Updated Notes on Membrane Transport:

● Barrier Function of the Lipid Bilayer: The hydrophobic core of cell membranes restricts the movement of
polar molecules, helping to maintain different solute concentrations inside and outside the cell.
● Transport Proteins: Essential for moving solutes across membranes to intake nutrients, remove waste, and
regulate ions. Transport proteins are crucial, making up 15–30% of membrane proteins in cells, with certain
cells dedicating significant energy to transport.
● Types of Transport Proteins:
○ Transporters: Bind specific solutes and undergo shape changes to transfer them across the
membrane. They can mediate either passive or active transport.
○ Channels: Form narrow pores for passive movement of ions and small molecules based on size
and charge, always facilitating passive transport.
○ Aquaporins: Specialized channels that increase water permeability, facilitating rapid water
movement.
● Passive and Active Transport:
○ Passive Transport: Moves solutes down the concentration gradient (no energy needed), with the
direction determined by the concentration and membrane potential in charged molecules.
○ Active Transport: Moves solutes against the electrochemical gradient, requiring energy from
sources like ATP or ion gradients.
● Electrochemical Gradients: Created by varying ion concentrations and charges across the membrane,
these gradients store energy for cellular functions like ATP synthesis and electrical signaling.
● Example of Transport Dysfunction: Mutations in transport proteins can lead to transport disorders, like
cystinuria, where amino acid transport issues cause cystine kidney stones.
● Structure of Transport Proteins: All are multipass proteins, spanning the membrane multiple times and
forming pathways that allow hydrophilic molecules to bypass the lipid bilayer’s hydrophobic core.

Detailed Notes on Transporters and Active Transport Mechanisms

Transporter Mechanism:

○ Transporters transfer solute molecules across membranes similarly to enzyme-substrate

interactions. They bind solutes without modifying them, moving them across the lipid bilayer by
changing shape.
○ These conformational changes expose binding sites alternately to either side of the membrane,
ensuring the solute is inaccessible on both sides simultaneously (an "occluded" state).

Saturation and Transport Rate:

○ Transporters reach a maximum rate of transport (Vmax) when fully saturated. This rate reflects how
quickly a transporter can switch between conformations.
○ The transporter’s affinity for a solute is quantified as Km, the solute concentration at half of Vmax.

Inhibition:

○ Solute transport can be blocked by competitive inhibitors (bind to the same site) or noncompetitive
inhibitors (bind elsewhere, altering transporter structure).
Active Transport Mechanisms:

○ Cells use active transport to move solutes against electrochemical gradients. This process is
powered through:
■ Coupled Transporters: Utilize concentration gradients by coupling uphill transport of one
solute with the downhill transport of another.
■ ATP-driven Pumps: Use ATP hydrolysis to drive uphill transport.
■ Light-/Redox-driven Pumps: Found in bacteria and organelles, these use light or redox
reactions for energy.

Evolutionary Insight:

○ Structural similarities between passive and active transporters suggest evolutionary relationships.
For instance, certain bacterial H+^++-driven sugar transporters are structurally related to passive
glucose transporters in animal cells.

Classes of Transporters:

○ Uniporters: Move a single solute across the membrane passively.

○ Coupled Transporters: Can either:
■ Symporters (Co-transporters): Move two solutes in the same direction.
■ Antiporters (Exchangers): Move two solutes in opposite directions.

Coupled Transport Mechanism:

● Coupled transporters use the energy from an electrochemical gradient of one solute (often an inorganic ion)
to drive the transport of a second solute against its gradient.
● The movement of the ion down its gradient releases free energy, which is "harvested" to transport the
second solute uphill.
● Coupled transporters include:
○ Symporters (Co-transporters): Move both solutes in the same direction.
○ Antiporters (Exchangers): Move solutes in opposite directions.

Na+-Driven Coupled Transport in Animal Cells:

● In animal cell plasma membranes, Na+ commonly serves as the co-transported ion, providing substantial
driving force for active transport of another molecule.
● This Na+ is later removed by an ATP-driven Na+-K+ pump, which maintains the Na+ gradient, indirectly
powering coupled transport. This type of transport is known as secondary active transport.

Primary vs. Secondary Active Transport:

● Primary Active Transport: Directly driven by ATP hydrolysis, moving solutes against their gradients (e.g.,
Na+-K+ pump).
● Secondary Active Transport: Relies on the electrochemical gradient of an ion (e.g., Na+) to indirectly
power the transport of another molecule.

