Unit 4: Nerve and Muscle

1. Resting Membrane Potential

Concept and Establishment

Neurons and muscle cells, like all living cells, maintain an electrical potential difference across their cell membrane when they are not actively signaling. This potential difference is known as the Resting Membrane Potential (RMP).

The Resting Membrane Potential (RMP) is the electrical potential difference across the plasma membrane of a cell when it is in an unexcited state. It is typically negative inside relative to the outside, around -70 mV for a neuron.

The RMP is primarily established and maintained by three factors:

1. Differential distribution of ions: There is a higher concentration of K+ ions inside the cell and higher concentrations of Na+ and Cl- ions outside the cell.
2. Selective permeability of the membrane to ions: The membrane is much more permeable to K+ ions than to Na+ ions at rest, mainly due to the presence of numerous K+ leak channels. The efflux of K+ ions makes the inside of the cell progressively more negative.
3. Activity of the Na+/K+ ATPase pump: This active transport pump expels 3 Na+ ions out of the cell for every 2 K+ ions it brings into the cell, actively contributing to the negative charge inside and maintaining the concentration gradients for these ions.

The efflux of K+ ions through leak channels makes the inside of the cell progressively more negative until the electrical gradient pulling K+ back in balances the concentration gradient pushing K+ out. This state is close to the equilibrium potential for K+.

2. Graded Potential

Definition and Properties

Graded potentials are small, localized changes in the membrane potential that vary in amplitude depending on the strength of the stimulus. They are typically generated at dendrites and cell bodies of neurons.

A Graded Potential is a temporary change in the membrane potential, the magnitude of which is directly proportional to the intensity of the stimulus. They can be depolarizing (less negative) or hyperpolarizing (more negative).

Key properties of graded potentials:

• Variable amplitude: The stronger the stimulus, the larger the graded potential.
• Decremental conduction: They lose strength as they spread from the point of origin because of current leakage across the membrane.
• Summation: Multiple graded potentials can add up (summate) in space (spatial summation) or time (temporal summation) to reach a threshold for an action potential.
• No refractory period: A second stimulus can produce another graded potential immediately.
• Can be depolarizing or hyperpolarizing: Depolarizing graded potentials make the membrane less negative (e.g., Excitatory Postsynaptic Potentials - EPSPs), while hyperpolarizing graded potentials make it more negative (e.g., Inhibitory Postsynaptic Potentials - IPSPs).

Origin

Graded potentials originate at specific regions of a neuron:

• Sensory receptors: In sensory neurons, they are called receptor potentials.
• Synapses: In postsynaptic neurons, they are called postsynaptic potentials (EPSPs or IPSPs).

If a depolarizing graded potential is strong enough to reach a specific voltage level, called the threshold potential, it can trigger an action potential.

3. Action Potential

Definition and Properties

Action potentials (APs) are rapid, large, and brief reversals of the membrane potential, followed by a return to the resting state. They are the primary means of long-distance communication in the nervous system.

An Action Potential is a brief, rapid, and stereotypical depolarization followed by repolarization of the neuronal membrane, propagating without decrement along the axon once a threshold stimulus is reached.

Key properties of action potentials:

• All-or-None principle: If a stimulus reaches the threshold potential, an action potential of a consistent magnitude is generated, regardless of the stimulus strength. If the threshold is not reached, no action potential occurs.
• Threshold potential: A critical level of depolarization (typically between -55 mV to -50 mV) that must be reached to trigger an action potential.
• Non-decremental conduction: Action potentials propagate along the axon without losing amplitude, regenerating themselves at each point.
• Refractory periods: Periods during and immediately after an action potential during which the neuron is either unable to generate another action potential (absolute refractory period) or requires a stronger than normal stimulus (relative refractory period).

Phases and Ionic Basis

An action potential typically involves several distinct phases due to the sequential opening and closing of voltage-gated ion channels, primarily for Na+ and K+.

1. Resting State: The membrane is at RMP (~-70 mV). All voltage-gated Na+ and K+ channels are closed. K+ leak channels are open, contributing to RMP.
2. Depolarization (Rising Phase):
   • A stimulus causes a graded depolarization.
   • If the membrane potential reaches the threshold potential, voltage-gated Na+ channels rapidly open.
   • Na+ ions rush into the cell due to both the electrical and concentration gradients, causing a rapid increase in membrane potential (e.g., from -55 mV to +30 mV). This is a positive feedback loop.
3. Repolarization (Falling Phase):
   • At the peak of depolarization, voltage-gated Na+ channels inactivate (close and become refractory).
   • Simultaneously, voltage-gated K+ channels open more slowly than Na+ channels.
   • K+ ions rush out of the cell, making the inside of the cell more negative, leading to repolarization.
4. Hyperpolarization (Undershoot):
   • Voltage-gated K+ channels close slowly, causing a brief period where the membrane potential becomes even more negative than the RMP (e.g., -80 mV).
   • This is due to the continued efflux of K+ ions while Na+ channels are still inactivated.
   • The Na+/K+ pump and K+ leak channels eventually restore the RMP.

