Lecture 3

• Action potentials are rapid electrical changes across cell membranes, propagating to adjacent cells, like in the heart.
• Pacemaker cells, about 1% of heart cells, set the heart's rhythm by generating new action potentials.
• These action potentials are conducted to the other 99% of heart cells, signaling them to pump.
• Pacemaker cells respond to action potentials, typically from neighboring pacemaker cells.
• If signals don't arrive, a pacemaker cell initiates its own action potential, termed automaticity.

Mapping Pacemaker Cells

• The sinoatrial node (SA node) is the primary clump of pacemaker cells, located in the right atrium.
• Pacemaker cells are also in internodal tracts, the atrioventricular (AV) node, the Bundle of His, & Purkinje fibers.
• This arrangement forms the electrical conduction system of the heart.
• Cardiomyocytes surround pacemaker cells and receive action potentials, though slightly slower.
• Pacemaker cells are like highways for rapid action potential transmission, while muscle cells act as slower side roads.
• This system is termed a functional syncytium, where cells act as one unit due to mechanical, chemical, and electrical connections facilitated by pacemaker cells.

Chemistry Behind Action Potentials

• Action potentials start with depolarization, the opposite of polarization.
• Polarization is when there's a higher negative charge inside the cell compared to outside, creating a membrane potential.
• Membrane potential is negative if the inside is more negative, positive if more positive, and 0mV if charges are equal.
• Membrane potential changes based on which ions move across the membrane and how permeable the membrane is to those ions.
• Depolarization occurs when ions shift across the membrane, reducing negativity or even causing the membrane potential to become slightly positive.
• Depolarization in one cell prompts ion flow into neighboring cells, triggering their depolarization, creating a depolarization wave.
• Depolarization waves dictate heart muscle contraction rate, with the wave rate setting the heart rate (e.g., one wave per second equals 60 beats per minute).

Pacemaker Cell Action Potential

• Action potential phases are displayed on a membrane potential vs. time graph, comprising five phases.

Phase 4: Pacemaker Potential

• Occurs when the pacemaker cell rests at around -65mV membrane potential.
• HCN channels, which open at negative membrane potentials (like -65mV), allow positively charged sodium ions into the cell.
• Inward rush of sodium ions creates the funny current, causing slow depolarization up to about -50mV.

Phase 0: Depolarization Phase

• Begins when the cell hits about -50mV, voltage-gated calcium channels open, allowing calcium influx.
• Sodium and calcium influx causes the membrane potential to surge past 0mV, peaking around +10mV within 0.5 milliseconds.
• Calcium channels remain open until about +10mV, then start closing.

Phase 3: Repolarization Phase

• Pacemaker cells skip phases 1 and 2, proceeding directly to repolarization.
• Potassium channels open, calcium channels close, enabling potassium to exit while sodium enters via HCN channels.
• The greater number of potassium channels leads to a net outward positive current, lowering the membrane potential back to about -65mV.
• Completes one heartbeat cycle, restarting with phase 4.
• Pacemaker cells automatically generate action potentials, setting heart rate.
• Action potentials spread through heart muscle cells as depolarization waves, leading to heartbeats.
• Pacemaker action potential phases: slow depolarization (phase 4), rapid depolarization (phase 0), and repolarization (phase 3).

Myocyte Action Potential: Phase 4 - Resting Phase

• Myocytes rest at -90 mV membrane potential.
• Gap junctions facilitate ion leakage (mainly calcium) from neighboring depolarized cells, raising the membrane potential to -70 mV.
• The -70mV threshold potential initiates phase 0.

Myocyte Action Potential: Phase 0 - Depolarization Phase

• Voltage-gated sodium channels respond to -70mV, allowing a rapid influx of sodium ions.
• Sodium influx surges the membrane potential to +20mV.
• Insufficient initial ion leakage to reach -70 mV threshold prevents channel opening and depolarization.
• Action potentials operate on an all-or-none principle.

Myocyte Action Potential: Phase 1 - Initial Repolarization

• Occurs when the membrane potential rises above -70 mV to +20 mV.
• Sodium channels close, voltage-gated potassium channels open at +20 mV, facilitating potassium ions leaving the cell.
• Outward current of positive potassium ions causes a drop in membrane potential, creating a notch on the graph.

Myocyte Action Potential: Phase 2 - Plateau Phase

• Voltage-gated calcium channels open, allowing calcium ions into the cell.
• Influx of positive calcium balances outflow of positive potassium, stabilizing the membrane potential.
• Calcium influx triggers myocyte contraction, determining action potential length and heartbeat.

Myocyte Action Potential: Phase 3 - Repolarization Phase

• Calcium channels close, potassium channels remain open, creating a net outward positive current.
• Ion pumps remove calcium, causing heart muscle relaxation.
• Membrane potential returns to -90 mV, restarting with phase 4.
• Cardiac myocytes receive action potentials from pacemaker cells, initiating rapid voltage changes.
• Phase 4 is the resting phase, phase 0 involves sodium influx and depolarization
• Phase 1 sees potassium outflux, reducing charge, phase 2 , calcium influx balances potassium outflux forming plateau
• Phase 3 concludes with calcium channels closing, potassium outflow repolarizing the myocyte to enter its resting state.
• Cardiac excitation-contraction coupling is the correlation between electrical signals (action potentials) and mechanical changes (contraction) in heart muscle cells (cardiomyocytes).

Cardiomyocyte Structure

• Branched cells with intercalated disks with gap junctions for ion flow.
• Depolarization in one cardiomyocyte triggers depolarization in neighboring cells via ion passage, forming a functional syncytium.
• Desmosomes, anchoring proteins, physically connect cells during contraction.
• Transverse tubules (T-tubules) are extensions that increase cell surface area and bring extracellular environment closer to inside cell. Think of a walk-through aquarium, where you can look at the creatures but not touch them.
• Sarcoplasmic reticulum stores intracellular calcium.

Excitation-Contraction Process

• Depolarization causes calcium ions to enter, initiating sodium channel opening if the threshold is reached.
• T-tubules facilitate calcium ion movement into the cell during depolarization.
• Intracellular calcium binds to ryanodine receptors on the sarcoplasmic reticulum, causing calcium-induced calcium release.
• Released calcium activates actin and myosin contractile proteins, converting a chemical signal into a mechanical one.
• Calcium ions bind to troponin C, causing tropomyosin to shift off of actin and expose binding sites and cause mysoin heads to bind to actin
• Myosin heads bind to actin, creating cross-bridges and power strokes, pulling filaments and shortening muscle, using ATP.
• Calcium removal via ion transporters relies on ATP or concentration gradients.
• Calcium is moved back into sarcoplasmic reticulum or extracellular environment, and some into mitochondria.
• Once calcium is gone, troponin reverts, blocking actin, preventing more cross-bridges.
• Cardiac excitation-contraction coupling involves action potentials converting to mechanical energy where Calcium ions enter via T-tubules and bind to troponin.
• Troponin changes, exposing actin sites, Myosin-actin bridges form with ATP contributing to power stroke.
• Power creates actin and myosin closer, creating the basis for muscle contraction.