N371: Ion channels (II + III)

How many subunits make up a K⁺ channel?

Four subunits arranged around a central pore (tetramer).

Where is the K⁺ channel gate located?

On the intracellular side of the pore.

How are Na⁺ channels organized compared to K⁺ channels?

One large protein with four internal domains (I–IV), all ecoded in one gene instead of four separate subunits.

What feature allows Na⁺ channels to inactivate?

A “hinged lid” formed by the DIII–IV linker that blocks the pore after opening.

What happens to the hinged lid during repolarization?

It swings away, removing the block and resetting the channel.

When does Na⁺ channel inactivation occur?

Shortly after depolarization, even if the stimulus remains.

Which segments in voltage-gated channels act as voltage sensors?

S1–S4.

Which segments in voltage-gated channels form the pore and gate?

S5–S6.

What is the after-hyperpolarization (AHP)?

Extra dip in membrane potential that happens after an action potential.

What is the functional role of AHP?

Limits further spiking immediately after an AP and helps reset membrane excitability

What’s the difference between hyperpolarization and AHP?

1. anytime the membrane gets more negative than rest.

2. special hyperpolarization immediately after an AP

How did the classic Hodgkin–Huxley model describe K⁺ channels?

As a single delayed-rectifier conductance that activates with a delay and does not inactivate.

What do K⁺ channels do during a single AP?

They help repolarize the membrane, shape the AP, set the resting potential, and generate AHP

What is spike-frequency adaptation in neurons?

The tendency for firing to start fast then slow down even if the stimulus is constant (neuron get tired 🥹)

What causes spike-frequency adaptation?

Each AP increases Ca²⁺ and K⁺ channel activity → stronger AHP → reduced excitability → slower firing

What happens if Ca²⁺ entry is blocked during repetitive firing?

Ca²⁺-activated K⁺ channels can’t open → no AHP → neuron keeps firing rapidly (continuous excitation).

What is the delayed-rectifier K⁺ current (Iₖ)?

A voltage-dependent activation

K⁺ current that activates with delay and repolarizes the AP

Classic HH type

Why are Ik channels called “delayed” “rectifyers”

1. Channel has four subunits that must all open, causing a sigmoidal delay in activation.

2. preferantially conducts current mainly outward (K⁺ leaving) when the membrane is depolarized.

What is the function of Ik channels?

Repolarizes the action potential, shapes its duration, and controls repetitive firing.

What effect do K⁺ channels have on AP patterning?

Limit repetitive firing, terminate bursts, reduce excitability by stabilizing membrane

What are the key properties of the M-current (Iₘ)?

A slowly activating, non-inactivating, voltage-dependent K⁺ current active near resting potential.

What is the main function of the M-current (Iₘ)?

Acts as a “brake” that stabilizes resting potential and limits repetitive firing (spike-frequency adaptation).

How do muscarinic acetylcholine receptors (M₁ type) affect M-channels?

ACh → M₁ GPCR → activates PLC → cleaves PIP₂ → Iₘ channels close → less K⁺ efflux → membrane becomes more excitable.

Why does removing PIP₂ make a neuron more excitable?

M-channels require PIP₂ to stay open; without it, K⁺ “brake” is lost, so depolarization is easier.

What is Retigabine and how does it act on neurons?

A drug that directly opens M-channels by shifting activation to more negative voltages, increasing K⁺ efflux and calming neuronal activity

Is Retigabine’s action mediated through the PLC/PIP₂ pathway?

❌ No — it acts directly on the channel protein, not through G-protein signaling.

What is the clinical use of Retigabine?

As an antiepileptic, because it reduces excessive neuronal firing.

What are Ca²⁺-activated K⁺ channels (BK channels)?

Large-conductance K⁺ channels that open when both intracellular Ca²⁺ increases and membrane depolarizes (dual-gated).

What are the main functions of BK channels?

They open during intense firing to rapidly repolarize the membrane and produce the fast AHP, helping to terminate bursts and limit further Ca²⁺ entry.

What makes BK channels unique structurally?

Their Ca²⁺-binding site is built into the channel protein (encoded by the gene itself).

What are SK channels (small-conductance Ca²⁺-activated K⁺ channels)?

