BISC 307L 2nd Edition Lecture 25 Current Lecture Excitation Contraction Coupling Relaxation This is a magnified portion of a cardiac muscle fiber The T tubular system is not quite as extensive as it is in the skeletal muscle Step 1 The red zone is an action potential in the plasma membrane or sarcolemma of the muscle fiber The inward current of this AP is not only carried by sodium ions but also by calcium ions Step 2 Ca ions coming through voltage gated Ca channels is going to bind to the Ryanodine receptorchannel and open it step 3 So the coupling between 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 triggers filament 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 the sarcoplasm so the concentration falls back down to the original very low levels The mechanism of 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 Contraction Catecholamines 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 relaxation phase 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 Currents Key points The current carried by an ion will be equal to the conductance which is the inverse of the resistance of the membrane for that ion multiplied by the difference between the membrane potential and the equilibrium of the ion Potassium current will always be outward Sodium current will always be inward Action Potential in Cardiac Contractile Cells This is the cardiac muscle action potential Graph of membrane potential on the Y axis and time in milliseconds on the X axis The range of voltages are familiar The time length of the AP is unusual however The AP s of skeletal muscles were 1 or 2 msec s long but these are hundreds 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 of the strong electrochemical gradient inward for sodium What triggers the AP where does the AP come 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 next step should be a direct plummeting dip downwards because of the delayed rectifiers But those don t exist here 2