LMP Ca Lec 04
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Questions and Answers

Which of the following is NOT a mechanism proposed for maintaining Ca2+ gradients?

  • Plasma membrane Ca2+ ATPase (PMCA)
  • Calreticulin (correct)
  • Sodium-calcium exchanger
  • Smooth endoplasmic reticular Ca2+ ATPase (SERCA)

    • What is the approximate concentration of Ca2+ ions in the cytoplasm?

  • 10 mM
  • 100 µM
  • 1 mM
  • 100 nM (correct)

    • Which of the following is NOT a factor that can activate plasma membrane ion channels involved in excitatory Ca2+ signaling?

  • Increased intracellular Ca2+ concentration (correct)
  • Extracellular ligand binding
  • Intracellular ligand binding
  • Changes in voltage

    • What is the approximate concentration gradient across which Ca2+ ions flow through plasma membrane ion channels during excitatory Ca2+ signaling?

    <p>100,000-fold (B)</p> Signup and view all the answers

    Which of the following enzymes is activated by both G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)?

    <p>Phospholipase C (PLC) (B)</p> Signup and view all the answers

    What role do IP3 receptors primarily play in muscle physiology?

    <p>They release calcium from the endoplasmic reticulum. (D)</p> Signup and view all the answers

    Which protein complex is associated with the stimulation of calcium release in skeletal muscle?

    <p>DHP receptor and RyR1 (B)</p> Signup and view all the answers

    What is a characteristic mutation associated with malignant hyperthermia in pigs?

    <p>R615C mutation in RyR1 (A)</p> Signup and view all the answers

    Which treatment is commonly used for managing malignant hyperthermia?

    <p>Dantrolene (D)</p> Signup and view all the answers

    What process is referred to as 'capacitative entry' in muscle physiology?

    <p>Slow, calcium-dependent entry activated by diminished calcium stores (C)</p> Signup and view all the answers

    What is the primary function of calmodulin in muscle physiology?

    <p>As a calcium sensor regulating various cellular processes (C)</p> Signup and view all the answers

    Which statement about Ryanodine receptors (RyR) is correct?

    <p>They are involved in calcium release from the sarcoplasmic reticulum. (B)</p> Signup and view all the answers

    What can lead to the depletion of calcium stores in muscle cells?

    <p>Calcium mobilizing agents like ionophores (B)</p> Signup and view all the answers

    What is the approximate resting cytosolic concentration of Ca2+ in cells?

    <p>100 nM (C)</p> Signup and view all the answers

    Which mechanism does calcium utilize to signal apoptosis in cells?

    <p>Activation of key catabolic enzymes (C)</p> Signup and view all the answers

    What role does calcium play in cellular homeostasis?

    <p>Regulates uptake, release, and expulsion of ions (B)</p> Signup and view all the answers

    Which of the following is NOT a function of intracellular Ca2+?

    <p>Biosynthesis of neurotransmitters (B)</p> Signup and view all the answers

    What is NOT a player in the expulsion or resequestration of calcium ions?

    <p>CAPT (A)</p> Signup and view all the answers

    Flashcards

    Resting cytosolic Ca2+

    Normal concentration of calcium ions in the cytosol at 100 nM.

    Ca2+ signaling pathways

    Calcium signals through uptake from outside and release from the ER/SR.

    Role of Ca2+ in apoptosis

    Calcium activates proteases, endonucleases, and other enzymes leading to cell death.

    Calcium homeostasis

    Regulation of calcium levels via uptake, release, expulsion, and resequestration.

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    Intracellular Ca2+ functions

    Calcium aids in signal transduction, muscle contraction, cytoskeletal dynamics, and apoptosis.

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    Ca2+ oscillations

    Repetitive fluctuations in calcium ion concentration in cells.

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    Calcium-induced calcium release (CICR)

    A process where calcium release from the ER causes more calcium release.

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    Role of PMCA and SERCA

    Maintain low cytoplasmic Ca2+ levels by pumping calcium out/in.

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    GPCR activation

    G protein-coupled receptors engage with ligands, leading to signal transduction.

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    Electrogenic Na/Ca exchanger

    A protein that helps regulate calcium levels and generates electrical signals in cells.

