Electrical and Synaptic Signaling in Neurons: Exhaustive Study Guide

Introduction to Signal Transduction and Neuronal Signaling

Cell membranes serve a critical role in regulating the flow of ions between the internal and external environments of the cell.
The nerve cell, or neuron, represents the most dramatic example of the regulation of a cell's electrical properties.
Neurons possess specialized mechanisms designed to utilize electrical potentials for the transmission of information over long distances within the body.

Cells of the Nervous System

The nervous system is composed of two primary cell types: neurons and glial cells.
Neurons: These cells are responsible for sending and receiving electrical impulses, commonly referred to as nerve impulses.
Glial Cells: This category encompasses a variety of cell types that support neuronal function.
Types of Neurons: - Sensory Neurons: A diverse group specialized in the detection of various stimuli. - Motor Neurons: These transmit signals from the Central Nervous System (CNS) to muscles and glands, a process known as innervation. - Interneurons: These process signals and facilitate information transmission between different parts of the nervous system.
Types of Glial Cells: - Microglia: These cells fight infections and are responsible for removing cellular debris. - Oligodendrocytes: These form the insulating myelin sheath around neurons located within the CNS. - Schwann Cells: These form the insulating myelin sheath around nerves in the peripheral nervous system. - Astrocytes: These control the access of blood-borne components into the extracellular fluid surrounding nerve cells, effectively forming the blood-brain barrier.

Structural and Functional Anatomy of Neurons

The neuron's cell body (soma) contains the nucleus and other standard endomembrane components, similar to other cell types.
Neurons feature specialized branches known as processes: - Dendrites: Processes specialized for receiving incoming signals from other neurons. - Axons: Processes specialized for conducting signals away from the cell body toward other cells.
Axon Features: - Axoplasm: The specific cytosol contained within the axon. - Myelin Sheath: A discontinuous, insulating layer surrounding many vertebrate axons. - Nodes of Ranvier: The gaps in the myelin sheath where the axon is exposed to the extracellular environment. - Nerve: A tissue composed of bundles of multiple axons. - Axon Hillock: The base of the axon where action potentials are typically initiated. - Synaptic Bouton/Terminal: The end branches of an axon that make contact with other cells.

Synaptic Foundations

Information is passed from one neuron to the next at a junction called a synapse.
This junction can occur between a nerve cell and another nerve cell, a gland, or a muscle cell.
Chemical Signaling: At the synapse, the synaptic terminal of one axon (the presynaptic cell) passes information to the receiving cell (the postsynaptic cell) via chemical messengers called neurotransmitters.
Integration occurs as dendrites receive signals and the axon transmits them, following a "one-way street" of signal flow.

Electrical Properties and Ion Movement

Neuron function is dictated by the movement of ions across the cell membrane through two mechanisms: - Ion Pumps: These use energy ( $ATP$ ) to move ions against their concentration gradients. - Ion Channels: These allow ions to move along their concentration gradients. Their full function depends on activation and the relative number of channels present.
Membrane Potential: Every cell possesses a voltage (electrical charge difference) across its plasma membrane.
Resting Potential: The membrane potential of a neuron when it is not sending signals. Changes in this potential serve as the basis for information processing and transmission.

Establishing and Maintaining the Resting Potential

In a mammalian neuron at resting potential, the ion concentrations are asymmetric: - Concentration of $K^+$ is highest inside the cell. - Concentration of $Na^+$ is highest outside the cell.
The Sodium-Potassium Pump ( $Na^+/K^+$ Pump): Uses $ATP$ to maintain these gradients by pumping sodium ions out and potassium ions in. - On average, the pump transports $3$ sodium ( $Na^+$ ) ions outward for every $2$ potassium ( $K^+$ ) ions inward.
Chemical Potential Energy: The concentration gradients of $Na^+$ and $K^+$ represent stored chemical potential energy.
Table 22-1: Ionic Concentrations Inside and Outside Axons and Neurons: - Squid Axon: - $Na^+$ : Outside $440\,mM$ , Inside $50\,mM$ - $K^+$ : Outside $20\,mM$ , Inside $400\,mM$ - $Cl^-$ : Outside $560\,mM$ , Inside $50\,mM$ - Mammalian Neuron (cat motor neuron): - $Na^+$ : Outside $145\,mM$ , Inside $10\,mM$ - $K^+$ : Outside $5\,mM$ , Inside $140\,mM$ - $Cl^-$ : Outside $125\,mM$ , Inside $10\,mM$

Conversion of Chemical Potential to Electrical Potential

Ion channels convert chemical potential to electrical potential.
Leak Channels: A resting neuron has many open $K^+$ leak channels and fewer open $Na^+$ leak channels. Consequently, $K^+$ diffuses out of the cell.
Charge Imbalance: The loss of positive $K^+$ ions leads to a buildup of negative charge within the neuron, which is the primary source of the negative resting membrane potential.
Ion Effects on Potential: - $K^+$ efflux makes the membrane potential more negative. - $Na^+$ influx drives the potential in a positive direction (depolarization). - $Cl^-$ tends to diffuse in but is largely repelled by the established negative membrane potential; increased $Cl^-$ permeability leads to hyperpolarization (more negative potential) and decreased excitability.

Electrical Excitability and Voltage-Gated Channels

Electrically excitable cells respond to stimuli with an action potential, a rapid series of changes in membrane potential.
These cells possess voltage-gated channels (in addition to leak channels and pumps).
Types of Channels: - Voltage-Gated Ion Channels: Respond specifically to changes in membrane voltage. - Ligand-Gated Ion Channels: Open when a specific molecule (ligand) binds to the channel.
Molecular Structure of Voltage-Gated Channels: - These channels contain specific domains that act as sensors and inactivators. - The S4 alpha helix acts as a voltage sensor, responding to changes in potential. - Selectivity Filter: Determines which specific ion passes through the pore. - Channel Gating: The open or closed state is "all-or-none." - Inactivation Partition: A second form of the closed state where the channel cannot reopen immediately after activation.