Conduction of Action Potentials

Action potentials propagate along the axon from the axon hillock to the axon terminal. The mechanism of conduction differs between unmyelinated and myelinated nerve fibers.

Conduction Across Non-myelinated Nerve Fibres (Continuous Conduction)

In unmyelinated axons, action potentials propagate in a continuous fashion:

1. An action potential at one point on the membrane depolarizes the adjacent region to threshold.
2. This triggers a new action potential in the adjacent region.
3. The wave of depolarization moves progressively along the axon.
4. The refractory period behind the propagating action potential prevents backward conduction, ensuring unidirectional flow.

This method is relatively slow because voltage-gated channels must open sequentially along the entire length of the axon.

Conduction Across Myelinated Nerve Fibres (Saltatory Conduction)

Myelinated axons are covered by a myelin sheath, an insulating layer formed by Schwann cells (PNS) or oligodendrocytes (CNS). Gaps in the myelin sheath, called Nodes of Ranvier, are rich in voltage-gated Na+ and K+ channels.

In myelinated axons, action potentials "jump" from one Node of Ranvier to the next:

1. An action potential is generated at one Node of Ranvier.
2. The current flows rapidly under the myelin sheath to the next Node of Ranvier (due to insulation, little current leaks).
3. This current flow depolarizes the membrane at the next Node to threshold, generating a new action potential.
4. This "jumping" propagation is called saltatory conduction (from Latin saltare, to leap).

Saltatory conduction is significantly faster and more energy-efficient than continuous conduction.

Comparison: Graded vs. Action Potential

Factors Affecting Conduction Velocity

The speed at which an action potential propagates along an axon is influenced by:

• Myelination: Myelinated axons conduct action potentials much faster than unmyelinated axons due to saltatory conduction.
• Axon Diameter: Larger diameter axons offer less resistance to current flow and thus conduct action potentials faster than smaller diameter axons.

4. Mechanism of Synaptic Transmission

Introduction to Synapses

A synapse is a specialized junction between two neurons or between a neuron and an effector cell (e.g., muscle cell or gland), allowing for the transmission of electrical or chemical signals.

• Electrical Synapses: Involve direct current flow through gap junctions, providing fast, bidirectional communication but less modifiable.
• Chemical Synapses: Involve the release of neurotransmitters, providing slower but highly regulable and unidirectional communication. Most synapses in the human nervous system are chemical.

Mechanism of Chemical Synaptic Transmission (Step-by-Step)

Chemical synaptic transmission is a complex process that converts an electrical signal (action potential) into a chemical signal (neurotransmitter release) and then back into an electrical signal (postsynaptic potential).

1. Action Potential Arrives at Presynaptic Terminal: An action potential propagates down the axon and reaches the presynaptic terminal.
2. Voltage-gated Ca2+ Channels Open: The depolarization of the presynaptic terminal by the action potential opens voltage-gated Ca2+ channels.
3. Ca2+ Influx into Presynaptic Terminal: Ca2+ ions rush into the presynaptic terminal from the extracellular fluid, driven by their concentration gradient.
4. Neurotransmitter Release (Exocytosis): The influx of Ca2+ triggers the fusion of synaptic vesicles (containing neurotransmitters) with the presynaptic membrane. Neurotransmitters are then released into the synaptic cleft (the space between pre- and postsynaptic neurons) via exocytosis.
5. Neurotransmitter Binding to Postsynaptic Receptors: Neurotransmitters diffuse across the synaptic cleft and bind to specific receptor proteins on the postsynaptic membrane.
6. Opening of Ion Channels and Postsynaptic Potential Generation:
   • Binding of neurotransmitters causes ligand-gated ion channels on the postsynaptic membrane to open.
   • This leads to a change in the postsynaptic membrane potential, called a postsynaptic potential (PSP).
   • If the channels allow Na+ influx (depolarization), it's an Excitatory Postsynaptic Potential (EPSP).
   • If the channels allow Cl- influx or K+ efflux (hyperpolarization), it's an Inhibitory Postsynaptic Potential (IPSP).
7. Integration and Generation of Action Potential: The postsynaptic neuron sums up all EPSPs and IPSPs. If the net depolarization reaches the threshold potential at the axon hillock, a new action potential is generated in the postsynaptic neuron.
8. Neurotransmitter Removal/Inactivation: Neurotransmitters are quickly removed from the synaptic cleft to ensure precise signaling and to allow the postsynaptic neuron to respond to new signals. Mechanisms include:
   • Enzymatic degradation: Enzymes break down neurotransmitters (e.g., Acetylcholinesterase degrading Acetylcholine).
   • Reuptake: Neurotransmitters are reabsorbed by the presynaptic terminal or glial cells.
   • Diffusion: Neurotransmitters diffuse away from the synaptic cleft.

