Principles of Neurologic Communication

What makes a cell excitable?

It can undergo rapid, brief changes in membrane potential that serve as electrical signals; neurons and muscle cells are classic excitable cells.

What three types of cells can a neuron signal?

Other neurons, muscle cells, and glands.

What is membrane potential?

The electrical voltage difference across a cell's plasma membrane, produced by unequal ion distribution and selective membrane permeability.

• The tendency for opposing-charged ions to move back towards each other can be harnessed for cell work (potential energy)

• The separated charges have the potential to perform work

At rest, how is a typical neuron polarized?

Its interior is negative relative to the extracellular fluid, commonly about -70 mV.

What structural feature of the plasma membrane blocks free ion movement?

The hydrophobic interior of the phospholipid bilayer.

Explain the Na+/K+ ATPase: transport, electrical effect, and importance.

• It is an active transport pump that uses ATP to move 3 Na+ out and 2 K+ into the cell per cycle

• Exports one more positive charge than it imports, making the inside relatively less positive, and establishes/maintains the Na+ and K+ gradients used for electrical signaling and action potentials

What three influences produce a neuron's negative resting membrane potential?

1. The electrogenic Na+/K+ATPase pump

   1. Pumping 3 Na+ out and 2 K+ in

2. Large negatively charged intracellular proteins that cannot readily cross the membrane (exist inside the cell and stay there)

3. Greater K+ than Na+ leak permeability, so K+ tends to diffuse out and leaves relatively negative charge behind.

Name the dominant extracellular cation, intracellular cation, and extracellular anion.

• Extracellular cation: Na+

• Intracellular cation: K+

• Extracellular anion: Cl-.

What does it mean for a membrane to be selectively permeable?

Some substances cross it more readily than others, usually because particular channels or transporters are present.

What is the electrochemical gradient for an ion?

The combined influence of its concentration gradient and the electrical attraction or repulsion created by membrane voltage.

Predict ion movement and Vm change when Na+, K+, or Cl- channels open at resting potential.

• Na+ usually enters and depolarizes the cell

• K+ usually exits and repolarizes or hyperpolarizes the cell

• Cl- commonly enters and makes the interior more negative, producing hyperpolarization or inhibition.

Define depolarization, repolarization, and hyperpolarization.

• Depolarization: Vm moves toward zero/more positive

• Repolarization: Vm returns toward its resting negative value after depolarization.

• Hyperpolarization: Vm becomes more negative than its usual resting value.

Does “resting membrane potential” mean the cell is inactive?

No. Ions and pumps remain active; it means the cell is not currently firing an action potential.

Compare leak and gated ion channels, including the four gating mechanisms.

• Leak channels are open and provide continual passive ion movement

• Gated channels open or close in response to a stimulus: voltage, chemical/ligand binding, mechanical deformation, or temperature.

Describe graded potentials: location, amplitude, polarity, and decremental nature.

• Local, variable-amplitude changes that commonly arise on dendrites and the cell body

• Size depends on stimulus strength and number/type of channels opened

• Can depolarize toward threshold or hyperpolarize away from threshold

• Decrease with time and distance as current leaks across the membrane.

Describe the process of going from resting potential to graded potential

• Starts at resting potential at some membrane segment in a neuron’s dendrite (input zone)

• Triggering event (i.e. action potential from an upstream neuron) opens ion channels → Na+ enters

• Na enters → membrane depolarizes → graded potential produced

• Those Na+ ions move lengthwise along the segments proximal and distal to the initiation point

Compare spatial and temporal summation.

• Spatial summation is addition of graded potentials arriving at different locations at about the same time

• Temporal summation is addition of repeated graded potentials arriving at the same synapse in rapid succession.

Why do graded potentials fade with distance?

• There is current loss across the membrane due to dissipation of charge from K+ leak channels

• A few micrometers away, there’s no more depolarization and the voltage goes farther from the stimulus/back to resting

• Graded potential has died out

If K+ leak channels were blocked, what would happen to resting potential and excitability?

The membrane would become less negative and closer to threshold, making inappropriate repetitive action potentials more likely.

What is the trigger zone, and why is it specialized for action-potential initiation?

It is the axon hillock/initial segment. It integrates incoming graded potentials and has a high density of voltage-gated Na+ channels.

What are the main functional regions of a neuron?

• Receiving region: dendrites/cell body

• Trigger zone: axon hillock

• Conducting region: axon

• Secretory region: axon terminals

What is threshold potential?