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    Phospholipase C (PLC)

    An enzyme that catalyzes the hydrolysis of PIP2 into IP3 and DAG, leading to calcium release.

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    IP3 (Inositol trisphosphate)

    A signaling molecule produced by PLC that stimulates calcium release from the endoplasmic reticulum.

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    Calmodulin

    A calcium-binding protein that functions as a calcium sensor and regulates various cellular processes.

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    Ryanodine receptors (RyR)

    Calcium release channels in the sarcoplasmic reticulum, involved in muscle contraction and excitation-contraction coupling.

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    Malignant hyperthermia

    A genetic disorder triggered by stress or certain anesthetics, causing excessive calcium release and muscle contraction.

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    E-C coupling (Excitation-Contraction coupling)

    The physiological process by which an electrical signal leads to muscle contraction, involving calmodulin and myosin light chain kinase.

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    Caffeine inhibition of IP3 receptors

    Caffeine can inhibit the action of IP3 receptors, affecting calcium signaling in cells.

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    Calcium mobilizing agents

    Substances that cause the release of calcium from stores, such as IP3 and ionophores.

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    Study Notes

    Calcium's Unique Roles

    • Resting cytosolic Ca²⁺ is approximately 100 nM.
    • Cells signal using Ca²⁺ uptake from extracellular spaces and release from internal stores (e.g., ER/SR).
    • Ca²⁺ plays both harmful and essential roles, regulating cell death/survival and causing injury while also performing many essential functions.

    Important Gradients

    • Na⁺: 10 mM in, 145 mM out
    • K⁺: 140 mM in, 5 mM out
    • Cl⁻: 5 mM in, 115 mM out
    • Ca²⁺: 10⁻⁴ mM in, 2 mM out

    Injury Mechanism and Increased Intracellular Calcium

    • An injurious agent increases cytosolic calcium.
    • This activates cellular enzymes, including phospholipases, proteases, endonucleases, and ATPases.
    • These enzymes disrupt membrane and cytoskeletal proteins, leading to membrane damage and nuclear damage.
    • Increased mitochondrial permeability transition occurs.

    Calcium and Apoptosis

    • Calcium activates key catabolic enzymes:
      • Proteases (e.g., calpain, nuclear scaffold protease)
      • Endonucleases (e.g., NUC18, DNase I)
      • Transglutaminases (stabilize structures and trigger degradation)
      • Actin-binding proteins (e.g., gelsolin)
    • Calcium depletion destabilizes the ER, releasing enzymes (e.g., NS, DNase I).
    • Calcium depletion also causes mitochondrial dysfunction.

    Functions of Intracellular Ca²⁺

    • Signal transduction
    • Excitation-contraction coupling
    • Cytoskeletal remodeling
    • Apoptosis

    Calcium Homeostasis

    • Resting cytosolic calcium is approximately 100 nM.
    • Calcium signals through extracellular ion uptake and ER/SR release.
    • Calcium uptake involves voltage-gated and ligand-gated channels, capacitative entry, and CRAC channels.
    • Calcium release involves IP₃R and RyR receptors.
    • Calcium extrusion involves plasma membrane pumps and exchangers.
    • Calcium resequestration is handled by P-type ATPase and SERCA.

    Phospholipases and Calcium Signaling

    • Phospholipase A₁ hydrolyzes phospholipids.
    • Phospholipase A₂ produces arachidonic acid from phospholipids.
    • Phospholipase D hydrolyzes phosphatidylcholine.
    • Phospholipase C produces inositol trisphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP₂).

    IP₃ Receptors

    • PLC activates IP₃ release.
    • IP₃ receptors are ~300 kDa peptides.
    • Two transmembrane regions anchored to the ER.
    • Form tetramers to create Ca²⁺ channels.
    • Activated by Ca²⁺ (amplification), inhibited by caffeine.
    • Some isoforms interact with CRAC channels.

    RyR Receptors

    • C-terminal transmembrane regions homologous to IP₃R.
    • ~565 kDa, with additional regulatory domains.
    • Form tetramers.
    • Include RyR1 (skeletal muscle) and RyR2 (cardiac muscle).
    • Calmodulin binding domain triggers by Ca²⁺ influx.
    • E-C coupling via calmodulin/MLCK.
    • Stimulated by caffeine.
    • RyR1 cytoplasmic tail associates with DHP receptor.
    • DHP acts as voltage sensor and a ligand-gated channel (cADP ribose?).

