Excitation Contraction

Excitation-Contraction Coupling

Presented by Ahmed Amr Darwish (72)

Organization of Cardiac Cells •A cardiac cell is composed of many contractile units called sarcomeres •Each myocyte is separated by intercalated discs which provide a low resistance junction •Each sarcomere is bounded by 2 zlines

Action Potential to Excitation-Contraction Coupling CICR

L-type Ca+2 channel

Calcium removal by Na/Ca exchanger

Calcium movement from uptake to release site

Calcium uptake by SERCA Force production

http://cvphysiology.com/Arrhythmias/A006.htm

Pictorial E-C Coupling Na+

Sarcolemma

Ca++

Na+ + Na

Na+/Ca++ Exchanger L-Type Ca Channel

++

Ca++

SERCA Ca++ ++ ++ Ca++Ca Ca++ Ca Ca++ ++ Ca++ ++ Ca ++ ++ Ca Ca++ Ca Ca ++Ca++ Ca++ Ca Ca++Ca++ Ca ++ SR RyR Ca++ Ca++Ca++ ++ ++ Ca Ca Ca ++ ++

Ca Ca++

Ca + + Ca + C ++ + a+ C+a + Ca ++ + + + Ca Ca

Ca ++

Ca++

Ca++

Ca ++ Ca ++ C Ca ++ a ++

Ca

++

Ca++ Ca++ Ca++

Plb

Ca++

Ca++

Ca + Ca ++

Ca++ Ca++ +

a+ ++ + C Ca ++ + Ca a+ C ++ Ca

Calcium Induced Calcium Release (CICR)

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Intracellular [Ca] 10-7 to 10-5 M

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Ca++ enters the cell through L-type calcium channels

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Ca++ stimulates Ca++ release from the SR via RyR

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Ca++ interacts with contractile proteins to initiate shortening of the myocyte

Calcium and Force Production

Ca++ binds to TN-C on thin filaments TN-I exposes site on actin which can bind to myosin head ATP hydrolysis supplies energy for actin-myosin conformational change ‘Ratcheting’ of actin-myosin and shortening of the sarcomere occurs Ca++ dissociates from TN-C and myosin unbinds from actin with energy from ATP

SR Calcium Uptake

Phospholamban

SR removes Ca++ through an ATP dependent pump (SERCA) Disinhibition of phospholamban increases the rate of calcium uptake Cytosolic Ca++ decreases and Ca++ is removed from TN-C Excess Ca++ is removed from the cell by other processes

Abnormalities in E-C Coupling 

CICR – Ion Channels – Channels operate differently and conductances change, possibly due to the effect of heart failure on membrane characteristics – Less Ca++ may move across membrane during each AP

Abnormalities in E-C Coupling 

CICR - SR – The RyR channel undergoes changes and calcium leaks out. – SR contains less calcium for release during each AP.

Abnormalities in E-C Coupling 

Phospholamban – Plb protein levels increase due the continued stimulation by the sympathetic nervous system. – SERCA2 protein levels decrease – This will lead to elevated diastolic calcium levels

Overview of E-C Coupling Changes in the Failing Heart :Regulation of Intracellular Calcium 1. Reduced Ca++ trigger thru L-type channel

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2. Reduced RyR function (Calcium leaks from SR) 3. Decreased sensitivity of TN-C to Ca++

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4. Reduced Ca++ uptake due to loss of SERCA function and increased Plb 5. Increased Na/Ca exchanger function

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