The critical membrane voltage at which sufficient voltage-gated Na+ channels open to initiate a self-propagating action potential; often near -55 mV.

Describe an action potential: all-or-none behavior, coding of stimulus intensity, and propagation.

• It is a rapid, all-or-none reversal of membrane potential that propagates without decrement

• Once threshold is reached it has a stereotyped full amplitude

  • Subthreshold stimulus produces nothing

• Intensity is encoded by firing frequency and recruitment of additional neurons, not AP size

• Each axon segment brings the next to threshold, regenerating the signal.

Outline the ion-channel basis of an action potential: depolarization through after-hyperpolarization.

• Depolarization begins when voltage-gated Na+ channels open and Na+ enters the cell

• Na+ channels then inactivate

• Repolarization results from Na+ inactivation plus delayed/slow opening of voltage-gated K+ channels and K+ moving out of the cell

• Hyperpolarization occurs because K+ channels close slowly, allowing continued K+ outflow.

• The Na+/K+ pumps are always active. They help return the ions to their respective spaces across the membrane and reestablish resting potential

Describe voltage-gated Na+ channel states, activation, and inactivation.

• States: closed but able to open; open (activated); and inactivated (closed and temporarily unable to open)

• For the open state, the activation gate will readily open rapidly at threshold, allowing Na+ influx

• Inactivation time refers to the slow closing of the inactivate gate that is triggered at the threshold (shortly after opening)

  • Even if depolarization continues, the channel must repolarize and reset to the closed-capable state before reopening.

Describe voltage-gated K+ channel states and timing.

They are closed or open. They are “delayed” because they open more slowly than voltage-gated Na+ channels after depolarization begins.

Compare the absolute and relative refractory periods, including one-way conduction.

• Absolute: no second/new AP can begin because voltage-gated Na+ channels are open or inactivated

  • It prevents the just-activated segment from firing again and ensures one-way propagation (travels unidirectionally)

• Relative: a stronger-than-normal stimulus is needed to produce a second AP because the membrane is hyperpolarized and some Na+ channels are resetting.

How do myelination and saltatory conduction increase conduction speed?

Myelin insulates the axon, decreases current loss, and confines most action-potential regeneration to nodes of Ranvier. The signal therefore appears to “jump” node to node (saltatory conduction).

Which axons conduct action potentials faster: larger or smaller diameter?

Larger-diameter axons, because they have lower internal resistance to current flow.

What would local anesthetics ending in “-caine” generally do to neuronal signaling?

They block voltage-gated Na+ channels, preventing action-potential initiation or propagation.

Scenario: a toxin keeps voltage-gated Na+ channels open. What immediate effect is most likely?

Persistent Na+ influx and sustained depolarization, followed by loss of normal excitability as channels inactivate and ion gradients are disrupted.

Scenario: a neuron receives a small depolarization that never reaches threshold. Does it fire an action potential?

No; it produces only a graded potential that fades unless summation brings the trigger zone to threshold.

Identify the parts of a chemical synapse.

A synapse is a specialized junction where a neuron communicates with another neuron, muscle, or gland

• The presynaptic terminal/synaptic knob is the axon ending that releases neurotransmitter

• The synaptic cleft is the narrow extracellular gap

• The postsynaptic membrane is the target membrane containing responsive receptors.

Outline chemical synaptic transmission, including Ca2+ driving force and receptor effect.

• An AP arrives, opening presynaptic voltage-gated Ca2+ channels

• Ca2+ enters because extracellular Ca2+ is high and the cell interior is relatively negative

• Ca2+ triggers vesicle fusion and exocytosis (vesicle fusion with plasma membrane)

• Neurotransmitter diffuses across the cleft, binds postsynaptic chemically gated receptor-channels, and changes their conformation to open/close ion channels and alter postsynaptic Vm.

What is an excitatory postsynaptic potential (EPSP)?

A depolarizing graded potential that moves the postsynaptic membrane closer to threshold.

• The ion movements that commonly produce EPSPs are a net inward positive current, often Na+ influx and/or Ca2+ influx exceeding K+ efflux.

What is an inhibitory postsynaptic potential (IPSP)?

A hyperpolarizing graded potential that moves the postsynaptic membrane farther from threshold.

• The ion movements that commonly produce IPSPs include K+ outflow or Cl- inflow

What is the grand postsynaptic potential (GPSP)?

The net effect of all simultaneous excitatory and inhibitory inputs integrated by a postsynaptic neuron.

