Myocardial Transports and Protein Evolution
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Questions and Answers

What is the primary function of PMCA in cardiac cells?

  • To increase Ca2+ binding affinity
  • To enhance ATP production
  • To fine-tune Ca extrusion during diastole (correct)
  • To accelerate ATP hydrolysis

    • Which statement correctly describes the role of phospholamban in the regulation of SERCA?

  • It enhances ATP turnover in heart failure
  • It reduces the phosphorylation and thus inhibits SERCA activity (correct)
  • It increases Ca2+ sensitivity under all conditions
  • It facilitates increased affinity for Ca2+ during systole

    • Which condition leads to a high ratio of phospholamban to SERCA2, impacting heart function?

  • Heart failure (correct)
  • Normal functioning cardiac muscle
  • Phosphorylation of phospholamban
  • Increased ATP levels

    • What is the stoichiometry of SERCA's ATP to Ca2+ binding?

    <p>1 ATP : 2 Ca2+</p> Signup and view all the answers

    What is the primary effect of SLN (sarcoplasmic reticulum protein) on calcium transport?

    <p>Uncouples Ca2+ transport from ATP degradation</p> Signup and view all the answers

    What effect does acidosis have on the modes of NCX regulation?

    <p>It inhibits both modes.</p> Signup and view all the answers

    Which of the following ions can act as a blocker of NCX?

    <p>Cd2+</p> Signup and view all the answers

    What is the primary role of NCX in calcium extrusion?

    <p>Extruding approximately 85% of calcium</p> Signup and view all the answers

    What occurs when hypocalcemia leads to increased sodium permeability of calcium channels?

    <p>Calcium overload and sustained calcium release.</p> Signup and view all the answers

    What is the stoichiometry involved in the PMCA structure?

    <p>1 ATP : 1 Ca2+</p> Signup and view all the answers

    How does the Ca-CaM complex influence PMCA activity?

    <p>Increases calcium sensitivity and Vmax.</p> Signup and view all the answers

    Which event is associated with arrhythmogenic occurrences involving NCX?

    <p>Ischemia-reperfusion conditions.</p> Signup and view all the answers

    Which channel variant is mentioned regarding the PMCA structure?

    <p>Alternative splicing leading to different isoforms.</p> Signup and view all the answers

    What is the stoichiometry of the Na/K pump in human cardiac muscle?

    <p>3 Na+ : 2 K+</p> Signup and view all the answers

    Which conformation of the Na/K pump has a high affinity for ATP?

    <p>E1 conformation</p> Signup and view all the answers

    What is the main disadvantage of direct flux measurements in assessing Na/K pump activity?

    <p>Na movement may occur through alternative pathways</p> Signup and view all the answers

    Which factor has a linear or sigmoid relationship affecting Na/K pump activity?

    <p>Intracellular Na+ concentration</p> Signup and view all the answers

    What is the correct interpretation of EC50 for extracellular K+ concerning pump activity?

    <p>Optimal activity occurs at 1-2 mM of K+</p> Signup and view all the answers

    What is a major regulatory role of ATP in the Na/K pump?

    <p>To provide energy for transport and catalysis</p> Signup and view all the answers

    What happens during depolarization in relation to Na+ and K+ movement?

    <p>Na+ efflux increases while K+ entry decreases</p> Signup and view all the answers

    What is the turnover rate of the Na/K pump in the cardiac muscle?

    <p>5 hours</p> Signup and view all the answers

    What role does the Na/K pump play in cardiac muscle function?

    <p>Maintains sodium and potassium gradients across membranes</p> Signup and view all the answers

    Which of the following compounds is classified as a cardiac glycoside?

    <p>Proscillaridin</p> Signup and view all the answers

    What is a potential effect of reduced Na/K pump function in cardiac diseases?

    <p>Increase in intracellular calcium levels</p> Signup and view all the answers

    What electrophysiological change can result from ouabain administration?

    <p>Induction of delayed afterdepolarizations (DAD)</p> Signup and view all the answers

    Which statement about the regulation of the Na/K pump by phospholemman is correct?

    <p>Phospholemman can affect pump activity through phosphorylation</p> Signup and view all the answers

    What characteristic is associated with the NCX1.1 isoform identified in cardiac tissue?

    <p>Electrogenic transport with a stoichiometry of 3 Na+ : 1 Ca2+</p> Signup and view all the answers

    Which of the following best describes the relationship between force and resting tension in cardiac muscle?

    <p>Linearly related to [Ca2+]e / ([Na+]e)^2</p> Signup and view all the answers

    Which cardiotonic steroid is associated with the inhibition of sodium-potassium pump activity?

    <p>Marinobufagenin</p> Signup and view all the answers

    What is the significance of the stoichiometry ratio of 1 ATP : 2 Ca2+ in SERCA?

    <p>It defines the energetic cost of calcium transport.</p> Signup and view all the answers

    Which condition is highlighted as having a greater inhibition of SERCA during heart failure due to increased ratios?