Low-conductance channels that are weakly voltage-dependent but strongly Ca²⁺-dependent.

How are SK channels activated?

Indirectly — Ca²⁺ binds to calmodulin, which is permanently attached to the channel (channel itself has no Ca²⁺-binding site).

What evidence shows SK (Iahp)channels depend on Ca²⁺?

Removing extracellular Ca²⁺ makes the AHP shrink or disappear, proving Ca²⁺ is required for their activation.

What is the function of SK (Iahp))channels in neurons?

They generate the slow AHP after bursts of action potentials and contribute to spike-frequency adaptation by reducing repetitive firing.

What happens when SK channels are blocked by apamin (bee venom toxin)?

The AHP disappears → neurons become more excitable → fire more rapidly.

What is the A-current (Iₐ) in neurons?

A transient, voltage-gated K⁺ current that activates at lower voltages than the delayed rectifier (Iₖ) and inactivates quickly.

Why is the A-current called “transient”?

Because it activates and inactivates rapidly, only present for a short time during depolarization.

What is the gating mechanism of A-current channels?

Ball-and-chain (N-type) inactivation: an activation gate opens with depolarization, then an inactivation gate quickly closes to stop current.

What is “prepulse-dependent activation” in A-currents?

Iₐ channels are inactivated at rest and need a prior hyperpolarization to recover before they can open again.

How do A-currents encode stimulus strength during weak input?

Iₐ active + has time to recover (hyperpolarize) between spikes → more K⁺ current → slower firing.

How do A-currents encode stimulus strength during strong input?

Iₐ stays inactivated (doesnt have time to recover) → less K⁺ brake → faster firing since Na+ (depolarizing) current dominats

What are inwardly rectifying K⁺ (KIR) channels?

K⁺ channels that preferentially conduct inward current (K⁺ entering the cell) at negative voltages and close during depolarization.

Are KIR channels voltage-gated?

❌ No — they’re not voltage-gated, but are blocked by intracellular Mg²⁺ and polyamines when the membrane is positive.

How do KIR channels produce inward rectification?

At negative Vm: blockers leave → K⁺ enters.
At positive Vm: blockers plug the pore → outward flow blocked.

What is the function of KIR channels in neurons?

They stabilize the resting membrane potential, keeping it close to Eₖ (~–90 mV) and preventing excessive depolarization.

What is the function of KIR channels in cardiac cells?

They close during the plateau phase of the cardiac AP to prevent early repolarization, allowing Ca²⁺ channels to stay open longer → sustained contraction.

What does the current–voltage (I–V) curve of a KIR channel look like?

• Negative voltages: steep inward current (K⁺ in).

• Positive voltages: flat region — outward flow blocked by Mg²⁺/polyamines.

What’s the difference between excitatory and inhibitory PSPs?

1. depolarization (inward current, membrane potential ↑).

2. hyperpolarization (outward current, membrane potential ↓).

What determines the open probability (Pₒ) of ligand-gated channels?

The concentration of ligand/agonist, not the voltage.

What are miniature postsynaptic potentials (mini PSPs)?

Tiny, random PSPs caused by spontaneous release of a single vesicle of neurotransmitter (no stimulation needed).

What are evoked PSPs?

Larger PSPs produced when presynaptic stimulation releases many vesicles at once.

What is desensitization in ligand-gated channels?

The receptor becomes nonresponsive even though the ligand is still bound (use “desensitization,” not “inactivation,” for these receptors).

What are ionotropic glutamate receptors (iGluRs)?

The main excitatory ligand-gated channels in the brain that open when glutamate binds.

What is the structure of ionotropic glutamate receptors?

Made of four subunits forming a central pore; each has a selectivity filter in the membrane region and a ligand-binding domain (LBD) extracellularly.

Why are iGluRs excitatory?

Their reversal potential is near 0 mV → opening causes depolarization (inward cation current) → drives excitation.

What ions pass through iGluRs?

They are non-selective cation channels — mainly pass Na⁺ and K⁺ (some types also Ca²⁺).

What are the main subtypes of iGluRs?

AMPA, kainate, and NMDA receptor families (classified by which agonist activates them).

What are AMPA receptors?

Fast-acting iGluRs that mediate most rapid excitatory synaptic transmission.

