Phys: Calcium Regulation Of Cardiac Performance

Front 1

What are the series of events in the external Calcium cycle?

Back 1

Ca enters T-tubules from the external cellular fluid (ECF) and is pumped into the cytosol
via L-type Ca channel. Calcium leaves the ECF via: 1) the plasma membrane calcium pump and 2) the Na/Ca exchanger

Front 2

What are the 3 pumps on the plasma membrane in cardiac myocytes and their basic characteristics?

Back 2

PMCA (plasma mem Ca pump)-
calcium pump (ATP req) has high affinity but low capacity.
Na/Ca exchanger (no ATP, due to Na gradient), moves out most of the Ca
Na/K pump (atp)
All are involved ultimately in getting the Ca out of the cytosol (Na/K indirectly)

Front 3

What are the series of events in the internal Calcium cycle?

Back 3

Ca enters cytosol from the SR via the SR Calcium release channel. Ca returns to SR via SarcoEndoplasmic Reticulum Ca-activated ATPase pump (SERCA2a) and diffuses back through SR towards release channel.

Front 4

What are the characteristics of the components of the internal Calcium cycle?

Back 4

Serca2a is an ATPase pump and is regulated by phospholamban.
Calsequestrin binds Ca, preventing it from leaving the SR.
The small amount of Ca from extracellular space causes a large Calcium release from the SR.
Calcium release channel

Front 5

What are the detailed characteristics of the L-type Ca Channels?

Back 5

Electrical, carries a depolarizing inward CA current in from T-tubule.
Provides small amt of Calcium to activate the contractile proteins (5% of activity)
Provides Ca to activate/open the intracellular Ca release channel (most important role)
Provides source of Ca to be retained in the SR, which augments the Ca release in subsequent contractions.

Front 6

What are the detailed characteristics of the Plasma membrane Ca pump (PMCA)?

Back 6

Plasma membrane Ca pump does active (ATP) transport of Ca out of the cytosol. It has high affinity, but low Ca capacity.

Front 7

What are the detailed characteristics of the Na/Ca exchanger (NCX)?

Back 7

The NCX does active transport of Ca out of the cell (against Ca gradient) but requires no ATP b/c of favorable Na gradient created by Na/K pump. ATP regulates the pump, has a high capacity.
Pump is electrogenic (carries current) b/c 3 Na+ enter the cytosol for on Ca++. The net inward current helps depolarize the cell ** can lead to clinical arrhythmias and sudden cardiac death.

Front 8

What are the detailed characteristics of the Na/K pump?

Back 8

Active transport of 3 Na out of cell (against conc. gradient) in exchange for 2K+, so generates a small REpolarizing curent, to maintain resting potential. Helps to assist NaCa exchanger move Ca out of cytosol.

Front 9

What are the detailed characteristics of the SR Ca release channels (ryanodine receptors/feet)?

Back 9

Opened by Ca entering cytoplasm from Ttube via L-type Ca channels. So, its a Ca-triggered Ca release.

Front 10

What does troponin C do?

Back 10

Receptor for Ca in the contractile proteins. Binds to Ca to initiate muscle contraction.

Front 11

What are the characteristics of the Sarcoplasmic Reticulum Ca pump ?

Back 11

ATP-dependent, pumps Ca against conc. gradient into the SR. Regulated by phospholamban, a substrate for cAMP--dependent protein kinase (PK-A)

Front 12

How does phopholamban (PL) regulate SERCA?

Back 12

when PL is phosphorylated by protein kinase A in response to sympathetic stimulation, it accelerates the Ca uptake into the SR by SERCA. Overall, you get a faster, more complete relaxation of the muscle. Also, the Ca stores in the SR increase, so more Ca released in subsequent contractions.
When PL is dephosphorylated, the basal state, it slows the Ca upstake into the SR by SERCA, reducing the rate and extent of relaxtion. Ca stores in SR are reduced, to less Ca released in subsequent contractions.

Front 13

What is the role of Calsequestrin?

Back 13

Like other SR Ca binding proteins, it stores Ca within the SR.

Front 14

What is the role of mitochondria in the intracellular cycle of cardiac myocyte contraction?

Back 14

Regenerates ATP needed for various processes, Mitoch can also take up Ca if there is cystolic Ca overload.

Front 15

Describe sarcomeres, A bands, I bands, titan and cross bridges.

Back 15

Sarcomeres like between two Z lines and contain one A band and two half I bands. Striations are created by distribution of thick and thin filaments.
A bands are darker, wider, and are rows of aligned thick filaments.
I bands are lighter, less wide, and are made up of thin filaments.

Cross bridges project from thick filaments (myosin) and interact with thin filaments.

Front 16

What is/are titan and cross bridges?

Back 16

Titan is a large protein that regulates growth of the heart, its not involved in contraction.
Cross bridges project from thick filaments and interact with thin filaments.

Front 17

How do cross bridges function?

Back 17

In resting muscle, cross bridge are at right angles to thick filaments, but they are not bound to thin filaments. In active muscles, the cross bridges Row/crank the thin filaments towards the center of the sarcomere using ATP as an energy source.

Front 18

Describe the sarcomere lengths normally found in the heart.

Back 18

The heart normally operates at sarcomere lengths where the thin filaments from opposite sides of the sarcomere cross meet or cross (“double overlap”) .
(Heart muscle doesn’t overstretch like skeletal can.)

Front 19

Describe the myosin protein.

Back 19

A “tadpole-shaped” macromolecule found in thick filaments where the “backbone” contains the “tails” and paired “heads” project as the cross-bridges.Made up of 2 heavy chains and 2 pairs of light chains.
Heavy chains hydrolyze ATP (myosin is an ATPase), which provides energy for cross-bridge motion, and interact with actin in thin filaments.
Light chains serve regulatory functions.