• Excitatory inputs dominate → brought closer to threshold

• Inhibitory inputs dominate → taken farther from threshold

• Excitatory and inhibitory are balanced → membrane potential remains close to resting

Scenario: several subthreshold EPSPs arrive rapidly at one synapse. What process may bring the neuron to threshold?

Temporal summation.

Scenario: several excitatory neurons activate different dendrites at once. What process may bring the neuron to threshold?

Spatial summation.

Why is synaptic integration important?

It allows neurons to weigh many inputs rather than responding automatically to every individual signal.

How can neurotransmitter signaling be terminated?

By reuptake into neurons or glia, enzymatic breakdown, diffusion away, or uptake/metabolism by nearby cells.

What are receptor-channels?

Membrane receptors that directly control an ion channel when a chemical messenger binds.

What is a receptor-enzyme complex?

A membrane receptor whose intracellular portion has enzymatic activity or activates an associated enzyme after ligand binding.

What is a kinase?

An enzyme that phosphorylates target molecules, often changing their activity.

• Ex: Tyrosine kinase

• The receptor itself is a tyrosine kinase enzyme molecule

• Binding of the signal molecule leads to phosphorylation of the tyrosine residues on the intracellular side of the receptor

• Then phosphorylation of effector proteins occur, which activates them

What is a G-protein-coupled receptor (GPCR)?

A membrane receptor that activates a heterotrimeric G protein and intracellular signaling pathway rather than directly forming an ion channel. They’re particularly important in physiology because they mediate responses to many neurotransmitters and hormones, including epinephrine, norepinephrine, and dopamine.

What are the three subunits of a heterotrimeric G protein?

Alpha, beta, and gamma.

What nucleotide exchange activates a G-protein alpha subunit?

GDP is exchanged for GTP.

What happens after an activated G-protein alpha subunit interacts with an effector?

It alters effector activity, generates second-messenger signaling, then hydrolyzes GTP to GDP and reassociates with beta-gamma.

What is a second messenger?

An intracellular signaling molecule generated or released after receptor activation that relays and amplifies the signal.

What is the major effector activated by a Gs alpha subunit?

Adenylyl cyclase.

What pathway follows Gs activation?

• Gs activates adenylyl cyclase, which produces cAMP

• cAMP activates protein kinase A (PKA)

• PKA phosphorylates target proteins.

What is cAMP?

Cyclic AMP, a second messenger produced from ATP by adenylyl cyclase.

What does protein kinase A do in the cAMP pathway?

It phosphorylates cellular proteins, changing their activity and producing a cell response.

What is the major effector activated by a Gq/11 alpha subunit?

Phospholipase C (PLC).

What pathway follows Gq activation?

• Gq activates PLC, which cleaves PIP2 into IP3 and DAG

• IP3 releases Ca2+ from the ER and DAG helps activate protein kinase C.

What is PIP2?

A membrane phospholipid that PLC cleaves to form the second messengers IP3 and DAG.

What does IP3 do?

It binds receptors on the endoplasmic reticulum and releases stored Ca2+ into the cytosol.

What does DAG do?

It remains in the membrane and, together with Ca2+, helps activate protein kinase C and downstream responses.

Why is intracellular Ca2+ a powerful second messenger?

A transient rise in cytosolic Ca2+ can regulate secretion, contraction, enzymes, and gene expression.

Scenario: a messenger activates a Gs-coupled receptor in a cell. Predict the key second messenger and kinase.

cAMP rises and activates PKA.

Scenario: a messenger activates a Gq-coupled receptor. Predict two second messengers and one major ion change.

IP3 and DAG are produced; IP3 increases cytosolic Ca2+ by releasing Ca2+ from the ER.

Why can water-soluble hormones not simply diffuse through the plasma membrane?

They are polar and cannot readily pass through the hydrophobic lipid bilayer.

Where do water-soluble hormones usually bind their receptors?

On the external surface of the plasma membrane.

How do water-soluble hormones change a cell despite staying outside it?

They activate membrane receptors and intracellular second-messenger or kinase cascades.

Why can lipophilic hormones cross the plasma membrane?

They dissolve in and diffuse through the lipid bilayer.

Where are receptors for many lipophilic hormones located?

In the cytosol or nucleus.

How do lipophilic hormones commonly alter cell function?

The hormone-receptor complex acts as a transcription factor that changes gene expression and protein synthesis.

Which response is generally faster: receptor-channel signaling or a lipophilic hormone changing transcription?