    <p>Increased PLB/SERCA2 ratio.</p> Signup and view all the answers

    What is the main role of SLN in the context of calcium transport?

    <p>Uncouples Ca2+ transport from ATP degradation.</p> Signup and view all the answers

    Which conformational state of SERCA is characterized as having high affinity for Ca2+?

    <p>E1 state</p> Signup and view all the answers

    What role does Mg2+ play in the regulation of SERCA activity?

    <p>Decreases turnover rate of calcium transport.</p> Signup and view all the answers

    What is a significant disadvantage of using ion-selective electrodes to measure pump activity?

    <p>They cannot distinguish between K+ and Rb+.</p> Signup and view all the answers

    How does ATP ratio influence the activity of the Na/K pump?

    <p>A higher ATP concentration increases the affinity for Na+.</p> Signup and view all the answers

    In which way does depolarization affect the movements of Na+ and K+?

    <p>Na+ efflux increases while K+ entry decreases.</p> Signup and view all the answers

    What is the consequence of hypokalemia on the Na/K pump activity?

    <p>It can lead to digitalis intoxication symptoms.</p> Signup and view all the answers

    What factors are essential for regulating the activity of the Na/K pump?

    <p>ATP, ADP, and Pi ratios.</p> Signup and view all the answers

    What is the primary role of the Na/K pump in maintaining cardiac function?

    <p>Regulating membrane potential and ion gradients</p> Signup and view all the answers

    How does oxidative stress impact the Na/K pump function in cardiac diseases?

    <p>Reduces Na/K pump expression and function</p> Signup and view all the answers

    What effect does the administration of ouabain have on cardiac myocytes?

    <p>Increases intracellular Na+ concentration and enhances calcium influx</p> Signup and view all the answers

    Which characteristic describes the sodium/calcium exchanger (NCX) in cardiac tissues?

    <p>Consists of dimeric structures with multiple transmembrane domains</p> Signup and view all the answers

    What is the relationship between catecholamines and the Na/K pump activity?

    <p>Catecholamines increase Na/K pump activity primarily through direct phosphorylation</p> Signup and view all the answers

    What explains the role of phospholemman in the Na/K pump regulation?

    <p>Decreased phosphorylation leads to enhanced Na/K pump activity</p> Signup and view all the answers

    Which cardiac glycoside is recognized for its effect on the sodium-potassium pump?

    <p>Digoxin</p> Signup and view all the answers

    What consequence arises from the activation of the Na+/Ca2+ exchanger (NCX) in cardiac myocytes?

    <p>Increased intracellular calcium concentration leading to enhanced contractility</p> Signup and view all the answers

    What is the role of NCX in relation to spontaneous Ca2+ release from the SR?

    <p>It facilitates release by exchanging Na+ for Ca2+</p> Signup and view all the answers

    Which of the following blockers is specifically designed to inhibit NCX?

    <p>KB-R 7943</p> Signup and view all the answers

    What is the significance of high doses of ATP in relation to NCX function?

    <p>It stimulates NCX activity as a lubricant</p> Signup and view all the answers

    How does the presence of inhibitors such as La3+ affect NCX?

    <p>They have a non-specific inhibitory effect</p> Signup and view all the answers

    What does an increase in reverse mode NCX activity typically lead to?

    <p>Depolarization and potential arrhythmias</p> Signup and view all the answers

    Which intracellular condition can lead to an increase in [Na+]i involving NCX?

    <p>Ischemia-reperfusion</p> Signup and view all the answers

    What mechanism allows PMCA to effectively regulate intracellular calcium levels?

    <p>Phosphorylation of the CaM binding site</p> Signup and view all the answers

    Study Notes

    Myocardial Transports

    • Myocardial transports are categorized according to energy demand, charge movement, and transported materials.

    Transport Details

    • Transport involves steps from the exterior to the cytoplasm.
    • Steps include diffusion, interaction with glycocalyx, entering the membrane, transferring across the bilayer, dissociation from receptors/carriers, and rehydration.
    • Cellular binding sites or compartments are involved.
    • Substances may exchange energy at different steps.
    • Transport rates depend on the slowest step.
    • Some processes can be diffusion-limited or slower due to low membrane partition.

    Evolution of Cation Pump Proteins

    • Various proteins with different functions and divergence times are listed.
    • Proteins like primitive ancestor, F₁ATPase, Actin, ATP-ADP exchanger, Phosphofructokinase, Ca pump, H,K pump, and a-subunit of the Na pump are categorized.
    • Divergence times (in millions of years) are provided for each protein.

    Transport in Cardiac Muscle

    • Structures and functions of various components related to excitation-contraction coupling are detailed.
    • Structures/components include plasma membrane, sarcolemma, Na channel, Ca channel, Ca pump, Na/Ca exchange, Na pump, transverse tubule, sarcoplasmic reticulum, subsarcolemmal cisternae, sarcotubular network, myofilaments, troponin C, and other proteins.
    • Functions related to activation and relaxation in cardiac muscle are described.