Examples in Epithelial Cells:

● Intestinal and Kidney Epithelial Cells: Use Na+-driven symporters to import related sugars or amino
acids. The Na+gradient "drags" the solute into the cell, increasing transport efficiency with a steeper
Na+gradient.
Structural Insights:

● Many transporters and channel proteins, such as aquaporins (water channels) and the Sec61 protein
channel, are built with inverted repeats in their structure, suggesting evolutionary adaptation and functional
efficiency.

Evolution of Channels from Transporters:

● Channels likely evolved from coupled transporters by losing their gating functions, allowing them to open to
both membrane sides simultaneously. This creates a continuous passage for ions and molecules.

H+vs. Na+Gradients Across Organisms:

● In bacteria, yeasts, plants, and animal cell organelles, H+ gradients, instead of Na+, commonly drive active
transport.
● For example, H+ gradients across bacterial membranes facilitate inward active transport of sugars and
amino acids.

Cytosolic pH Regulation via Plasma Membrane Transporters:

● Optimal enzyme function requires specific pH levels: lysosomal enzymes prefer acidic (~5), while cytosolic
enzymes need near-neutral (~7.2) pH.
● Cells maintain cytosolic pH with Na+^++-driven antiporters:
○ Na+-H+ Exchanger: Uses Na+ influx to export H+.
○ Na+-Driven Cl−--HCO3−​Exchanger: Imports Na+ and HCO3− while exporting Cl− and H+, twice
as effective at maintaining pH as the Na+-H+ exchanger.

Additional pH Control Mechanisms:

● Na+-Independent Cl−-−-HCO3−_−​Exchanger: Activated in alkaline conditions, exports HCO3−_3^-3−​to

lower cytosolic pH.
● H+ Pumps: In organelles like lysosomes, ATP-driven H+ pumps create an acidic environment, helping
maintain the organelle’s function.

Transcellular Transport in Epithelial Cells:

● In absorptive cells (e.g., intestinal cells), transporters are non-uniformly distributed across the membrane:
○ Apical Domain: Na+-linked symporters absorb nutrients.
○ Basolateral Domain: Uniporters release nutrients down the gradient into the bloodstream.
● Microvilli on the apical surface increase absorptive area, enhancing transport capacity by up to 25-fold.
Three Classes of ATP-Driven Pumps: ATP-driven pumps, or transport ATPases, use the energy from ATP
hydrolysis to move ions or solutes across membranes. There are three main classes:

● P-type Pumps: Multi-pass transmembrane proteins that phosphorylate themselves during their cycle. They
help maintain ion gradients (e.g., Na+, K+, Ca2+, H+).
● ABC Transporters: Primarily pump small molecules across membranes and differ structurally from P-type
pumps.
● V-type Pumps: Involved in pumping protons (H+) into organelles like lysosomes or vacuoles to acidify their
interiors.

F-type ATPases (ATP Synthases):

● F-type ATPases, related to V-type pumps, are responsible for ATP synthesis in bacteria, mitochondria, and
chloroplasts, typically using H+ gradients to produce ATP instead of using ATP hydrolysis to pump protons.

P-Type ATPase in Muscle Cells:

● The P-type Ca2+ ATPase in the sarcoplasmic reticulum (SR) of muscle cells pumps Ca2+ from the cytosol
back into the SR, crucial for muscle relaxation after contraction.
● The SR is a specialized endoplasmic reticulum in muscle cells, storing Ca2+until it's needed for contraction.

Maintaining Ionic Gradients:

● P-type pumps help maintain ionic gradients across cell membranes, especially for Ca2+, to control
processes like muscle contraction.
● Na+-Ca2+exchangers are also involved in controlling the Ca2+ gradient using the Na+electrochemical
gradient.

Molecular Mechanism of P-Type ATPases:

● Structure: P-type ATPases, including the SR Ca2+ pump, have 10 transmembrane α helices and three
cytosolic domains.
● Ca2+Pump Cycle:
○ Ca2+ binding triggers conformational changes.
○ ATP hydrolysis phosphorylates a conserved aspartate, causing a conformational change and Ca2+
release into the SR lumen.
○ Two Ca2+ ions are replaced by H+ and a water molecule to stabilize the binding site.
○ Hydrolysis of the phosphoryl-aspartate bond returns the pump to its initial conformation.

The Na+-K+ Pump:

● Function: Maintains Na+ and K+ gradients across the plasma membrane.

● Mechanism: Pumps three Na+ out and two K+ in per ATP, making it electrogenic and contributing to the
membrane potential.
● Energy Consumption: Uses a significant amount of cellular energy, especially in nerve cells and kidney
tubule cells.
ABC Transporters:

● Structure: Contain two ATP-binding cassettes (ATPase domains) that undergo conformational changes
upon ATP binding and hydrolysis.
● Function: Transport solutes by alternating exposure of binding sites on either side of the membrane.
● Importance: Largest family of membrane transport proteins, with clinical relevance. ABC transporters are
critical in bacterial nutrient uptake, among other processes.

