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BIOL 4510
Peter Backxx

Now that we have discussed the molecular properties of some key contractile proteins we will now discuss several important functional properties of the contractile systemThese 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 ie 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 2that the relaxation of muscle is also controlled by Ca However this is 2technically only partially true Although reductions in Ca are necessary for relaxation under normal physiological conditions the 2decline in Ca 2words while Ca must fall for relaxation to occur the actual speed of 2relaxation is dictated by the contractile proteins Even if the Ca levels were instantaneously reduced to resting diastolic levels the rate of force pressure relaxation would be minimally alteredEvidence 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 Caduring the cardiac cycle the noisy lines for a muscle 2 To follow how the force and Ca change during the cardiac cycle you need to follow these lines relationships in the counterclockwise 2directionThe single line shows the steadystate forceCa relationship 2in the same muscle measured by fixing the Ca concentration at various levels and measuring the force the steadystate data is shown in the left bottom panel So by going counterclockwise in the phase2plots starting when Ca and force are both low ie near the origin we 2see that the Ca rises steeping with little change in force this 22represents the release of Cafrom the SR before or while the Ca 2binds to TnC Once Ca has bound to TnC the force rises while the 22Ca actually falls primarily due to Ca binding to TnC as well as due to 2SR Ca uptake by the SR The force then peaks and begins to fall1 2However the forceCa relationship is actually to the left of the steady 2state relationship which means that Ca is not the cause of the fall in force There is also a lot of other evidence that we will not discuss that 2also supports the conclusion that it is not the fall in Ca that is the 2primary determinant of forcepressure relaxation the fall in Ca is permissive 2 The speed of relaxation of force is very dependent on the affinity of Ca binding to the contractile protein which as will see below is in turn determined by sarcomere length high affinity at long sarcomere lengths sarcomere length22m EC 400nM sarcomere length17m 50EC 1200nM Also the higher the affinity the greater the cooperativity 50also discussed below2 Now why is the Ca 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 durationsym Elevated HR without changes in systolic durationNormal 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 situationBig 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 perioddiastolic period at a fairly fixed value 12 For this to occur the systolic period must be reduced by about 3fold Now since the contractile proteins dictate relaxation it is clear that their relaxation properties must be changed when heart rates are increasedThe primary mechanism for the2 enhanced relaxation properties of the contractile proteins is TnI phosphorylation as discussed nextRegulation of contractile proteins by phosphorylationfour contractile proteins are phosphorylated cTnI Myosin binding protein C TnT and MLC2the effects of phosphorylation of Myosin binding protein C cTnT and MLC2 are mentioned in the previous lecture These effects are of relatively less importance than the phosphorylation of TnI by PKA Phosphorylation by PKA occurs in Nterminal region of TnI unique to cardiac TnI not found in sTnI 2TnI phosphorylation phosphorylated by PKA reduces affinity of Ca binding to 22TnC by enhancing Ca unbinding rates causes rightward shift in forceCa 2relationship This means that the concentration of Ca required to produce 50 2of the maximal force ie the EC goes up Remember the Ca binding affinity 502is the inverse of the Ca dissociation constant which determined by the ratio of 22the rate of unbinding of Ca from cTnC divided by the rate of binding of Ca to 2cTnC Because the rate of Ca unbinding from cTnC goes up the binding 222constant for Ca goes up ie less Ca binds at any Ca level PKA 2phosphorylation of cTnI also reduces the Ca cooperativity of force generation2 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 34 times 2during 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 2 by enhancing Ca unbinding rates from contractile proteins pressure and force relaxation is increased with phosphorylation of cTnI3
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