Membrane mechanisms

What is an action potential (AP)?

An all-or-none rapid change in membrane voltage that allows neural communication.

Why can neurons have different AP firing patterns?

Different neurons express different types and combinations of ion channels, producing different firing behaviours. Some neurons can also switch between firing patterns.

Ion channel diversity → diversity of AP firing patterns

What are the four main types of ion channels?

LVML

Ligand-gated: opened by molecule binding. Fast

Voltage-gated: has a voltage sensory that opens/closes by changes in membrane voltage.

Mechanically gated: opened by pressure/physical membrane movement.

Always-open/leak: continuously allow ions to move down their concentration gradient.

What are the main steps of neurotransmission?

• AP reaches the axon terminal.

• Depolarisation opens voltage-gated Ca²⁺ channels.

• Ca²⁺ influx triggers vesicle docking to presynaptic cleft and neurotransmitter exocytosis.

• Neurotransmitter crosses the synapse and binds postsynaptic receptors/channels.

Why can the same neurotransmitter produce different effects?

t can bind different receptor subtypes/subunit combinations, which have different kinetics and produce different neuronal responses.

Key idea: the receptor determines the effect on the target cell, not simply the neurotransmitter.

What is an ionotropic receptor?

How do excitatory and inhibitory ionotropic receptors usually work?

A ligand-gated ion channel that opens directly when a neurotransmitter binds, producing a very fast response

Increase Na⁺ permeability → depolarisation.

Increase K⁺ or Cl⁻ permeability → hyperpolarisation.

How do non-NMDA//AMPA glutamate receptors work?

Glutamate binds directly to the receptor → ion channel opens.

Why is the NMDA receptor unusual, what is its process once the ligand binds and what is it co-located with?

Why is Ca²⁺ influx through NMDA receptors important?

It is both ligand- and voltage-dependent:

• Requires glutamate + glycine binding.

• At resting membrane potential, it is blocked by Mg²⁺.

• Depolarisation removes the Mg²⁺ block.

• Opening allows a large Ca²⁺ influx.

• co-located with AMPA, without it it’s a silent synapse as it needs AMPA for depolarization

Synaptic plasticity

How can zinc modulate NMDA receptors?

NNMDA receptors contain a zinc-binding site; increased Zn²⁺ can antagonise/reduce NMDA receptor activity. This may help limit glutamate excitotoxicity.

How can zinc and copper affect neuronal firing?

They can inhibit voltage-gated Ca²⁺ currents, reducing neuronal firing.

How can Ca²⁺ provide self-limiting feedback on Ca²⁺ channels?

After Ca²⁺ enters:

Ca²⁺ can bind directly to its own channel and inhibit further flow.

Ca²⁺ can activate calcineurin, which dephosphorylates the channel and causes inactivation.

What is the absolute refractory period?

Period when the neuron is inactive and cannot generate another AP.

Can be caused by an inactivation gate

What is the relative refractory period?

Some channels have recovered while others remain inactive, so an AP can occur with a sufficiently strong depolarising stimulus.

Resting potential drops lower than usual so it’s still in a refractory period but can be activated with enough stimulation

What is post-inhibitory rebound?

neuron becomes more likely to fire/burst after an inhibitory signal ends.

When inhibition ends, the increased pool of available Na+ channels makes a neuron more likely to fire strongly or burst

How does hyperpolarisation cause post-inhibitory rebound?

Hyperpolarisation allows more voltage-gated Na⁺ channels to recover from inactivation → more Na⁺ channels are available when inhibition ends → increased firing.

Do classical axonal K⁺ channels have a refractory period?

Generally no. Some remain open and do not inactivate until membrane potential decreases.

What currents occur during voltage-clamp depolarisation?

First: inward Na⁺ current → Then: delayed outward K⁺ current.

What does tetrodotoxin (TTX) block? Why is TTX useful experimentally?

