OBI 814 - Estus Lecture 2 - Exam 2

• These notes cover action potential mechanisms, synaptic transmission, and related topics in neuroscience.

Action Potentials and Synaptic Transmission

• This section will cover how neurons generate electrical signals and communicate with each other.

Learning Objectives

• Understand how the sodium-potassium ATPase generates ion gradients across cell membranes.
• Identify what contributes to setting the resting membrane potential.
• Describe ion movement patterns during action potential.
• Explain why action potentials move in one direction in axons.

Membrane Ion Channels

• Membrane ion channels allow for the diffusion of ions across the cell membrane.
• Passive channels allow ions to move along their concentration or electrical gradients.
• Ligand-gated ion channels open or close in response to a chemical ligand, like acetylcholine or glutamate.
• These channels facilitate ion movement based on concentration or electrical gradients.
• Voltage-gated ion channels open at specific membrane potentials; voltage-gated Na+ channels contain four homologous domains, each with a positively charged alpha helix (S4).
• When the cell interior is negative, the helix lies flat against the cytosol, closing the channel. If the cell is depolarized (more positive), the helix is repelled into the membrane, opening the channel.

Comparison of Na+ and K+ Voltage-Gated Channel Cycle

• Sodium Channels: These channels open and then rapidly inactivate.
• Potassium Channels: These open and close more slowly compared to sodium channels.
• After opening, sodium channels enter an inactive state.

Sodium-Potassium ATPase

• The sodium-potassium ATPase generates an ion imbalance across the plasma membrane.
• It pumps Na+ and K+ against their concentration gradients, consuming up to 40% of cellular ATP.
• The pump exchanges 3 Na+ ions out of the cell for every 2 K+ ions pumped in.
• This results in a negative charge inside the membrane.
• Combined with K+ leak channels, these pumps maintain approximate Na+ and K+ concentrations.
• Cytosol: Na+ at 14mM, K+ at 150mM; Extracellular: Na+ at 145mM, K+ at 3.5-5mM.

Ion Movement Direction

• The direction of ion diffusion through an open channel depends on electrical and concentration gradients.
• Sodium is driven into cells by its concentration gradient and the negative charge within the cell.
• Potassium is pushed out by its concentration gradient but pulled in by the negative charge.
• Concentration effects usually outweigh charge effects under physiological conditions.

Equilibrium Potential

• Equilibrium potential refers to the membrane potential at which there is no net ion movement.
• Sodium is high outside and low inside the cell; potassium is the opposite.
• The inside of the cell must be very positive to repel outside sodium and neutralize the concentration gradient effect.
• The cytosol must be very negative to keep potassium inside the cell, against its concentration gradient.

Nernst Equation

• The Nernst equation estimates equilibrium potential for a given ion across a membrane.
• The formula is Eion = 61/Z log (Cout/Cin), where:
  • Eion is the equilibrium potential for a given ion.
  • Z is the valence of the ion (Na+, K+, Cl- are all 1).
  • Cout is the concentration outside the cell.
  • Cin is the concentration inside the cell.
• For Na+: Eion = 61/1 log (145/15) ≈ +60 mV.
• For K+: Eion = 61/1 log (5/150) ≈ -90 mV.
• Sodium will rush into the cell, up to membrane potential +60mV. Potassium will rush out until the membrane potential is -90mV.

Sodium Gradient Regulation

• Cells use the sodium gradient to regulate other ions and chemicals of interest.
• Examples:
  • A Na+/glucose symporter uses the energy from letting two Na+ ions into the cell to transport one glucose into the cell.
  • A Na+/Ca+2 exchanger uses the energy from letting 3 Na+ ions into the cell to pump one Ca+2 out.

Resting Membrane Potential

• It is defined as the membrane potential of a non-stimulated cell, generally around -70mV.

Components of Resting Membrane Potential

• Balance results primarily from Na+/K+ ATPase activity and leaky K+ channels.
• Na+/K+ ATPase (a) maintains a negative membrane potential by pumping Na+ out and K+ into the cell, against their concentration gradients.
• Leaky K+ channels allow some K+ to flow out of the cell driven by its concentration gradient.
• There is minor Na+ influx through regulated channels.

Graded Potential

• A graded potential is a local change in membrane potential in response to stimulus.
• During depolarization, the membrane potential becomes less negative.
• During hyperpolarization, the membrane potential becomes more negative.
• These potentials decay with time and distance from the initial stimulus site.
• Several graded potentials close in time or space can summate or neutralize each other.

Action Potential Initiation

• The stimulus depolarizes the membrane, creating a graded membrane potential.
• Channels open in response to sufficient depolarization, causing further depolarization.
• Action potential starts if voltage-gated Na+ channels are present, that initiates a feed-forward chain reaction of Na+ channel opening.
• Na+ influx → depolarization → more Na+ channel opening → more Na+ influx = "action potential initiation."

Local Anesthetics

• Voltage-gated Na+ channels are primary targets of local anesthetics; Lidocaine/articaine are used to numb pain signaling
• They act by reversibly binding to and inhibiting voltage-gated Na+ channel and may also bind to other channels.
• Typically administered with epinephrine (a vasoconstrictor) to reduce bleeding.