Front 20

Describe the actin protein.

Back 20

: A globular protein organized in two strands that make up the backbone of the thin filament. Interacts with and activates myosin to effect muscle contraction.

Front 21

What are the regulatory proteins for muscle contraction?

Back 21

Tropomyosin, Troponin C, Troponin I, And Troponin T

Front 22

Describe role of Tropomyosin

Back 22

Tropomyosin (TM): A rigid elongated protein that lies in the groove between the two actin strands in the thin filament.

Front 23

Describe role of Troponin I

Back 23

Troponin I (TN-I): When troponin C is not bound to Ca, troponin I inhibits actin-myosin interactions

Front 24

Describe role of Troponin C

Back 24

An intracellular high-affinity E-F hand Ca binding protein. When TN-C is not bound to Ca, active sites on actin that interact with myosin cross-bridges are blocked by the regulatory proteins. Binding of Ca to TN-C activates contraction by allowing active sites on actin to interact with myosin.

Front 25

Describe role of Troponin T

Back 25

Troponin T (TN-T): Binds tropomyosin, troponin C and troponin I to thin filament

Front 26

How does calcium control contraction and relaxation?

Back 26

Binding of Ca to TN-C causes the rearrangment the Troponin I, T, and tropomysosin proteins, whcih move out of active site on actin. Then the active sites on actin can interact with myosin.

Front 27

Define preload and afterload in regards to skeletal muscle.

Back 27

Preload: Load supported by the muscle before the latter contracts (pre-contraction)
Afterload: Load encountered by the muscle only after contraction begins

Front 28

Define preload and afterload in regards to cardiac muscles.

Back 28

Preload is related to the end-diastolic pressure (resting pressure) at which the ventricle fills; afterload is related to the systolic pressure when the ventricle ejects.

Front 29

Describe how max afterload effects how a muscle performs work.

Back 29

When there is maximal afterload, you get an isometric contraction, max force is created by actin/myosin interactions, but muscle cannot shorten.

Front 30

Describe how zero afterload effects how a muscle performs work.

Back 30

When there is zero afterload, the cross-bridge can cycle at max rate, that is, as fast as myosin ATPase can go.

Front 31

Describe how increasing afterload effects muscle efficiency. How is this applied to patients with CHD (coronary heart disease) and/or heart failure.

Back 31

Afterload determines effecieny, as it increases, more energy is used as internal work (to stretch internal elasticities as the muscle contracts). So energy is expended for internal work, and is lost as heat when the muscle relaxes, reducing efficiency.
Drugs that reduce afterload (vasodilators) increase cardiac effec and so have an energy sparing effect that can be useful in patients with CAD and/or heart failure.

Front 32

What determines maximal force when afterload is high?

Back 32

Its proportional to the number of actin sites that interact with myosin cross-bridges. Determined in part by the amount of Ca bound to TN-C.

Front 33

What determines the maximal shortening velocity at zero afterload?

Back 33

The cross-bridge turnover rate, and is determined by myosin heavy chain isoform. It is independent of the number of active sites.

Front 34

What is muscle length determined by?

Back 34

Muscle length is determined by the preload that stretches the resting muscle before it begins to contract (tension).

Front 35

Describe cardiac muscle in relation to resting tension.

Back 35

Cardiac muscle has a low compliance (high stiffness) so that as length increases,
resting tension rises rapidly.

Front 36

At what lengths do cardiac muscle and skeletal muscle normally contract?

Back 36

Near the rest lengths near where tension is maximum.

Front 37

Why must the heart operate on the ascending limb of its length-tension curve?
(External control by PRELOAD)

Back 37

Because operating on the descending limb (more than 100% muscle length)
1. Dilatation increases wall stress (Law of Laplace, next lectures). Don’t want to overstretch cardiac muscle.

2. The beating heart cannot achieve a steady state on descending limb;
for example an increase in venous return would set up a vicious cycle:
increased venous return ->increased muscle length ->reduced ejection
->increased muscle length
->reduced ejection

so pumping ability decreases, causing acute pulmonary edema (acute dilation)

Front 38

Why sarcomere problems are found at the descending and ascending limb of its length-tension curve? (not peak tension)

Back 38

Descending limb: Long sarcomere lengths.
Thin filaments “pulled out” of lattice, reduces number of myosin cross-bridges that can interact with actin.
Ascending limb: Short sarcomere lengths, that is, double overlap. (Not due to mechanical interference between thin filaments in the region of double overlap).
Due to at least 2 mechanisms:
Length-dependent changes in Ca affinity of troponin.
Length-dependent changes in Ca release from SR.

Front 39

What is contractility (inotropy) and change in contractility?

Back 39

The “ability of heart muscle to develop tension or perform work at any given length”...the manifestation of all of the variables that
act on the contractile proteins to modify shortening and tension development.

A change in contractility:
For cardiac muscle: any change in the ability to do work not caused by a change in preload (muscle length) or afterload.
For the working heart: any change in the ability to do work not caused by a change in preload (e.g. venous return) or afterload (e.g. aortic pressure).

Front 40

What are two major determinants of contractility?

Back 40

Number of interactions between myosin and actin, determined by amount of Ca bound to thin fil (1/3 of troponin C in basal conditions.
Turnover rate of interactions, proportional to myosin ATPase activity in vitro.

Front 41

How can the heart increase Ca binding to troponin?
And what does that cause?

Back 41

Increase the Ca affinity of the troponin complex.
Modify the extracellular and intracellular Ca cycles so as to increase the flux of Ca into the cytosol during excitation-contraction coupling.
Increased contractility

Front 42

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Back 42

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