    Na+/K+ Pump

    • The Na+/K+ pump is composed of an alpha subunit (7 transmembrane domains, 100-110 kDa, catalytic) and a beta subunit (1 transmembrane domain, 40 kDa glycoprotein, possibly another subunit in renal cells ).
    • It has binding sites for ATP, ADP, P₁, and Na+/K+.
    • The pump has different conformations (E1 and E2) with varying affinities for ATP and ions.
    • The pump operates in normal and reverse modes.
    • Pumps current is measured in voltage-clamped cells, as well as using radioactive isotopes.

    Regulation of Pump Activity

    • Pump activity is related to Na+ concentration; higher Na+ implies higher activity.
    • K+ concentration affects pump activity at specific levels (EC50).
    • ATP, ADP, and Pi ratios affect pump activity, also in conditions such as hypokalemia and digitalis intoxication.
    • Membrane potential (MP) affects the pump in different modes.
    • Other regulators include hormones (catecholamines, T3, aldosterone, corticosteron), increasing pump activity.
    • And ANP, inhibiting the pump.
    • Cardiac glycosides (ouabain, digoxin, digitoxin) affect pump activity.

    Endogenous Cardiotonic Steroids

    • Endogenous cardiotonic steroids, like ouabain, MBG, bufalin, and telocinobufagin are naturally produced, affecting cardiac function in various ways.
    • They affect the Na+/K+ pump.
    • They have short-term and long-term effects on the heart.

    Role of Na+/K+ Pump in Cardiac Muscle

    • The Na+/K+ pump is vital for creating and maintaining Na+ and K+ gradients, essential for membrane potential and excitability.
    • It plays a critical role in driving secondary active transport, such as NCX.

    Localization of Na+/K+ Pump in Cardiac Myocytes

    • The Na+/K+ pump exhibits different concentrations in the sarcolemma and T-tubules of cardiac myocytes.
    • It relates to the Na+/Ca2+ exchange activity.

    Regulation of Na+/K+ pump by Phospholemman

    • The alpha subunit of the Na+/K+ pump is regulated by phospholemman.
    • Phospholemman and its various isoforms (FXYD1, FXYD2 etc) interact with the pump and have different functions.

    Regulation of Na+/K+ pump by Phospholemman

    • The Na+/K+ pump is regulated by various factors, including factors and concentrations, and by several phospholemman interactions.

    Regulation of NCX

    • NCX is regulated by ions (Na+, Ca2+), membrane potential (MP).
    • Acidosis inhibits and alkalosis stimulates NCX activity.
    • Several ion blockers modulate NCX, including La3+, Cd2+, Ni2+, amiloride, and certain benzamil derivatives.

    Role of NCX in Calcium Extrusion

    • NCX extrudes Ca2+ from cardiac cells, playing an important role in cellular calcium homeostasis.
    • This process occurs by the exchange of Na+ and Ca2+.
    • This process is active during different phases of the cell cycle, and it involves various other molecules.

    Role of NCX in Pacemaking

    • NCX plays a critical role in sinoatrial node (SAN) pacemaker activity.
    • Elimination of the Sodium-Calcium Exchanger (NCX) stops this activity.
    • This activity relates to heart rate through depolarisation mechanisms.

    Role of NCX in Force-Frequency Relationships

    • Changes in beat frequency and twitch tension relate, in part, to the activity of the NCX.
    • These changes affect the interplay of Ca and Na.

    Role of NCX in Arrhythmogenic Events

    • NCX plays a role in arrhythmogenic processes, particularly during ischemia-reperfusion.
    • Hypocalcemia and reperfusion, which alter Na+ permeability in calcium channel, influence NCX activity.
    • This leads to Ca overload and spontaneous Ca2+ release, potentially contributing to arrhythmias.

    Selective Inhibition of Sodium-Calcium Exchanger

    • Selective inhibitors of the sodium-calcium exchanger (such as SEA-0400) can reduce early and delayed afterdepolarizations in canine hearts.
    • These interactions are sometimes observed in certain drug treatment procedures.

    The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX)

    • The influence of a novel NCX inhibitor (ORM-10962) is presented on the functionality of the heart.

    PMCA

    • PMCA is a plasma membrane calcium pump, crucial for calcium extrusion from cells and their homeostasis.
    • The PMCA has various isoforms, due to alternative splicing of genes.
    • Activity is regulated by different factors (i.e. phosphorylation).

    SERCA

    • SERCA is a sarcoplasmic reticulum calcium ATPase essential in pumping calcium back into the sarcoplasmic reticulum.
    • It shows several splice variants, increasing its variety of isoforms.
    • It can be regulated by the phosphorylation of its partner molecule, phospholamban.

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    Description

    Explore the intricate processes involved in myocardial transports, including energy demand and charge movements. This quiz covers the steps of transport from the exterior to the cytoplasm, along with the evolution of key cation pump proteins and their divergence times. Test your understanding of cellular transport mechanisms and protein functions in cardiac physiology.

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