Synaptic transmission: Neurotransmitters and receptors Flashcards
What drives vesicle filling?
Vesicular proton pump uses ATP energy to create the gradient of H+ and electric charge gradient
Cationic transmitters such as monoamines and ACh depend on ΔpH whereas glutamate uses primarily the electric component.
How to identify a neurotransmitter?
- Present in presynaptic terminal with synthesis machinery and specialized vesicular transporter
- Released upon presynaptic stimulation
- When added to extracellular fluid should mimic effects of presynaptic stimulation
- A mechanism for removal of neurotransmitter
Types of neurotransmitters
Classical
Neuropeptides
Others
Factors of neurotransmitters synthesis
Occurs in the neuronal cell body and synapse
Specific to neuron types
Neurons can change the neurotransmitters they synthesize
Describe the biosynthesis of acetylcholine
Choline and acetyl coenzyme A (acetyl-CoA) join via choline acetyltransferase ChAT
This forms Coenzyme A and acetylcholine
How does the action of neurotransmitter depends on functional properties of its receptor
Depends on
- binding of ligand
- activation of receptor
- desensitization of receptor (even at constant presence of transmitter receptor is not active but stays transmitter bound)
How are receptors held in place?
Receptors are held in place by scaffolding proteins
Receptors undergo dynamic bi-directional trafficking to the cell surface and back to the cytoplasm
Types of receptors
Ionotropic
- Direct gating of channel by ligand
Metabotropic
- Ion channel separate is from receptor
- Receptor communicates to channel via intracellular messenger molecules ( G-proteins)
- G-protein coupled receptors
Describe metabotropic receptors
The interaction between receptor and enzyme or channel is mediated by a third
protein, called a GTP-binding regulatory protein (G-protein)
- The G-protein is a hetero-trimer that disassemble when activated.
- The α-chain binds and hydrolyzes GTP and interacts with effector protein
• Many GPCR pathways converge to increase in concentrations of two
important intracellular messengers, cAMP and Ca2+
Types of acetylcholine receptors
Nicotinic
- Ionotropic
- Increase cations (Na+)
- Fast excitatory
Muscarinic
- Metabotropic
- Influences K+ permeability
- Slow excitatory/inhibitory
What is the structure of the nicotinic ACh receptor?
Hetero-pentamer of four related subunits
Hetero-pentamer of four related subunits (αβγδ).
Each subunit has a transmembrane α-helix (the M2 helix).
The five M2 helices combine to form the pore.
Each α-subunit contains an acetylcholine binding site.
Binding of acetylcholine ‘opens’ the receptor.
How does the nicotinic acetylcholine receptor open?
Bulky hydrophobic Leu side chains of M2 helices close the channel
Binding of two acetylcholine molecules causes twisting of the M2 helices
M2 helices now have smaller polar residues lining the channel
Different glutamate receptors
AMPA
- Ionotropic
- Increase cations (Na+)
- FAST excitatory
NMDA
- Ionotropic
- Increase cations (Ca2+)
- Slow excitatory blocked by Mg2+
Metabotropic
- Metabotropic
- Increase IP3
- Modulatory mixed
Describe ionotropic glutamate receptors
AMPA receptors mediate main
part of excitatory synaptic input
in majority of brain neurons
• NMDA receptors are not active at resting membrane potential because of Mg2+-block but can be activated after depolarization cause by AMAR Rs. NMDA receptors provide Ca2+ influx
• AMPA and NMDA receptors mediate
many brain functions,
such as memory and cognition.
• In case of excessive release of Glu, Ca2+-influx via NMDA receptors can trigger a vicious cycle of cell damage (excitotoxicity). This cycle is involved in many neurological disorders (ischemia, epilepsy, etc
Describe GANA receptors
Glutamic acid from Kreb’s cycle becomes GABA via glutamic acid decarboxylase
2 types
GABA A
- ionotropic
- Increase Cl-
- Fast inhibition
GABA B
- metabotropic
- Increase K+
- Decrease Ca2+
- Slow inhibition