Receptor-channel signaling is generally faster; transcription-mediated effects are slower to begin but can be longer lasting.

What type of receptor is the insulin receptor?

A receptor tyrosine kinase.

How does insulin receptor signaling promote glucose uptake in many cells?

Insulin activates receptor kinase signaling that promotes GLUT4 transporter insertion into the plasma membrane, increasing glucose uptake.

Why is an acetylcholine receptor at the neuromuscular junction considered chemically gated?

Acetylcholine binding directly opens its ion channel.

What happens when two acetylcholine molecules bind the nicotinic ACh receptor at skeletal muscle?

The receptor-channel opens, allowing monovalent cation movement and typically depolarizing the muscle end plate.

Why can the ACh receptor channel depolarize a cell even though both Na+ and K+ can pass?

At resting potential, Na+ influx is greater than K+ efflux, producing net inward positive current.

What is signal amplification in a second-messenger pathway?

One receptor activation can activate many downstream molecules, greatly magnifying the initial signal.

What is signal transduction?

The conversion of an extracellular signal at a receptor into specific intracellular changes and a cellular response.

Scenario: acetylcholine opens an ion channel on a neuron. Is the response automatically excitatory?

No. Its effect depends on the receptor subtype and which ions move through the activated channel.

Scenario: extracellular K+ rises substantially. How does this tend to affect resting membrane potential?

It reduces the K+ concentration gradient, making the membrane less negative (depolarizing it) and potentially altering excitability.

Scenario: voltage-gated Ca2+ channels at a presynaptic terminal are blocked. What happens to chemical neurotransmitter release?

It falls dramatically because Ca2+ entry is the trigger for vesicle fusion and exocytosis.

Scenario: a postsynaptic cell opens many Cl- channels. What happens to its chance of firing?

It generally decreases because Cl- entry hyperpolarizes or stabilizes the membrane below threshold.

Scenario: a drug prevents Na+/K+ ATPase activity for a prolonged period. What eventually happens to neural signaling?

Na+ and K+ gradients dissipate, resting potential and action potentials cannot be maintained, and cell volume may increase as water follows Na+.

What is the relationship between graded potentials and action potentials?

Graded potentials provide local input; their summed effect at the trigger zone determines whether an all-or-none action potential begins.

What is the relationship between an action potential and neurotransmitter release?

An action potential arriving at the terminal opens voltage-gated Ca2+ channels, and Ca2+ entry triggers release.

What is the relationship between neurotransmitter release and a postsynaptic graded potential?

Released transmitter binds postsynaptic receptors, changing ion conductance and creating an EPSP or IPSP.

Compare graded potentials with action potentials: amplitude.

Graded potentials vary in amplitude with stimulus strength; action potentials have a stereotyped all-or-none amplitude once threshold is reached.

Compare graded potentials with action potentials: distance.

Graded potentials decay with distance; action potentials regenerate and travel without decrement.

Compare graded potentials with action potentials: location.

Graded potentials usually occur in dendrites and cell body; action potentials begin at the trigger zone and propagate along the axon.

Compare EPSPs and IPSPs.

EPSPs depolarize and increase the likelihood of threshold; IPSPs hyperpolarize or stabilize the membrane and decrease the likelihood of threshold.

Compare ionotropic and metabotropic receptors.

Ionotropic receptors directly gate ion channels and act rapidly; metabotropic receptors (often GPCRs) act through signaling cascades and are slower but more modulatory/amplified.

Compare Gs and Gq pathways.

Gs activates adenylyl cyclase -> cAMP -> PKA; Gq activates PLC -> IP3 + DAG -> increased Ca2+ and PKC signaling.

Compare water-soluble and lipophilic hormone signaling.

Water-soluble messengers use membrane receptors and rapid intracellular cascades; lipophilic messengers enter cells, bind intracellular receptors, and often alter transcription.

Why is the Na+/K+ pump not the immediate cause of an action potential's rapid upstroke?

The rapid upstroke is caused by Na+ moving through voltage-gated Na+ channels down its electrochemical gradient; the pump maintains that gradient over time.

Why is a neuron not constantly firing at resting potential?

Resting potential is below threshold, and the balance of leak conductances and inhibitory/excitatory inputs normally prevents sufficient voltage-gated Na+ channel activation.

Why is the absolute refractory period physiologically useful beyond one-way conduction?

It limits the maximum firing rate and helps keep action potentials as distinct, time-ordered signals.