For what does the heart utilize electrical signaling ?

• to maintain rhythm

• to drive force of contraction

How does a cardiomyocyte action potential contribute to muscle contraction ?

• depolarization ➡️ voltage-gated channels ➡️ calcium-induced-calcium-release

What is the sarcomere and what are its components ? Be familiar with the steps in cardiomyocyte contraction

• sarcomere = elemental contractile unit of cardiomyocytes

  • they contain myofilaments

  • defined as the region of myofilaments between two Z-lines/discs.

  • bundled as myofibrils , allowing for coordinated contraction across the whole myocyte.

• steps in cardiomyocyte contraction :

  1. phase 0 = depolarization

     • rapid influx of sodium via voltage-gated channels

  2. phase 1 = "notch"

     • inactivation of sodium channels

     • start of potassium efflux

  3. phase 2 = "plateau"

     • calcium influx begins

     • continued potassium eflux

     • contraction begins here

  4. phase 3 = "rapid repolarization"

     • calcium channels close

     • continued potassium efflux

  5. phase 4 = "resting potential"

     • RMP restored via : inward rectifying potassium channels , sodium-potassium and sodium-calcium exchangers

What structural features allow cardiomyocytes to interact with neighboring cells and their interstitial environment ?

• intercalcated discs ( ICDs ) and costameres

What are the three components of the intercalated disc ( ICD ) ? How do desmosomes and adherens junctions differ ?

• 3 components of ICD = desmosomes , GAP junctions , and adherins junctions

Know the proteins found in the three components of the ICD and be familiar with what they do

• 3 components of cadherin :

  • extracellular region

  • intracellular region

  • linker protein

What are the different connexin isoforms found in the heart , what do they do and what is important about their differences ?

• 40 , 43 , 45

  • they have different gating and conduction properties that change contraction force

• they allow small molecules and ions to diffuse between cells

• gap junctions are formed by 2 adjacent cells via their connexins

Know differences between thin filaments ( actin ) and intermediate filaments ( desmin )

• thin = cytoskeleton

  • link to sarcomere

  • contraction

• intermediate = interact with organelles

  • structural

How do adherens junctions contribute to cardiomyocyte signaling ?

• β-catenin pathway acts as transcription factor

Be familiar with what the area composita is

• 3 components

• overlapping regions = "area composita"

• recent data suggests that regions of overlap between desmosomes and adherens junctions are more likely the dominant organizational pattern

• the overlap of the desmosomes and adherens junctions within the intercalated disc is referred to as the area composita

What are costameres , where are they found , what are they composed of , and what do they do ?

• they are found on lateral membrane

• they interact with the ECM to provide more efficient contraction

• The costamere is a submembranous structure in striated muscle

• found at the lateral membrane of cardiomyocytes

• composed of two major protein complexes :

  • the dystrophin–glycoprotein complex

  • integrin-vinculin-talin complex

• Vinculin and talin are cytoplasmic proteins that tether integrins to the cytoskeleton

What is mechanotransduction ? What are the two different types ?

• mechanotransduction is the conversion of mechanical tension outside the cell to intracellular biochemical signals.

  • Integrins play a critical role in this process.

    • integrin signaling mediated by Akt , MAPK ( mitogen activated protein kinase ) , and the GTPase RhoA ( ras homolog family member A )

• 2 Different Types :

  • outside-in :

    • Upon Ligand binding ( laminin ) the integrin conformation is altered leading to interactions with the cytoskeleton and other intracellular signaling molecules critical to cell survival or initiation/propagation of cardiomyocyte hypertrophy

    • Thus , mechanical tension outside the cell is converted to intracellular biochemical signals through integrins

  • inside-out :

    • In addition to extracellular events causing integrin-mediated intracellular signaling events , intracellular signals can cause the integrins to alter their ability to bind to the extracellular matrix ( ECM )

      • Agonist binding ( angiotensin , epinephrine , norepinephrine ) to a nonintegrin receptor initiates an intracellular signaling cascade leading to :

        • Increased affinity of individual integrins for ECM binding ( short-term )

        • Integrin clustering and increased avidity of integrin-ECM binding ( long-term )

ARVC Mutation Screening