Epilepsy

• Epilepsy is characterized by excessive neuronal firing, with a prevalence of less than 1%.
• Partial: affects only a part of the brain.
• Simple: awareness intact.
• Complex: impaired awareness with potential autonomic symptoms, abnormal sensations, hallucinations.
• Generalized: affects the entire cortex.
• Absence: staring, impaired consciousness, and eye blinking.
• Atonic: abrupt loss of muscle tone, loss of consciousness, and sudden collapse.
• Myoclonic: sudden jerking of arms and/or legs and impaired consciousness.
• Tonic-clonic: loss of consciousness, repetitive jerking, sustained stiffening, post-seizure amnesia, and cyanosis.

Treatment of Epileptic Dental Patients

• Obtain a thorough medical history, noting potential seizure triggers and frequency, and level of seizure control
• Schedule appointments when risk is low; if bright light is a trigger, be aware and minimize.
• Be aware of gingival hyperplasia due to phenytoin (anti-epileptic medication); surgical reduction may be needed. Prosthetic restorations must be durable and resistant to displacement to avoid choking hazards.
• If a seizure occurs, remove instruments, lay patient supine and on their side, and use passive restraint
• To help prevent them from falling out of the chair.

Action Potential Propagation in Axons

• Depolarization spreads by sequential opening of voltage-gated Na+ channels.
• Membrane ahead is depolarized toward threshold by local current.
• The movement is unidirectional because of Na+ channel inactivation and the resulting refractory period.

Saltatory Conduction

• Myelinated axons exhibit saltatory conduction, where action potentials “jump” from one node of Ranvier to the next.
• Insulation is provided by myelin, and voltage-gated Na+ channels are concentrated at nodes of Ranvier.
• These jumps are essential for fast conduction.

Function of Myelination

• Myelination increases action potential conduction velocity.
• Larger diameter neurons conduct faster due to less resistance.

Communication Between Neurons

• Electrical synapses: Depolarization spreads directly from one neuron to another via gap junctions.
• Chemical synapses: Depolarization induces neurotransmitter release at synapses to transfer information.

Electrical Synapses

• Rare instances where ions flux through direct connections formed by gap junctions, facilitating rapid and bidirectional communication.
• Mammalian hypothalamic neurons use these junctions to synchronously release hormones.
• Gap junctions also exist between astrocytes.

Chemical Synapses

• Neurotransmitters released from presynaptic neuron upon Ca+2 influx. Vesicles then fuse with plasma membrane, resulting in neurotransmitters that diffuse across synaptic cleft where they bind with postsynaptic cell.
• Can target neurons or tissues.
• Synapses are unidirectional.

Neurotransmitter Overview

• Small Molecule Transmitters: synthesized locally within the axon terminal.
• Peptide Transmitters: synthesized in cell body as a larger pre-peptide and processed in the endoplasmic reticulum, then packaged in Golgi and transported as storage vesicles down the axon to the terminal.

Neurotransmitter Receptor Overview

• Ionotropic: ligand-gated ion channel that causes opening in response to a stimulus. Causes rapid onset (<1 msec) and closing (10s of msec).
• Metabotropic: slower onset (2-10 msec) but more persistent (over 100 msec); G-protein is activated which results in varied cellular responses through an intracellular messenger.

Small Molecule Excitatory Neurotransmitters

• The most common excitatory neurotransmitter is Glutamate in the CNS.
• Ligand-gated glutamate receptors: Kainate and AMPA receptors that allow an influx of Na+ (as well as K+ in some cases), and depending on which subunits are present, can allow Ca2+ influx. There are also NMDA receptors.
• These also require partial depolarization in order to trigger a response as they are voltage sensitive.

Inhibitory Neurotransmitters

• Gamma-aminobutyric acid (GABA) is the most common inhibitory neurotransmitter in the brain.
• GABA_A and GABA_C receptors cause Cl- influx that results in cell to be hyperpolarized, and thus, harder to have action potentials
• GABA_B are metabotropic receptors.

Biogenic Amines

• These include catecholamines (dopamine, norepinephrine, epinephrine), norepinephrine and epinephrine: main stimulators for sympathetic neuron transmitters.
• Dopamine is critical for inhibiting Parkinson's Disease. Serotonin is responsible for mood control, temperature regulation, and sensory reception.

Biogenic Amine Synapse

Ca2+ causes vesicles to fuse with the plasma membrane, dumping its neurotransmitter, NE (neropinephrine ) into cleft where it activates receptor Removal of NE signals the activation to stop as it diffuses from synapse.

Neurotransmitters as Peptides

Peptides may act as hormones or neuromodulators and bind primarily metabotropic receptors. An example would be those of opioid peptides Example: Opioid peptides (enkephalins, endorphins, dynorphins).

Neurotransmitter Removal

Removal can be achieved through processes such as degradation, reuptake (glial or presynaptic), and diffusion from synaptic cleft/ combination of various mechansims

Small Molecule Neurotransmitter

Important ones to note are Acetylcholine (ACh) where it’s Synthesized by ChAT from acetyl-CoA and choline in an essentially diffusion limited process

Myasthenia Gravis

Autoimmune attacks ACh receptors. AChE (acetylcholinesterase inhibitors) increase [ACh] concentration. BBB prevents drug effects in central nervous system.

Explore neuron communication through electrical signals. Understand ion gradients, resting membrane potential, and action potential movement. Learn about membrane ion channels, including passive, ligand-gated, and voltage-gated channels, and their roles in neuronal function.