1. Bacterial ABC Transporters:

○ Location: In bacteria like E. coli, ABC transporters are embedded in the inner membrane. Auxiliary
systems capture nutrients and deliver them to the transporters.
○ Function: Transport a variety of molecules including inorganic ions, amino acids, sugars, lipids,
and drugs.
2. Eukaryotic ABC Transporters:
○ Multidrug Resistance (MDR): Proteins like P-glycoprotein, found in cancer cells, pump out
hydrophobic drugs, leading to chemotherapy resistance. Up to 40% of cancers exhibit this
resistance.
○ Plasmodium Resistance: P. falciparum, the malaria parasite, develops resistance to chloroquine
via ABC transporters.
3. TAP Transporter:
○ Located in the ER membrane, it pumps peptides into the ER for antigen presentation to cytotoxic T
cells, important in immune response.
4. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR):
○ Function: CFTR controls Cl⁻ ion movement across epithelial cells in the lungs. Mutations cause
cystic fibrosis, characterized by improper ion regulation. Unlike other ABC transporters, CFTR
functions as a gated channel rather than using ATP to transport ions.
Channels and the Electrical Properties of Membranes

1. Channel Proteins: Unlike transporters, channels form pores across membranes, allowing molecules to
pass through. For example, gap junctions connect adjacent cells, but most ion channels in plasma
membranes are narrower and highly selective, enabling the passage of ions like Na+, K+, Ca2+, and Cl–.
2. Ion Channels: These channels are crucial for many cell functions, particularly in neurons. Ion channels
mediate passive transport (downhill), allowing ions to diffuse down their electrochemical gradients. They
are more efficient than transporters, moving up to 100 million ions per second.
3. Aquaporins: Special channels for water, aquaporins allow rapid water transport while blocking ions. They
achieve selectivity by having a narrow pore, permitting only water molecules to pass through, and preventing
the passage of hydrated ions. This is essential for maintaining cell volume and osmotic balance. Aquaporins
are crucial in cells that need to move large amounts of water, such as kidney and exocrine cells.

Key Concepts:

● Ion Channels: High selectivity, passive transport.

● Aquaporins: Selective water transport, blocking ions.

Aquaporin Selectivity

● Immunity to Ion Conductance: Aquaporins cannot conduct ions (K+, Na+, Ca2+, Cl–, or H+) due to their
narrow pore and specific structural features.
● H+ and Hydronium Ions (H3O+): Hydronium ions diffuse through water using hydrogen bond relay, which
aquaporins block.
● Asparagine Role: Two asparagines in the aquaporin pore bind to water molecules, preventing the H+ relay
by blocking the hydrogen bond-making process, making the pore impermeable to H+.
● Water Transport: The pore allows water to pass rapidly but prevents ions from disrupting cellular gradients.
● The hydrogen bond relay in aquaporins is a way water molecules move through the channel by "passing"
their hydrogen bonds to each other. As each water molecule enters the aquaporin channel, it forms a
hydrogen bond with the next water molecule, creating a chain. This allows water to move quickly through the
pore. However, ions like protons (H⁺) are blocked because they don’t form the same hydrogen-bonding
network and can't participate in the relay. This ensures that only water molecules pass through, not ions.
● In aquaporins, asparagine residues in the pore are key to blocking ions like H⁺. They bind directly to the
water molecules passing through, helping to hold onto them and prevent the formation of hydrogen bonds
that would allow protons to move through. This prevents H⁺ ions from using the "hydrogen bond relay"
system that they would normally use to move through water, ensuring that only water molecules can pass
through the channel.

Ion Channels: Key Properties and Function

1. Ion Selectivity:
○ Ion channels allow specific ions to pass through based on size and charge.
○ Channels have narrow pores where ions lose water molecules to pass through, often in single file.
○ The selectivity filter controls which ions can pass.
2. Gating Mechanism:
○ Ion channels are gated (can open/close), unlike continuous pores.
○ Gates open in response to:
■ Voltage changes (voltage-gated)
■ Mechanical stress (mechanically gated)
■ Ligand binding (ligand-gated)
○ Channels can also be regulated by phosphorylation and dephosphorylation.
3. K+ Leak Channels:
○ Common in plasma membranes.
○ Important for maintaining the membrane potential by allowing K+ to move freely.
 ○ Contribute significantly to cell’s resting membrane potential, alongside other ion gradients.
4. Membrane Potential:
○ Generated by differences in ion concentrations, especially K+.
○ Nernst equation can calculate theoretical membrane potential.
○ K+ Leak Channels establish an equilibrium condition where K+ movement stops when electrical
and concentration gradients balance.
5. Effect of Na+-K+ Pump:
○ The Na+-K+ pump helps maintain ion gradients, affecting membrane potential.
○ Without the pump, the K+ equilibrium mechanism persists for a while, but Na+ leaks in, reducing
the resting potential over time.
6. Resting Membrane Potential:
○ Varies between -20 mV to -120 mV depending on the cell type.
○ Affected by ion permeability and gradients.
○ Ion channels play a critical role in changing membrane potentials, crucial for cellular excitability.

