BISC 307L 2nd Edition Lecture 25 Current LectureExcitation-Contraction Coupling & RelaxationThis is a magnified portionof a cardiac muscle fiber.The T-tubular system is notquite as extensive as it is inthe skeletal muscle. Step 1: The red zone is anaction potential in theplasma membrane, orsarcolemma, of the musclefiber. The inward currentof this AP is not onlycarried by sodium ions butalso by calcium ions. Step 2: Ca ions comingthrough voltage gated Cachannels is going to bindto the Ryanodine receptor-channel and open it(step3). So the couplingbetween membrane depolarization and opening of the ryanodine receptor is not mechanical like in skeletal muscles, but it’s actually Ca ions acting as secondary messengers. Step 4: Ca ions that previously were sequestered in the SR are released. That calcium triggers contraction. Step 5: Calcium from other sources contributes to the increase in intracellular Ca, which triggersfilament sliding in the same way it would in skeletal muscles (binding to troponin, tropomyosin moves out of the way, cross bridge cycling, etc.). How much of the Ca that causes contraction comes out of the SR and how much comes out of the plasma membrane? About a 90/10 ratio, respectively. So everything happening on the left is what triggers contraction and couples excitation to contraction. On the right side of the figure is what triggers relaxation – removal of Ca from thesarcoplasm, so the concentration falls back down to the original very low levels. The mechanismof removal of Ca is the same as in skeletal muscles. Ca pumps in the membrane of the sarcoplasmic reticulum (step 8) resequesters the Ca. But there is an additional secondary mechanism, a Ca/3 Na antiport at the top(step 9), which couples the extrusion of Ca against the concentration gradient to the inward movement of 3 Na ions in the direction of its gradient. The Na that would otherwise accumulate inside is pumped out by Na/K pump. (step 10)Catecholamine Modulation of ContractionCatecholamines (norepi and epi) are part of the sympathetic response. They will increase cardiac output, the amount of blood the heart pumps out per unit time. The scheme below explains how a catecholamine binding to an adrenergic receptor results in a more forceful contraction and greater stroke volume. Increasing both of those is an important way in which epi and norepi increase cardiac output and blood pressure.Starting from the top. Catecholamines bind to beta 1 receptors in the plasma membrane of cardiac muscle fibers. This activates a cAMP mediated phosphorylation, a kinase A phosphorylation of two important target proteins inside the skeletal muscle. -First, are the voltage gated Ca channels in the membrane, which get phosphorylated on the cytoplasmic side, resulting in an increase in the mean open time of the channels.That increase in channel open time increases Ca entry into the cell, which 1.) gets sequestered into the SR and builds up calcium stores there and 2.) acts as the signal that triggers the release of Ca from the SR. This produces a bigger increase in Ca for a given cardiac AP and that results in more forceful contraction. -The second target of the phosphorylation is a regulatory protein on the right hand side called Phospholamban. Phospholamban is a protein that regulates the activity of the Ca ATPase in the membrane of the SR. Dephosphorylated phospholamban acts to inhibit the Ca ATPase in the membrane of the SR. Phosphorylated phospholamban does not. There is a normal baseline level of dephosphorylated phospholamban in the cell, so the appearance of epi or norepi and their phosphorylation will remove the inhibition from the SR Ca pumps. That stimulation of the Ca pump will have two effects: 1.) build up Ca stores as the pump sequesters more Ca which results in more Ca being released and a more forceful contraction and 2.) remove Ca from the cytosol faster which shortens the Ca-troponin binding time (it is Ca binding to Troponin that triggers contraction) which will result in a shorter contraction and longer relaxation phase of the cardiac cycle. Why? That longer relaxationphase is going to result in a greater End Diastolic Value. Relaxation of the heart is diastole, when the heart is filling with blood. The pressure in the veins that drain to the heart are very low, so it takes time for the blood to fill the heart. The longer relaxation phase results in greater filling such that at the end of diastole, its volume is greater. That results in a greater stroke volume because if there is more blood in the heart, it can pump out more blood. Refresher on Ionic CurrentsKey points: -The current carried by an ionwill be equal to theconductance, which is theinverse of the resistance of themembrane for that ion,multiplied by the differencebetween the membranepotential and the equilibriumof the ion. -Potassium current will alwaysbe outward. -Sodium current will always be inward.Action Potential in Cardiac Contractile Cells This is the cardiac muscleaction potential. Graph ofmembrane potential on the Yaxis and time in milliseconds onthe X axis. The range of voltages arefamiliar. The time length of theAP is unusual, however. TheAP’s of skeletal muscles were 1or 2 msec’s long, but these arehundreds of msec’s. It is due to the action of voltage gated ion channels, and the main players are shown on the left. The vg-Na, vg-Ca, and vg-K channel. This potassium channel is unique – it is called the voltage gated inward potassium rectifier. It is open at negative potentials, and closes when you depolarize. It is the opposite of what we are used to. There is no delayed rectifier, the one that is responsible for the action potential of the nerves (it opens during hyperpolarization to bring the AP down more quickly). The initial rising phase is due to influx of sodium through its channel. And it rises fast because ofthe strong electrochemical gradient inward for sodium. What triggers the AP/where does the APcome from? It comes from the adjacent cardiac muscle fiber, which just underwent an AP, and its currents are spreading ahead and out of it through gap junctions, causing the sodium channels to open and depolarize.4: Is the most negative the cell gets. It is the cell’s resting potential. It is just before the action potential occurs. 0: Maximum sodium current is depolarizing the cell. 1: These sodium channels begin deactivating – membrane potential stops going up. In other AP’s that we’ve studied, the