltage) gated, and voltage sensitive. Now, muscle fiber contractions are triggered by internal Ca concentration. And at rest, Ca concentration is low enough that there are no contractions. This low internal Ca concentration ismaintained by a Ca ATPase in the SR membrane, a uniport that takes Ca out of the cytoplasm and pumps I into the lumen of the SR. The Ca held inside the lumen of the SR, is not free, but is bound so that the pump isn’t working across a gigantic Ca gradient. These Ca ATPases in the smooth ER membrane of all cells are largely responsible for maintaining the low cytoplasmic Ca concentrations that all cells have, by hiding the Ca in the lumen of the SR. But now, when the SR ryanodine Ca channels open, there is an electrochemical gradient for Ca to go out into the cytoplasm, raising intracellular calcium concentration, allowing crossbridge cycling, and consequently, contractions to happen. This continues until Ca is sequestered again. Ca levels need to rise about 100x to activate contraction. Random tangent by Herrera: The total capacitance of a muscle fiber is way higher than that of an axon. Total amount of membrane between inside and outside of a cell is way higher in a muscle fiber because of all the internal membranes.How Calcium triggers contractionTropomyosin is the long grey protein surrounding the actin, and troponin is the brown kidney shaped protein. Troponin has a Ca binding protein, and at a Ca conc. of 10^-8 M or below, Ca is NOT bound to TN, and tropomoyosin is in the position shown, where it is blocking the binding site on G-actin for myosin. In this state, very few of the cross bridges are attached and the muscle is free to relax. But when Ca rises 10-100x, there is sufficient Ca to bind to troponin, and the resulting conformational change causes tropomyosin to shift and uncover the binding site on actin to which cross bridges can bind. And this cycle can continue as long as binding is permitted. Muscles are characterized by how fast force builds up and decays, due to one AP. -The rate at which force builds up during a twitch is a function of the ATPase activity of myosin. Muscle cells carry several different genes for myosin that code for different isoforms of final proteins, each different in a number of properties, including ATPase activity. Which gene gets expressed and what mixture of different myosin is made is different in different organs and individuals and in different developmental stages. -The rate at which force falls off is determined by how fast Ca is resequestered, and that is a function of the number and activity of Ca pumps in the SR. So these two processes – ATPase activity and Ca pumping – determines the duration of the twitch. Force Length RelationshipExperimentation on musclefollows the same principle:pass a current through awhole organ, enough for oneAP, and see how it behaves. However, muscles not onlygenerate force, but they alsoshorten. It is better to look atthese variables separatelybecause they can be exclusive.For example, it is possible totry to pick something up but be too weak – in this case, force would be generated but length wouldn’t change. This would be called an isometric contraction, and it is shown in the experiment pictured above.Simply fix a muscle at a certain length, stimulate it, and see what force it generates. Thenstretch it a little(but keep it fixed), stimulate it, and record again. What you find as you stretch it more and more, is that the force generated gets weaker. If you fix it at a shorter length, force falls off as well. Recording the data creates a U shaped curve between force and length. This canbe understood to be a function of the extent of overlap between thick and thin filaments. L0, thelength at which you get maximum force, occurs when the muscle has optimal overlap between filaments. As


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