Structure and Function of a Bacterial K+ Channel

1. Channel Structure:
○ Composed of four identical transmembrane subunits forming a central pore.
○ Each subunit has:
■ Two transmembrane α-helices, tilted outward, forming a cone.
■ A pore helix and selectivity loop, which protrude into the cone’s wide section, creating
the selectivity filter.
2. Selectivity Filter:
○ Short, rigid, narrow pore lined with carbonyl oxygen atoms from the peptide backbone.
○ K+ ions shed water molecules to interact with these oxygens.
○ Oxygens are spaced to fit K+ ions perfectly but are too far apart to stabilize smaller Na+ ions.
3. Ion Selectivity:
○ K+ ions pass through due to optimal interaction with carbonyl oxygens.
○ Na+ ions cannot enter due to insufficient stabilization after losing water molecules.
4. Channel Gating:
○ Ion channels open and close by movements of helices:
■ Closed State: Inner helices tilt, constricting the pore and blocking ions with bulky
hydrophobic amino acids.
■ Open State: Helices tilt, rotate, or bend to allow ion flow.
○ Gating is coupled to:
■ Ligand binding.
■ Changes in membrane potential.
■ Other conformational changes.
5. Mechanism of Action:
○ Gating helices are allosterically linked to the ion-conducting pathway.
○ Conformational changes in the gating domain directly influence the channel’s open or closed state.

Mechanosensitive Channels in Bacteria: Response to Osmotic Pressure

1. Role and Importance:

○ Mechanosensitive channels allow cells to sense and respond to mechanical forces like osmotic
pressure, membrane bending, and environmental stress.
○ In bacteria, these channels protect against extreme osmotic pressure by releasing small molecules
to prevent cell rupture.
2. Mechanism in Hypotonic Conditions:
○ Under hypotonic stress (e.g., rainwater), water influx increases osmotic pressure.
○ Mechanosensitive channels open to release small molecules (amino acids, sugars, ions) while
retaining macromolecules, enabling recovery once conditions normalize.
 3. Channel Types:
○ MscS (Small Conductance Channel):
■ Opens at low/moderate pressure.
■ Composed of 7 subunits forming a 1.3 nm pore for small molecules and ions.
○ MscL (Large Conductance Channel):
■ Opens under high pressure, forming a >3 nm pore to release molecules before cell
bursting.
4. Structural Insights:
○ Channels embed in the lipid bilayer and respond to membrane stretching.
○ Large cytoplasmic domains limit the size of molecules entering the channel.
5. Experimental Demonstrations:
○ Biophysical studies apply forces (e.g., micropipette suction) on lipid bilayers containing these
channels.
○ Different mechanosensitive channels activate at varying pressure thresholds.
6. Challenges in Study:
○ Mechanosensitive ion channels are rare and embedded in complex cellular structures, complicating
reconstitution and analysis.

Structure and Function of Neurons

1. Purpose and Tasks:

○ Neurons are specialized to receive, conduct, and transmit signals.
○ The elongated structure is essential for efficient signal transmission, often spanning long distances
(e.g., up to 1 meter in humans).
2. Structure:
○ Cell Body: Contains the nucleus and integrates signals.
○ Axon: Long projection transmitting signals away from the cell body to distant targets. Axons often
branch to connect multiple targets.
○ Dendrites: Short, branching processes receiving signals from other neurons, sometimes
accommodating up to 100,000 inputs.
3. Signal Transmission:
○ Passive Spread: For short distances, signals pass without amplification, adequate for small
neurons.
○ Active Signaling (Action Potential):
■ Used in larger neurons for long-distance communication.
■ Electrical disturbances are amplified as they propagate along the plasma membrane.
■ Signals travel rapidly (up to 100 m/s) without weakening.
4. Action Potential:
○ Triggered when a stimulus exceeds a threshold.
○ Propagates as a wave of electrical excitation across the axon.
○ Enabled by voltage-gated cation channels, ensuring consistent signal strength.