5. Mechanism of Skeletal Muscle Contraction

Introduction to Muscle Structure

Skeletal muscles are responsible for voluntary movements. They are composed of muscle fibers, which in turn contain numerous myofibrils. Myofibrils are made up of repeating functional units called sarcomeres. Sarcomeres contain two types of protein filaments:

• Thick filaments: Composed primarily of the protein myosin. Myosin heads have actin-binding sites and ATP-binding sites.
• Thin filaments: Composed of actin, tropomyosin, and troponin.
  • Actin: Forms the backbone, with myosin-binding sites.
  • Tropomyosin: A rod-shaped protein that covers the myosin-binding sites on actin in a relaxed muscle.
  • Troponin: A complex of three proteins that binds to actin, tropomyosin, and Ca2+.

Other key structures:

• Sarcoplasmic Reticulum (SR): A specialized endoplasmic reticulum that stores and releases Ca2+ ions.
• T-tubules (Transverse tubules): Invaginations of the muscle cell membrane (sarcolemma) that extend deep into the muscle fiber, allowing action potentials to rapidly reach the interior.
• Neuromuscular Junction (NMJ): The synapse between a motor neuron and a skeletal muscle fiber.

Excitation-Contraction Coupling

This is the process by which an electrical signal (nerve impulse) is converted into a mechanical response (muscle contraction).

1. Nerve Impulse at Neuromuscular Junction (NMJ): An action potential arrives at the axon terminal of a motor neuron.
2. Acetylcholine (ACh) Release: The arrival of the action potential opens voltage-gated Ca2+ channels at the axon terminal, causing Ca2+ influx. This triggers the release of the neurotransmitter Acetylcholine (ACh) into the synaptic cleft of the NMJ.
3. ACh Binding to Receptors: ACh diffuses across the synaptic cleft and binds to nicotinic ACh receptors on the motor end plate of the muscle fiber.
4. Generation of End-Plate Potential (EPP): ACh binding opens ligand-gated ion channels, primarily allowing Na+ influx into the muscle fiber. This causes a local depolarization called an End-Plate Potential (EPP).
5. Muscle Action Potential (MAP): If the EPP reaches the threshold, it triggers voltage-gated Na+ channels on the adjacent sarcolemma (muscle cell membrane) to open, generating a muscle action potential (MAP).
6. MAP Propagation into T-tubules: The MAP propagates along the sarcolemma and down into the T-tubules.
7. Ca2+ Release from Sarcoplasmic Reticulum (SR): The MAP in the T-tubules triggers the release of Ca2+ ions from the terminal cisternae of the sarcoplasmic reticulum into the sarcoplasm (muscle cell cytoplasm). This is mediated by dihydropyridine receptors (DHP receptors) on the T-tubules interacting with ryanodine receptors (RyR) on the SR.

Sliding Filament Theory of Muscle Contraction

The released Ca2+ ions initiate the actual muscle contraction through a series of events involving the thick and thin filaments, known as the Sliding Filament Theory.

1. Ca2+ Binds to Troponin: Ca2+ ions released from the SR bind to troponin on the thin filaments.
2. Tropomyosin Shift: The binding of Ca2+ to troponin causes a conformational change in troponin. This change pulls tropomyosin away from the myosin-binding sites on the actin molecules. The actin binding sites are now exposed.
3. Myosin Head Activation (ATP Hydrolysis): Before binding, the myosin head is "cocked" in a high-energy state. This occurs when ATP binds to the myosin head and is hydrolyzed into ADP and inorganic phosphate (Pi), causing the myosin head to pivot and extend towards the actin.
4. Cross-Bridge Formation: The activated myosin head, now with ADP and Pi bound, binds strongly to the exposed myosin-binding site on actin, forming a cross-bridge.
5. Power Stroke: The release of ADP and Pi from the myosin head triggers a conformational change, causing the myosin head to pivot and pull the thin filament (actin) towards the center of the sarcomere. This movement is the power stroke.
6. Cross-Bridge Detachment: A new ATP molecule binds to the myosin head. This binding reduces the affinity of the myosin head for actin, causing the cross-bridge to detach.
7. Myosin Head Re-cocking: The newly bound ATP is again hydrolyzed to ADP and Pi, re-energizing the myosin head and causing it to return to its high-energy, cocked position, ready to bind to another actin site further along the thin filament (if Ca2+ is still present).

This cycle of attachment, power stroke, detachment, and re-cocking continues as long as Ca2+ ions are present in the sarcoplasm and ATP is available. As the thin filaments slide past the thick filaments, the sarcomeres shorten, leading to muscle contraction.

Muscle Relaxation

Contraction ends when:

• ACh Breakdown: Acetylcholinesterase (AChE) in the synaptic cleft rapidly breaks down ACh, preventing continuous stimulation of the muscle fiber.
• Ca2+ Reuptake: Ca2+-ATPase pumps actively transport Ca2+ back into the sarcoplasmic reticulum, lowering Ca2+ concentration in the sarcoplasm.
• Tropomyosin Blockade: With low Ca2+, troponin releases Ca2+, causing tropomyosin to return to its original position, covering the myosin-binding sites on actin. This prevents further cross-bridge formation, and the muscle relaxes.