    Intracellular Calcium Channels

    • Detailed structure and amino acid information is presented for RYR1, RYR2, RYR3, and IP₃R receptors.

    Calmodulin

    • Calmodulin (CaM) is a 148 amino acid protein.
    • Has four Ca²⁺-binding sites within E-F hand structures.
    • Acts as a Ca²⁺ sensor, playing a role in:
      • E-C coupling (MLCK)
      • Metabolism (e.g., phosphorylase kinase, glucose, calcitonin, lipids)
      • Neurochemistry (CaMK II)

    A Calmodulin "Switch"

    • Calmodulin binds to and activates target proteins based on calcium binding
    • Calcium binding shape shifts calmodulin

    RyR and IP₃ Receptors: Dual Regulation

    • Both receptors are modulated by ATP, cAMP, and intracellular messengers.
    • Both receptors are potentiated (activated) by different concentrations of calcium.

    Calcium Homeostasis

    • Detailed diagrams depict the roles of calreticulin, calsequestrin, and other factors in storing and releasing calcium within cells.

    Malignant Hyperthermia

    • Susceptibility in pigs involves stress-induced muscle contraction leading to hyperthermia, often fatal.
    • Affected pigs have a RyR1 mutation that prevents proper closure, increasing excitability.
    • In humans, inhalational anaesthetics trigger MH episodes.
    • Most cases are related to RyR1 mutations.
    • Diagnosis involves muscle biopsies with caffeine-halothane tests.
    • Dantrolene and cooling are treatments.

    Mechanisms in Malignant Hyperthermia

    • Anaesthetics trigger skeletal muscle contraction.
    • Rhabdomyolysis occurs, causing muscle breakdown.
    • Myoglobin release can lead to kidney failure.
    • Potassium increases.
    • Increased O₂, CO₂, and H⁺ leads to hypermetabolism.
    • Increased heart rate triggers tachycardia.
    • Cerebral damage can result from MH.

    Depletion of Ca²⁺ Stores

    • Ca²⁺ mobilizing agents, ionophores, and ER pump inhibitors can deplete calcium stores.

    Replenishment of Ca²⁺ Stores

    • Capacitative entry and conformational coupling (using CRAC channels) replenishes stores.
    • This is analogous to RyR1/DHPR.
    • Slow entry and privileged pathways also replenish stores.

    Calcium Oscillations

    • Excitable cells use calcium oscillations, avoiding sustained increases.
    • Oscillations can be caused by IP₃ via G protein, receptor/PLC, and PKC inactivation.
    • Two-pool calcium-induced calcium release (CICR) involves an IP₃-insensitive capacitative pool filling first.
    • IP₃-independent pathways involve RyR-sensitive stores.

    Voltage-Operated Ca²⁺ Channels

    • Different types (T, N, P, L) have varying activation and inactivation voltage ranges.
    • These channels are important in neurons, heart cells and muscle.

    Ca²⁺ Channel Blockers

    • Used to treat hypertension
      • Vasorelaxation happens.
      • Calmodulin and MLC phosphorylation decrease.
      • Arterial vasodilation occurs, decreasing afterload.
      • Endothelial reactions are reversed.
    • Used to treat Myocardial Infarction (MI)
      • Demand for O₂ decreases.
      • Heart rate decreases.
      • Afterload decreases with vasodilation.
      • Contractility decreases.
      • Response to endothelin-1 is limited.
    • Used to treat Congestive Heart Failure (CHF)
      • Meta-analysis shows limited benefit.
      • Inotropic effect is decreased, along with ejection fraction.
      • Troponin C-Ca²⁺ interaction is inhibited.
      • DHPs may raise heart rate.
      • Chronic increase in plasma norepinephrine.

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    LMP 200H – Lecture 4 Calcium PDF

    Description

    Explore the significant and multifaceted functions of calcium in cellular processes. This quiz covers topics such as calcium signaling, its roles in injury mechanisms, and the relationship between calcium and apoptosis. Test your understanding of the critical concentrations and gradients involved.

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