Voltage-Gated Cation Channels and Action Potentials

1. Electrically Excitable Cells:

○ Found in neurons, muscle, endocrine, and egg cells.
○ Voltage-gated cation channels generate action potentials in response to membrane depolarization
(shift to less negative potential).
2. Action Potential Mechanism:
○ Trigger: Depolarization opens voltage-gated Na⁺ channels, allowing Na⁺ influx.
○ Positive Feedback: Influx amplifies depolarization, opening more channels.
○ Membrane potential shifts from resting (-70 mV) to near Na⁺ equilibrium potential (+50 mV).
3. Prevention of Overactivation:
○ Na⁺ Channel Inactivation: Channels automatically close, stopping Na⁺ entry.
 ○ Voltage-Gated K⁺ Channels: Open to restore negative membrane potential.
4. Na⁺ Channel Structure:
○ Four homologous domains (evolved from gene duplication).
○ Each domain has an S4 helix acting as a voltage sensor with positively charged residues.
5. Refractory Period:
○ Na⁺ channels remain inactive until the membrane repolarizes.
○ Limits the frequency of action potential firing.
6. Propagation:
○ Local depolarization spreads to adjacent regions, triggering a wave of action potentials along the
membrane.

The Use of Channelrhodopsins in Neural Circuit Studies

1. Overview:
○ Channelrhodopsins are photosensitive ion channels derived from photosynthetic green algae.
○ Respond to light by opening ion channels, allowing cation influx.
○ Use retinal as a light-sensitive molecule that triggers conformational changes to open the channel.
2. Mechanism:
○ Similar to bacteriorhodopsin in structure but functions as a light-driven cation channel instead of a
proton pump.
3. Applications in Research:
○ Genetic Engineering: Channelrhodopsins can be expressed in various cells using genetic
techniques.
○ Neuron Activation: Light flashes can precisely control neuronal firing rates in cultured neurons
and in vivo.
○ Behavioral Studies: Channelrhodopsins were used to activate specific neuronal populations, e.g.,
aggression circuits in mice, demonstrating light-controlled behavior modulation.

Myelination and Action Potential Propagation

1. Function of Myelination:
○ Myelin sheaths insulate axons, significantly increasing the speed and efficiency of action potential
conduction.
○ In diseases like multiple sclerosis, the destruction of myelin impairs nerve impulse propagation,
causing severe neurological effects.
2. Formation:
○ Schwann Cells: Myelinate axons in peripheral nerves.
○ Oligodendrocytes: Myelinate axons in the central nervous system.
○ Myelinating glial cells wrap their plasma membrane in tight spirals around the axon, reducing
current leakage.
3. Nodes of Ranvier:
○ Small, unmyelinated gaps where Na⁺ channels concentrate.
○ Action potentials "jump" between nodes via saltatory conduction.
4. Advantages:
○ Speed: Faster propagation of action potentials.
○ Efficiency: Reduced energy expenditure since depolarization is confined to the nodes.
Findings from Patch-Clamp Studies

● All-or-Nothing Channel Behavior:

○ Ion channels open and close randomly.
○ When open, channels exhibit uniform conductance, allowing ~1000 ions/millisecond to pass.
● Aggregate vs. Individual Currents:
○ Whole-cell currents reflect the number of open channels, not individual channel behavior.
○ Individual channels contribute to the summed current.

Voltage-Gated Na⁺ Channels

● Opening Mechanism:
○ Sensitive to the electrical field across the membrane (~100,000 V/cm due to the 40–100 mV
potential difference across a ~5 nm thick membrane).
○ Conformations (closed, open, inactivated) shift based on random thermal movements and changes
in membrane potential.
○ Voltage changes alter the stability of these states.

Physical Principles of Voltage-Gating

● Electrical Field Effects:

○ Charged proteins, such as Na⁺ channels, respond strongly to the high voltage gradient across the
membrane.
● Conformational Flipping:
○ Channels switch states when random thermal energy or membrane potential shifts destabilize their
current state.
○ This results in voltage-gating properties observed during action potential propagation.

Voltage-Gated Cation Channels Are Evolutionarily and Structurally Related

Overview of Voltage-Gated Cation Channels

● Types of Channels:
○ Include Na⁺, K⁺, and Ca²⁺ channels.
○ Enable action potential generation in various cell types (e.g., neurons, muscle, endocrine, and egg
cells).
○ Structural and functional diversity arises from:
■ Multiple genes encoding these channels.
■ Alternative splicing of RNA transcripts.

