Ion channel-coupled receptors & neuronal signalling

Neuronal Communication: General Principles

• Primary function of neurons is to communicate with other cells via the release and reception of neurotransmitters, which are chemical signals.
• Synaptic transmission involves neurotransmitters secreted by neurons diffusing across the synaptic cleft to a target cell.
• Target cells must have receptors for the neurotransmitter to receive the signal.
• Neurons have two vesicle types:
  • Dense-cored secretory vesicles (seen in other cells) contain peptide neurotransmitters.
  • Small synaptic vesicles contain small-size neurotransmitters called classical neurotransmitters.

Neurotransmitter Release

• An action potential, also known as a "spike" or "impulse," occurs when a neuron sends information down the axon.
• This leads to ion exchange (e.g., Na^+ goes in, K^+ goes out) and changes in membrane voltage.
• Synaptic vesicles are stored near the membrane, awaiting signals to release their contents.
• Nerve stimulation involves:
  • Action potential.
  • Opening of Ca^{2+} channels.
  • Increase in intracellular Ca^{2+}.
  • This promotes vesicle docking at the membrane and exocytosis.
• Neurotransmitters are released into the synaptic cleft via exocytosis and act on specific postsynaptic receptors.

Fate of Classical Neurotransmitters

• Neurotransmitters bind to receptors.
• They're rapidly inactivated by enzymatic degradation.
• Most are recycled through reuptake of the neurotransmitter or its metabolites in the presynaptic terminal by specific transporters, allowing quick re-packaging into vesicles.
• The effect of neurotransmitters is brief; quick removal ends signal transmission, preventing further inadequate stimulation of the postsynaptic cell.
• Deficits in neurotransmitter reuptake (e.g., glutamate) can lead to overstimulation of postsynaptic neurons and cell death.
• Example: In Alzheimer’s disease, there is a deficit in synaptic transmission by Acetylcholine (Ach).
• Cholinesterase inhibitors are administered to prevent Ach degradation.

Synaptic Vesicle Cycle

• Synaptic vesicles can form directly from endocytic vesicles (local recycling) and neurotransmitter reuptake/recycling.
• This allows for ready-to-go pools to ensure rapid and repeated bursts of neurotransmitter release.

Synaptic Transmission vs. Hormone Signalling

Neurotransmitter Mode of Action

Action of neurotransmitters on postsynaptic receptors leads to the opening or closing of ion channels.

Receptor Types

• Neurotransmitters bind to:
  • Ion channel-coupled receptors (ligand-gated ion channels or ionotropic receptors).
  • Metabotropic receptors: G-protein coupled receptors (GPCRs).

Ion Channel Coupled-Receptors

• Ligand-gated ion channels combine receptor and channel functions in a single protein complex.
• The extracellular domain binds neurotransmitters.
• The membrane-spanning domain forms an ion channel.
• They are multimers made up of at least four or five individual protein subunits.
• Activation:
  • Neurotransmitter binds to the receptor (often two sites).
  • This causes a conformational change in the receptor.
  • Leads to a channel opening through the membrane, allowing ions to flow.
• Ligand-gated ion channels are directly activated upon binding of a neurotransmitter.

Ion Channel Receptor Selectivity

• Ion channels are highly selective in what can pass through, unlike simple aqueous pores.
• Some only allow K^+, Na^+, Ca^{2+} or Cl^− to pass.
• Selectivity is due to receptor structure, subunit composition, and preference for cations or anions.
• Receptor subunits are highly variable in tissues, leading to different selectivity.

Effect of Neurotransmitter

• Determined by receptor subtype and localization.
• One class of receptors can have many subtypes.
• Each receptor subtype can have a broad or restricted tissue/cell distribution.

Ligand-Gated Ion Channel Receptors

• Involved in fast synaptic transmission.
• Ion channels are gated: they open briefly and close again, unlike simple aqueous pores that are always open.
• Allow fast transport of high fluxes of specific ions across the membrane by passive diffusion.
• Ions flow according to pre-existing gradients (from high to low concentration).
• Effect is rapid but transient.
• Many pathologies are associated with abnormal over-activation or inhibition of these receptors.
• Genetic mutations can promote epilepsy.
• Some classes of ionotropic receptors can also become desensitized: with prolonged stimulation, they enter a prolonged closed state.
• Can lead to Depolarization or Hyper-polarization.

Modulation of Ionotropic Receptors

• Many natural compounds and drugs modulate ionotropic receptors.
• Example: ionotropic GABA-A receptors promote chloride influx, leading to inhibition of synaptic transmission (termination of action potentials).
• Many compounds target this receptor:
  • Receptor potentiated by barbiturates and benzodiazepines (= sedative-anxiolytics), alcohol, anaesthetics, neurosteroids…
  • Compounds bind to specific receptor subunits, increasing the affinity of GABA for the receptor or preventing its dissociation.
  • Leads to increased channel opening frequency or duration.

Metabotropic Receptors

• Metabolic steps precede the movement of ions through a channel.
• Effects are indirect.
• These receptors are monomeric proteins and do not have ion channels as part of their structure.
• They are G-protein-coupled receptors (GPCRs).
• Neurotransmitter binding to metabotropic receptors activates G-proteins, which then dissociate from the receptor and:
  • Interact directly with ion channels.
  • Induce the production of second messengers that open or close ion channels.
• Activated G-proteins can modulate ion channels directly or indirectly through intracellular effector enzymes and second messengers.

Neurotransmitter Action Overview

• Some neurotransmitters can bind to both ionotropic and metabotropic receptors.
• Complexity of neurotransmitter action is a challenge for targeted drug treatment.

Dopamine Signaling

• Overactive dopamine system is linked to hallucinations, delusions, psychosis.
• It is a target of antipsychotics.

Summary

• Key function of neurons is to communicate with other cells (neurotransmission).
• Neurotransmitters are released by exocytosis into the synaptic cleft.
• Neurotransmitters bind to ionotropic or metabotropic (GPCR) receptors on target cells.
• Ligand-gated ion channels combine receptor and channel functions in a single protein complex and are directly activated upon binding of a neurotransmitter.
• Metabotropic receptors activate G-proteins that can modulate ion channels directly or indirectly through intracellular effector enzymes and second messengers.
• Many natural compounds and drugs modulate ionotropic and metabotropic receptors.