What genes encode AMPA receptor subunits?

GluA1–GluA4

What ions do AMPARs conduct?

Mainly Na⁺ and K⁺

How do AMPA receptors respond to different agonists?

Desensitize when activated by glutamate or AMPA, but not by kainate.

What are kainate receptors?

A slower iGluR subtype that responds to glutamate and kainate.

What is unique about kainate receptor subunits?

KA1 and KA2 subunits alone are nonfunctional — they must combine with other GluR subunits to form working channels.

What ions do kainate receptors conduct?

Mainly Na⁺ and K⁺ (similar to AMPARs).

How do kainate receptors behave during activation?

They desensitize when activated by glutamate or AMPA, but not by kainate (same as AMPAR)

What are the functional roles of kainate receptors?

• Mediate slightly slower excitatory currents than AMPARs.

• Found both pre- and postsynaptically, where they modulate neurotransmitter release and excitability.

What are NMDA receptors (NMDARs)?

Ionotropic glutamate receptors that require both glutamate and glycine to open and act as coincidence detectors for synaptic activity.

What is the typical structure of an NMDA receptor?

Usually heteromeric — composed of NR1 plus NR2 (A–D) or NR3 subunits

Can NR1 form functional channels by itself?

Yes, NR1 can form homomeric tetramers, but the resulting currents are very small.

What ions are NMDA receptors permeable to?

Na⁺, K⁺, and Ca²⁺

What is the role of NR2A-D NDMAR subunits?

Determines kinetics and Ca²⁺ permeability.

Why are NMDA receptors considered “voltage dependent” even though they’re ligand gated?

At resting potential, Mg²⁺ blocks the pore; depolarization expels Mg²⁺, allowing current to flow only when the membrane is already depolarized.

What makes NMDA receptors “coincidence detectors”?

They open only when presynaptic glutamate release and postsynaptic depolarization occur together — both ligand and voltage required.

What are the current properties of NMDA receptors?

Slow and long-lasting currents that are stronger at positive potentials; they conduct poorly at negative voltages.

How can you isolate NMDA currents experimentally?

Apply APV (an NMDA antagonist) — remaining fast current comes from non-NMDA (AMPA/kainate) receptors.

What are the main functions of NMDA receptor currents?

Produce large Ca²⁺-mediated currents that drive processes like LTP, plasticity, and excitotoxicity.

How do AMPA and NMDA receptors work together in an EPSP?

AMPA: fast, early peak; NMDA: slow, prolonged component → together create a two-phase EPSP (quick + sustained).

What are GABA-A receptors?

The main inhibitory ligand-gated channels in the brain; they open in response to GABA and conduct Cl⁻.

What is the structure of a GABA-A receptor?

Pentameric (5 subunits) — commonly 2α, 2β, and 1γ, arranged around a central pore.

What is the typical ionic mechanism of GABA-A receptors?

They allow Cl⁻ to flow, driving the membrane potential toward E₍Cl₎ ≈ –60 to –70 mV, usually causing hyperpolarization (inhibition).

Do GABA-A receptor currents follow Ohm’s law?

Yes ✅ — their current–voltage relationship is linear under physiological conditions.

How do GABA-A receptors contribute to PSPs?

They generate inhibitory postsynaptic potentials (IPSPs); can also produce mini PSPs, which last longer than glutamatergic mini PSPs.

How does chloride movement determine IPSP direction?

• If Em > E₍Cl₎, Cl⁻ enters → hyperpolarization.

• If Em < E₍Cl₎, Cl⁻ leaves → depolarization (still inhibitory if below spike threshold).

What drugs act on GABA-A receptors?

Benzodiazepines — positive allosteric modulators that increase GABA’s effect without directly opening the channel.

What is the effect of benzodiazepines on GABA-A function?

Increase receptor affinity for GABA → channels open more frequently and longer → stronger inhibitory currents.

What are the behavioral effects of benzodiazepines?

Calming, sedative, anticonvulsant, and anti-anxiety effects from enhanced inhibition.

How do excitation and inhibition integrate in neurons?

The neuron’s membrane potential reflects the sum of all EPSPs (glutamate) and IPSPs (GABA) occurring at the same time.