Evolutionary Relationships

● Shared Superfamily:
○ Na⁺, K⁺, and Ca²⁺ channels share significant amino acid sequence similarities.
○ Reflect common evolutionary origins and similar design principles.
● Example of Diversity:
○ Yeast (S. cerevisiae): Contains a single voltage-gated K⁺ channel gene.
○ Worm (C. elegans): Possesses 68 genes for different K⁺ channels, highlighting the complexity of
even simple nervous systems.
Clinical Relevance

● Diseases Linked to Mutations:

○ Mutant genes encoding ion channels can cause diseases in nerves, muscles, brain, or heart,
depending on the affected cell type.
○ Examples:
■ Myotonia:
■ Caused by mutations in Na⁺ channels in skeletal muscle.
■ Leads to delayed muscle relaxation due to defective inactivation, causing
prolonged Na⁺ entry and repeated depolarization.
■ Epilepsy:
■ Linked to mutations in Na⁺ or K⁺ channels in the brain.
■ Results in excessive synchronized neuronal firing, leading to seizures.

Role in Neuronal Function

● Diversity of Neuronal Responses:

○ The specific combination of Na⁺, K⁺, and Ca²⁺ channels in neurons determines their firing patterns:
■ High-Frequency Firing: Up to 300 action potentials per second.
■ Burst Firing: Short bursts of action potentials separated by silence.
■ Minimal Firing: Rare action potentials.
○ This diversity underpins the complexity of brain functions.

Different Neuron Types and Synaptic Transmission

Neuron Types and Stable Firing Properties

1. Neuronal Diversity:
○ Human brain has ~10¹¹ neurons and ~10¹⁴ synapses.
○ Neurons adjust ion channel expression to maintain stability amidst constant changes in
connections, learning, and aging.
2. Self-Tuning Mechanism:
○ Neurons regulate the number of depolarizing (Na⁺, Ca²⁺) and hyperpolarizing (K⁺) ion channels.
○ Homeostatic control preserves characteristic firing patterns (e.g., high-frequency or rare firing).
3. Unresolved Mystery:
○ Mechanisms underlying this ion channel adjustment remain unclear but are crucial for neuronal
stability.
Transmitter-Gated Ion Channels at Synapses

1. Mechanism of Chemical Transmission:

○ Presynaptic Steps:
■ Action potential triggers voltage-gated Ca²⁺ channel opening.
■ Ca²⁺ influx induces neurotransmitter release from synaptic vesicles via exocytosis.
○ Postsynaptic Steps:
■ Neurotransmitters diffuse across the synaptic cleft.
■ Bind to transmitter-gated ion channels (ionotropic receptors), causing a transient
permeability change.
2. Signal Termination:
○ Rapid neurotransmitter removal by:
■ Enzymatic degradation.
■ Reuptake into the presynaptic neuron or surrounding glial cells.
○ Ensures precise spatial and temporal control of signaling.
3. Graded Response:
○ Transmitter-gated channels produce local depolarizations.
○ Summation of these depolarizations can trigger action potentials by opening nearby voltage-gated
channels.
4. Comparison with Electrical Synapses:
○ Chemical Synapses:
■ More versatile and adaptable.
■ Rely on neurotransmitter-induced signals.
○ Electrical Synapses:
■ Utilize direct ion flow via gap junctions, less common in neurons.

Chemical Synapses - Excitatory and Inhibitory

Types of Chemical Synapses:

1. Excitatory Synapses:
○ Open cation channels (e.g., Na⁺, Ca²⁺).
○ Cause depolarization, moving the membrane potential closer to the action potential threshold.
○ Common neurotransmitters: Acetylcholine, Glutamate, Serotonin.
2. Inhibitory Synapses:
○ Open Cl⁻ channels or K⁺ channels.
○ Cause hyperpolarization, making it harder to reach the threshold.
○ Common neurotransmitters: GABA, Glycine.
○ Example: Cl⁻ channels buffer depolarization by allowing Cl⁻ influx to counteract positive charges.
3. Dual Role of Neurotransmitters:
○ A single neurotransmitter (e.g., acetylcholine) can be excitatory or inhibitory depending on receptor
type and ionic environment.

Types of Neurotransmitter Receptors:

1. Ionotropic Receptors (Fast):

○ Ligand-gated ion channels directly mediate rapid signaling.
○ Found at synapses using Acetylcholine, Glycine, Glutamate, GABA.
○ Response: Immediate, brief.
2. Metabotropic Receptors (Slow):
○ G-protein-coupled receptors indirectly affect ion channels.
○ Used by most neurotransmitters, including Acetylcholine, Glutamate, GABA.
○ Response: Slower, more complex, and long-lasting.
Acetylcholine Receptor at Neuromuscular Junction:

1. Structure:
○ Pentameric receptor with 5 transmembrane subunits.
○ Two identical subunits have acetylcholine-binding sites.
2. Mechanism:
○ Binding of 2 acetylcholine molecules induces conformational change, opening the channel.
○ Allows Na⁺ influx, leading to depolarization.
○ Channel flickers between open and closed states with ~90% probability of being open when bound
to acetylcholine.
3. Regulation:
○ Acetylcholinesterase hydrolyzes acetylcholine to terminate signaling.
○ Channel closes within ~1 ms, avoiding desensitization (occurs after prolonged stimulation).

