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York University
BIOL 4510

Now that we have discussed the molecular properties of some key contractile proteins we will now discuss several important functional properties of the contractile system. These properties are very relevant with respects to both normal physiological function of muscle as well as the changes in function that occur in disease. In the document below, the text written in red represents additions made to original notes (i.e. these are the supplements). Contractile Proteins determine the rate of relaxation of force (and pressure) 2+ - As mentioned in previous lectures, a rise in Ca is responsible for the activation of the contractile system. Therefore, it is natural to assume that the relaxation of muscle is also controlled by Ca . However, this is technically only partially true. Although reductions in Ca 2+ are necessary for r2+axation, under normal physiological conditions, the decline in Ca is only permissive for relaxation to occur. In other words, while Ca 2+ must fall for relaxation to occur, the actual speed of relaxation is dictated by the contractile proteins. Even if the Ca 2+ levels were instantaneously reduced to resting diastolic levels, the rate of force (pressure) relaxation would be minimally altered. Evidence for the importance of the contractile proteins is provided by the figure below, which you have seen before. The bottom right panel (B) shows phase 2+ plots of the relationship of force and Ca during the cardiac cycle (the noisy lines) for a muscle. - To follow how the force and Ca 2+change during the cardiac cycle you need to follow these lines (relationships) in the counter-clockwise 2+ direction. The single line shows the steady-state fo2+e-Ca relationship in the same muscle measured by fixing the Ca concentration at various levels and measuring the force (the steady-state data is shown in the left bottom panel). So by going counter-clockwise in the phase- 2+ plots starting wh2+ Ca and force are both low (i.e. near the origin), we see that the Ca rises steeping with little change in force (this represents the release of Ca from the SR before (or while) the Ca 2+ binds to TnC). Once Ca 2+ has bound to TnC, the force rises while the 2+ 2+ Ca a2+ually falls (primarily due to Ca binding to TnC as well as due to SR Ca uptake by the SR). The force then peaks and begins to fall. 1 However, the force-Ca 2+relationship is actually to the left of the steady state relationship, which means that Ca 2+ is not the cause of the fall in force. There is also a lot of other evidence that we will no2+discuss that also supports the conclusion that it is not the fall in Ca that 2+ the primary determinant of force/pressure relaxation: the fall in Ca is permissive. - The speed of relaxation of force is very dependent on the affinity of Ca 2+ binding to the contractile protein which (as will see below) is in turn determined by sarcomere length (high affinity at long sarcomere lengths (sarcomere length = 2.2m, EC = 4050M; sarcomere length = 1.7m, EC =50200nM). Also, the higher the affinity, the greater the cooperativity (also discussed below). - Now why is the Ca 2+ sensitivity so important? Well as I discussed in class, when you increase heart rate (which the primary mechanism for increasing heart rate) you MUST accelerate the rate of force relaxation. The reason for this can be readily appreciated by the following diagram. Elevated HR with changes in systolic duration (+ sym) Elevated HR without changes in systolic duration Normal heart rate pressure 1 second The solid line is showing (very diagrammatically) the pressure changes occurring if the heart rate is 60 beats per minute (1 beat per second). The systolic period is shown to be about 333 milliseconds. Now what would happen if the heart rate tripled (3 beats per second), if there was no change in the systolic period? Well the solid line plus the dashed lines attempts to illustrate this situation. Big problem: there is virtually no diastolic period which means the heart would be beating without pumping blood (because the heart will have no opportunity to fill with blood from the veins). As I said previous in class, when you heart rate changes, the heart is capable of keeping the ratio of the (systolic period)/(diastolic period) at a fairly fixed value (~1/2). For this to occur, the systolic period must be reduced by about 3-fold. Now since the contractile proteins dictate relaxation, it is clear that their relaxation properties must be changed when heart rates are increased. The primary mechanism for the 2 enhanced relaxation properties of the contractile proteins is TnI phosphorylation as discussed next. Regulation of contractile proteins by phosphorylation - four contractile proteins are phosphorylated: cTn-I, Myosin binding protein C, Tn-T, and MLC-2 - the effects of phosphorylation of Myosin binding protein C, cTn-T, and MLC-2 are mentioned in the previous lecture. These effects are of relatively less importance than the phosphorylation of Tn-I by PKA. - Phosphorylation by PKA occurs in N-terminal region of Tn-I; unique to cardiac Tn-I (not found in sTn-I) - Tn-I phosphorylation: phosphorylated by PKA reduces affinity of Ca 2+binding to 2+ 2+ Tn-C by enhancing Ca unbinding rates causes rightwa2+ shift in force-[Ca ] relationship. This means that the concentration of Ca required to produce 50% of the maximal force (i.e. the EC 50goes up). Remember the Ca 2+ binding affinity is the inverse of the Ca 2+dissociation constant which determined by the ratio of 2+ 2+ the rate of unbinding of Ca fr2+ cTn-C divided by the rate of binding of Ca to cTn-C. Because the rate of Ca unbinding from cTn-C goes up, the binding constant for Ca 2+ goes up (i.e. less Ca 2+binds at any Ca 2+ level). PKA phosphorylation of cTn-I also reduces the Ca 2+ cooperativity of force generation 2+ - since contractile proteins, not Ca , controls the maximum speed of force relaxation, it is essential for the contractile system to relax more quickly when the sympathetic system is activated (remember heart rate can go up 3-4 times 2+ during sympathetic stimulation); increased speed of Ca cycling in cytosol (discussed in next lecture) is insufficient for a proper response of the heart to changes in heart rate - by enhancing Ca 2+unbinding rates from contractile proteins pressure and force relaxation is increased with phosphorylation of cTn-I. 3 Effects of beta-adrenergic stimulation (activation of PKA) with isoproterenol (relationship. Notice the large rightward shift in the steady state force-Ca relationship (lower panel) and the enhanced rate of force decline in Panel A. 2+ -Notice that the Ca transient amplitude has incre2+ed along with force when ISO is applied. Thus, even though the Ca sensitivity of the contractile system is decreased, there is a sufficient amount of extra Ca 2+ released into the cytosol to cause a net increase in force (the phosphorylation of other contractile proteins also contributes to the enhanced force). - PKA-dependent phosphorylation of MyBPC and MLC-2 are also critical for ensuring proper responses of the contractile system to increased demand for cardiac output. Both speed up cross-bridge cycling rates. Ca 2+ cooperativity in contraction of cardiac muscle 2+ 2+ - Closely related to Ca affinity and force relaxation is the concept of Ca cooperativity in force generation. I will begin by discussing what cooperativity mean and then come back to its significance 2+ - steady-state force-[Ca ] relationship are characterized/quantified by the Hill equation: 2+ n 2+ n F = force = F max * ( [Ca ] / ([Ca ] + EC ) 50 2+ 2+ where [Ca ] is the free Ca concentration, F m2+ = the maximal force that the muscle can generate at high [Ca ], "n" is the Hill coefficient (= measure of cooperativity), EC 50
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