Voltage-gated Na⁺ channels. Blocking Na⁺ currents allows the delayed K⁺ current to be isolated.

What does tetraethylammonium (TEA) block? Why is TEA useful experimentally?

Voltage-gated K⁺ channels.

Blocking K⁺ currents allows the inward Na⁺ current to be isolated.

What makes A-type K⁺ channels different from classical K⁺ channels?

What is the main function of A-type K⁺ channels?

They inactivate. After opening, their outward K⁺ current gradually decreases despite continued depolarisation.

Regulate interspike intervals by delaying subsequent depolarisation/AP firing

When are A-type K⁺ channels inactivated vs available?

Inactivated at around normal membrane potential -50 or higher (towards -60 or more)

After hyperpolarisation: become available again.

How do A-type K⁺ channels increase the time between APs?

During the next depolarisation, they produce an outward K⁺ current, opposing depolarisation and delaying threshold and increasing interspike interval.

Why can hyperpolarisation cause delayed firing through A-type K⁺ channels?

Hyperpolarisation makes A-type channels available → subsequent depolarisation opens them → K⁺ exits → temporary hyperpolarising current opposes depolarisation → delays Na⁺ channel activation and AP firing.

How may reduced Kv channel function contribute to neuropathic pain?

Reduced Kv function/expression may increase firing of primary afferent nociceptive neurons, contributing to hypersensitivity.

What channels contribute to firing-rate adaptation?

Ca²⁺-activated K⁺ channels.

How do Ca²⁺-activated K⁺ channels produce firing-rate adaptation?

Depolarisation → voltage-gated Ca²⁺ channels open → Ca²⁺ enters → activates Ca²⁺-activated K⁺ channels → K⁺ exits → late hyperpolarisation → firing slows as interval between spikes increases eventually stopping firing.

What does EBIO do?

Enhances the effectiveness of Ca²⁺-activated K⁺ channels.

What happens to firing-rate adaptation if Ca²⁺ entry is blocked?

It disappears because no calcium entry means the potassium channels are still closed so there is still constant firing

How do T-type (low theshold) Ca²⁺ channels contribute to burst firing?

They become available during hyperpolarisation (~−75 mV). Subsequent depolarisation opens them, changing neuronal excitability and promoting burst firing.

Do not open when depolarizing stimulus is given at normal membrane potential

When do H-type channels open?
What happens when H-type channels open?

In response to hyperpolarisation (~−70 mV).

Na⁺ and K⁺ movement produces a small depolarisation, which activates T-type Ca²⁺ channels, followed by normal voltage-gated Na⁺ channels

How can H-type and T-type channels generate rhythmic burst firing?

Hyperpolarisation → H-type channels open → small depolarisation → T-type Ca²⁺ channels open → Na⁺ channels open → AP burst → strong depolarisation closes H-type/T-type activity → hyperpolarisation returns → cycle repeats.

What is a metabotropic receptor and why are they smaller compared to ionotropic receptors?

Usually a G-protein-coupled receptor (GPCR) that affects ion channels indirectly through intracellular signalling pathways.

They require G-protein/enzyme signalling cascades rather than directly opening an ion channel.

What is the difference between active and inactive G-proteins?

GTP-bound = active (guanosine diphosphate)
GDP-bound = inactive (guanosine triphosphate)

Can GPCRs directly regulate ion channels?

Ligand bind G protein receptors, causes change in g protein which opens or closes g protein gated ion channel

How can metabotropic receptors indirectly regulate ion channels?

Ligand binds to g protein coupled receptor which activates/causes changes in g protein which activates adenylyl cyclase which causes an increase in cAMP which activates protein kinases that open or close the ion channels

What processes can metabotropic signalling affect besides ion channels?

Longer-term intracellular processes including:

• neuronal excitability

• synaptic plasticity

• cell death

• gene transcription.

Why are metabotropic receptors important for signal amplification?

Each activated signalling component can activate multiple downstream molecules, progressively amplifying the original signal.