Pathophysiological Insight:

● Toxins:
○ E.g., Strychnine blocks glycine receptors, causing muscle spasms and convulsions by preventing
inhibitory signaling.

Structure and Function of the Acetylcholine Receptor

Structure:

● Pentameric arrangement: Five subunits form a ring with a water-filled transmembrane channel.
● Pore structure:
○ Narrow central pore widens into vestibules at both ends.
○ Hydrophobic amino acid ring blocks the channel in the closed state.
○ Acetylcholine binding rotates pore-lining helices outward, disrupting the hydrophobic ring and
opening the channel.
● Charge selectivity:
○ Clusters of negatively charged amino acids at both ends exclude negative ions and allow
positive ions (diameter < 0.65 nm) to pass.

Ion Flow:

● Selectivity: Allows Na⁺, K⁺, and some Ca²⁺, with little preference between cations.
● Driving forces:
○ For Na⁺: Voltage and concentration gradients drive large influx into the cell.
○ For K⁺: Net driving force is near zero at resting potential.
○ For Ca²⁺: Minor contribution due to lower extracellular concentration.
● Ion flux rate: Peak of ~30,000 Na⁺ ions per channel per millisecond.

Function:

● Membrane depolarization:
○ Na⁺ influx leads to depolarization of the muscle membrane.
○ Depolarization signals muscle contraction.

This rapid and precise ion transport enables acetylcholine-receptor channels to mediate neuromuscular
communication effectively.
Diversity of Transmitter-Gated Channels in Neurons

Structural Similarities and Differences:

● Common structure:
○ Channels for acetylcholine, serotonin, GABA, and glycine:
■ Made of homologous subunits forming pentameric transmembrane pores.
■ Similar mechanism to ionotropic acetylcholine receptors.
○ Glutamate-gated channels:
■ Built from a distinct family of subunits.
■ Assemble as tetramers, resembling K⁺ channels.

Subunit Diversity:

● Each class of transmitter-gated ion channel has multiple subunit forms:

○ Encoded by distinct genes or produced via alternative RNA splicing.
○ Subunits combine in diverse ways to create channel subtypes.
● Subtypes differ in:
○ Ligand-binding affinities.
○ Channel conductance and ion selectivity.
○ Opening/closing rates.
○ Drug and toxin sensitivities.

Example: Acetylcholine-Gated Channels:

● Neuronal channels differ from muscle cell channels:

○ Composed of two subunits of one type and three of another.
○ Gene diversity:
■ At least nine genes for one subunit type.
■ At least three genes for the other type.
○ Subunit combinations vary across neuronal subpopulations.

Psychoactive Drugs and Their Effects on Synapses

Drugs Targeting Transmitter-Gated Ion Channels:

● Curare:
○ Blocks acetylcholine receptors on skeletal muscles.
○ Causes muscle relaxation; used in surgery.
● GABA Receptor Modulators:
○ Drugs like barbiturates, Valium, and Ambien bind to GABA receptors.
○ Potentiate GABA's inhibitory effects, enabling lower concentrations to open Cl⁻ channels.
○ Used for treating insomnia, anxiety, and other conditions.

Reuptake Inhibitors:

● After neurotransmitter release, Na⁺-driven symporters clear neurotransmitters via reuptake.

● Antidepressants:
○ E.g., Prozac inhibits serotonin reuptake.
○ Others target both serotonin and norepinephrine reuptake, enhancing synaptic transmission.
Neuromuscular Transmission and Ion Channel Activation

Overview

Neuromuscular transmission involves a sequential activation of at least five ion channel types to convert a nerve
impulse into muscle contraction within milliseconds.

Steps in the Process

1. Arrival of Nerve Impulse

● Nerve Terminal Depolarization:

○ Voltage-gated Ca²⁺ channels open in the presynaptic membrane.
○ Ca²⁺ influx triggers acetylcholine (ACh) release via exocytosis into the synaptic cleft.

2. Acetylcholine Action

● ACh binds to its receptors in the muscle cell membrane.

● Opens cation channels leading to Na⁺ influx and local depolarization.

3. Propagation of Action Potential

● Voltage-gated Na⁺ channels amplify the depolarization.

● A self-propagating action potential spreads across the muscle membrane.

4. T-Tubule Activation

● Generalized depolarization activates voltage-gated Ca²⁺ channels in T-tubules.

