Signaling: Ion Channel Coupled Receptors

Neuronal Communication

• General Principles:
  • Signal generation and propagation in neurons.
  • Neurotransmitter release via exocytosis.
  • Neurotransmitter action on receptors.
  • Distinction between metabotropic and ionotropic receptors.
  • Importance of neurotransmitter degradation, inhibition, and recycling for rapid signaling.
  • Synaptic vesicle cycle.
  • Function of ion channel coupled receptors.
  • Ligand-gated ion channels (ionotropic channels) combine receptor and channel functions within a single protein complex.
  • Direct activation upon neurotransmitter binding opens the ion channel.

Neuronal Signaling

• Neurons communicate by releasing chemical signals from axon ends to nearby target cells.
• Target cells can be other neurons (dendrites), muscle cells, or glandular cells.
• Neuronal signaling can induce hormone secretion in glandular cells.
• Neurotransmitters:
  • Chemical messengers released from axon ends.
  • Travel short distances (20-40 nanometers) across the synaptic cleft.
  • Act on target cells (neurons, muscles, glands).
  • Example of local signaling.
• Specificity:
  • Depends on the synapse between the axon and target cell.
  • Neurotransmitters are rapidly degraded to prevent excessive signal propagation.
  • Different types of neurotransmitters exist on different types of receptors.
• Types of Neurotransmitters:
  • GABA: Calming neurotransmitter, inhibits neuron firing in the central nervous system.
    • High levels can aid focus; low levels can cause anxiety.
    • Controls motor control and vision.
  • Acetylcholine: Involved in learning, activates muscle contraction, and is associated with attentiveness and wakefulness.
  • Glutamate: Involved in memory, propagation of memory, creation of new nerve pathways, and creation of new nerves.

Release of Neurotransmitters

• Process:
  • Stimulation occurs upstream on dendrites.
  • Action potential opens ion channels.
  • Action potential travels down the axon to terminal axon ends (synaptic knobs).
  • High concentration of mitochondria in synaptic knobs for energy.
  • Vesicles containing neurotransmitters.
• Vesicle Types:
  • Neurohormones are packaged into large, dense-core vesicles (synthesized in response to a stimulus).
  • Small neurotransmitters (GABA, acetylcholine, glutamate) are packaged into small synaptic vesicles (packaged constitutively).
• Release Mechanism:
  • Action potential triggers release.
  • Action potential opens calcium channels, allowing calcium influx.
  • Calcium facilitates exocytosis of synaptic vesicles.
• Neurotransmitter Types and Functions:
  • GABA: Calming, inhibits neuron firing.
    • High GABA levels improve focus, low levels cause anxiety.
    • Controls motor function and vision.
  • Acetylcholine: Learning, muscle contraction, attentiveness.
  • Glutamate: Memory, creation of new nerve pathways.
• Synaptic Cleft:
  • Neurotransmitters diffuse across the synaptic cleft (approximately 20 nanometers).
  • Bind to receptors on the target cell membrane.
  • Neurotransmitters can be excitatory (e.g., glutamate, adrenaline) or inhibitory (e.g., GABA, glycine, serotonin).
  • Neuromodulators (e.g., acetylcholine, dopamine) can tweak receptor cell signal reception and affect multiple neurons.
• Action Potential:
  • Also called a spike or impulse.
  • Signal received by dendrites opens ion channels.
  • Changes in ion concentration propagate the signal.
  • Sodium ions enter; potassium and chloride ions change.
  • Membrane voltage change converted to a chemical signal (neurotransmitter release).
  • Multiple axon branches affect multiple target cells.

Neurotransmitter Release Mechanism

• Action potential activates voltage-gated calcium channels in the synaptic know:
• Calcium influx into the nerve terminal.
• Preformed synaptic vesicles fuse with docking proteins on the axon's plasma membrane.
• This process induces opening of secretory vesicles filled with neurotransmitters.
• Secretory vesicles fuse with the plasma membrane and release the neurotransmitters into the synaptic cleft.
• Example: Glutamate, activated by calcium influx, causes exocytosis and neurotransmitter release.
• Neurotransmitter Characteristics:
  • Short half-life.
  • Low binding affinity to target receptors.
• Removal mechanisms:
  • Degradation. Diffuses.
  • Reuptake into the nerve terminal via transporter proteins.
  • Packaged into new synaptic vesicles.
  • Defects in reuptake can lead to overstimulation and neuronal cell death. Example: Glutamate excitotoxicity.
• Acetylcholine:
  • Synthesized in the nerve terminal from acetyl coenzyme A (acetyl CoA) and choline.
  • Packaged into synaptic vesicles.
  • Action potential, calcium influx, vesicle fusion, and release of acetylcholine.
  • Acetylcholine then binds to target receptors on the next neuron.
  • Acetylcholine is broken down into acetate and choline by acetylcholinesterase.
  • Deficits in acetylcholinesterase lead to excessive acetylcholine and signaling.

The Process Synaptic Vesicle Cycle

• Cell body of the neuron and axon.
• Secretory vesicles are generated from the Golgi network and have proteins destined for the plasma membrane.
• These proteins are now on the surface of the plasma membrane ready to do a job.
• Endosomes:
  • Enable Neurotransmitter Packaging. Pinching off of Plasma Membrane Regions.
  • Plasma membrane regions are pinched off by endocytosis.
  • Fuse with the endosome.
  • The endosome can then package the neurotransmitters into secretory vesicles ready to come out.
  • Direct Vesicle Packaging.
  • Uptake by neurotransmitter channels packaged into secretory vesicles for release. Action potential exocytosis of the neurotransmitter.

Synaptic vs. Endocrine Signaling

Neurotransmitter Mode of Action

• Neurotransmitters reach target cells.
  • Results in opening or closing of an ion channel.
  • Opening or closing of the ion channels can be either be direct or indirect.
• Ion channel coupled receptors / Ligand-gated ion channels / Ionotropic.
  • Receptor and Ion Channel.
  • Neurotransmitter causes a change in the confirmation that opens up ion channels.
• Metabotropic receptors. * Act just like G protein coupled receptors.
  • Neurotransmitter binding to the receptor that causes binding of the G protein and activation of the subunit via change of GTP.
  • This can then activate an effector protein that induces second messengers.
  • Those second messengers can cause changes to an ion channels. Confirmation change of the ion channel and a flux of ions either in or out of the cell.