Phases of the Action Potential

An action potential involves a brief but large electrical depolarization and repolarization.
1. Resting State: All gated $Na^+$ and $K^+$ channels are closed. The resting potential is approximately $-60\,mV$ .
2. Depolarizing Phase: A stimulus triggers the opening of some $Na^+$ channels. If the membrane is depolarized by about $20\,mV$ to reach the threshold potential ( $\approx -40\,mV$ ), more $Na^+$ channels open. - Hodgkin Cycle: A positive feedback loop where $Na^+$ influx causes further depolarization, opening even more $Na^+$ channels. - The potential rapidly reaches a peak of approximately $+40\,mV$ .
3. Repolarizing Phase: $Na^+$ channels become inactivated and voltage-gated $K^+$ channels open. $K^+$ rushes out of the cell, returning the membrane to a negative potential.
4. Hyperpolarizing Phase (Undershoot): $K^+$ channels remain open slightly longer than needed, and $Na^+$ channels close. The membrane potential becomes more negative than the resting potential, reaching approximately $-75\,mV$ .
5. Return to Rest: As voltage-gated $K^+$ channels close, the membrane potential stabilizes back at $-60\,mV$ .

Refractory Periods

Absolute Refractory Period: A period of a few milliseconds during which it is impossible to trigger a second action potential because the sodium channels are in an inactivated state.
Relative Refractory Period: Occurs during the undershoot phase. Sodium channels can reopen, but because potassium channels are also open, the membrane potential is well below the threshold, making it very difficult to trigger another action potential.

Propagation of Electrical Signals

Passive Spread: Depolarization at one point spreads to adjacent regions but decreases in magnitude over distance.
Active Propagation: To travel long distances, the action potential must be actively regenerated along the membrane.
Mechanism in Nonmyelinated Axons: - Stimulation results in $Na^+$ influx and polarity reversal. - This depolarization spreads to nearby regions, which, if above threshold, trigger their own $Na^+$ influx. - The original region repolarizes as $K^+$ rushes out. The impulse moves only away from the initial site due to the refractory nature of the previous segment.

The Myelin Sheath and Saltatory Conduction

The myelin sheath serves as an electrical insulator, decreasing the membrane's capacitance (ability to retain charge).
This allows signals to spread further and faster.
Saltatory Propagation: In myelinated neurons, action potentials are renewed only at the Nodes of Ranvier. The depolarization "jumps" from one node to the next, which is significantly more rapid than continuous propagation.

Synaptic Transmission Mechanics

Electrical Synapses: The presynaptic and postsynaptic neurons are connected via gap junctions (formed by connexins). Ions move directly between cells with no transmission delay.
Chemical Synapses: The cells are separated by a synaptic cleft. Signals must be transmitted via neurotransmitters stored in neurosecretory vesicles.
Direct Action (Ionotropic): The neurotransmitter receptor is an ion channel itself.
Indirect Action (Metabotropic): The receptor exerts effects indirectly through messenger systems.

Neurotransmitters: Classification and Criteria

Criteria to be a Neurotransmitter: 1. Elicit the appropriate response when introduced to the synaptic cleft. 2. Occur naturally in the presynaptic neuron. 3. Be released at the correct time upon stimulation of the presynaptic neuron.
Primary Neurotransmitter Groups: - Acetylcholine: Excitatory; used in cholinergic synapses. - Catecholamines: Includes Dopamine, Norepinephrine, and Epinephrine; used in adrenergic synapses. - Amino Acids: Histamine, Serotonin (excitatory), $\gamma$ -amino butyric acid (GABA, inhibitory), Glycine (inhibitory), and Glutamate (excitatory). - Neuropeptides. - Gases and Lipids.
Receptor Effects: - Excitatory receptors cause depolarization. - Inhibitory receptors cause hyperpolarization.
Agonists and Antagonists: - Antagonists: Compete for receptors and prevent depolarization (e.g., substances competing with acetylcholine). - Agonists: Bind to receptors and cause depolarization but cannot be rapidly inactivated.

Mechanism of Neurotransmitter Secretion

An action potential arrives at the synaptic bouton.
Depolarization opens voltage-gated calcium channels.
$Ca^{2+}$ ions move into the terminal.
Synaptotagmin binds to the calcium, causing a conformational change that allows t-SNAREs and v-SNAREs to interact.
Vesicles "dock" at the active zone and fuse with the plasma membrane.
Neurotransmitter release: Released via exocytosis into the cleft. - Kiss-and-run exocytosis: A transient method where a vesicle fuses, releases some neurotransmitter, and immediately reseals.
Binding of neurotransmitter to postsynaptic receptors alters channel properties, allowing ion flow and potential action potential generation.

Neurotransmitter Inactivation and Regulation

Neurotransmitters must be removed shortly after release to prevent abnormally prolonged stimulation.
Degradation: Enzymes like Acetylcholinesterase hydrolyze neurotransmitters (e.g., Acetylcholine is broken into acetic acid and choline). - Potent inhibitors include carbamoyl esters, organic phosphates (insecticides like parathion/malathion), and nerve gases (tabun/sarin).
Reuptake: Pumping neurotransmitters back into the presynaptic cell or support cells. - Antidepressant drugs like Prozac work by blocking the reuptake of specific neurotransmitters.
Neurotoxins: Substances like tetanus and botulism interfere with the docking and release of vesicles at the synapse.