5. Sarcoplasmic Reticulum (SR) Ca²⁺ Release

● T-tubule Ca²⁺ channels trigger Ca²⁺-release channels in the SR via mechanical coupling.
● Stored Ca²⁺ is released into the cytosol.

6. Muscle Contraction

● The cytosolic Ca²⁺ surge stimulates myofibril contraction.

Key Features

● Precision and Speed: Multiple channels coordinate to produce rapid, precise signaling.
● Structural Coupling: T-tubule and SR channels work in tandem for effective Ca²⁺ release.

Single Neurons as Complex Computational Devices

Overview

● Neurons in the central nervous system are highly interconnected and can process vast amounts of input.
● A single neuron can receive signals from thousands of other neurons and, in turn, form connections with
many other cells.
Structure and Input Integration

1. Synaptic Inputs:
○ A motor neuron in the spinal cord can have thousands of synapses covering its dendrites and cell
body.
○ These synapses include:
■ Excitatory inputs (e.g., brain/spinal cord signals).
■ Inhibitory inputs (e.g., sensory feedback from muscles or skin).
2. Postsynaptic Potentials (PSPs):
○ Excitatory PSPs (EPSPs): Small membrane depolarizations.
○ Inhibitory PSPs (IPSPs): Small hyperpolarizations.
○ Individual PSPs are localized and decrease with distance from the synapse.

Signal Processing

● Summation:
○ Signals from multiple synapses are summed in the dendritic tree.
○ Total PSPs in a region combine, with inhibitory signals reducing the overall PSP.
● Threshold for Action Potentials:
○ Most dendrites/cell bodies lack sufficient voltage-gated Na⁺ channels to fire an action potential
directly.
○ PSPs must converge on the cell body and be strong enough to cross the threshold.
● Encoding and Output:
○ Combined PSP magnitude is encoded into the frequency of action potentials.
○ Greater depolarization → Higher frequency of action potentials.

Functional Implications

● Neurons integrate diverse inputs (excitatory/inhibitory) to decide whether to fire.

● Their ability to process signals is key to controlling movement, sensory interpretation, and complex
behaviors.

Neuronal Computation and K⁺ Channels

Encoding Stimulus Intensity

1. Action Potential Frequency Encoding:

○ Intensity of neuronal stimulation is encoded in action potential frequency.
○ Occurs at the axon hillock (initial segment), where the axon meets the cell body.
○ This region contains a high density of voltage-gated Na⁺ channels and at least three types of K⁺
channels.
2. Three Types of K⁺ Channels:
○ Delayed K⁺ Channels:
■ Open during the action potential’s falling phase.
■ Restore membrane potential to allow Na⁺ channels to recover from inactivation.
○ Rapidly Inactivating K⁺ Channels:
■ Modulate firing rate near the threshold, ensuring firing frequency is proportional to
stimulus intensity.
○ Ca²⁺-Activated K⁺ Channels:
■ Reduce responsiveness to prolonged stimuli, facilitating adaptation.
Role of Ca²⁺ Channels in Adaptation

● Voltage-Gated Ca²⁺ Channels:

○ Open during action potentials, allowing Ca²⁺ influx.
● Ca²⁺-Activated K⁺ Channels:
○ Respond to increased cytosolic Ca²⁺ levels.
○ Slow firing rate during prolonged stimulation, enabling neurons to detect changes rather than
constant signals.

Synaptic Plasticity and Learning

1. Long-Term Potentiation (LTP):

○ Strengthens synaptic transmission after repetitive presynaptic activity.
○ Depends on NMDA receptors, which:
■ Open only when glutamate binds and the membrane is depolarized.
■ Allow Ca²⁺ influx, triggering downstream changes.
○ Enhanced sensitivity is achieved by adding AMPA receptors to the postsynaptic membrane.
2. Long-Term Depression (LTD):
○ Weakens synaptic strength by reducing AMPA receptors.
○ Also requires NMDA receptor activation and modest Ca²⁺ levels.

Ion Channels and Synaptic Complexity

● Functional Diversity:
○ Hundreds of ion channel genes, alternative splicing, and subunit combinations allow neurons to
perform specialized functions.
● Synaptic Location:
○ K⁺ and Ca²⁺ channels are strategically located for distinct tasks, e.g.,:
■ Encoding action potentials at the axon hillock.
■ Modulating inputs at dendrites.
● Plasticity in Learning:
○ Changes in synaptic strength underlie learning and memory, aided by glutamate-gated channels
like AMPA and NMDA receptors.

Adaptation and Computational Strategy

● Neurons adapt to prolonged stimuli to stay responsive to changes (e.g., detecting a light touch despite
background pressure).
● This adaptability is essential for encoding nuanced information.