Week 4: Neurotransmission Flashcards
Extrinsic Synaptic Plasticity
Factors outside the neurons that can influence the entry of Ca++ into the terminal
Axo_axonic synapses
neurons that have axon branches that terminate on the terminals of other neurons
How does extrinsic synaptic plasticity work?
the terminal of another neurons will influence the VM and the amount of Ca++ influx to ultimately influence the amount of transmitter released and the size of the PSP
Presynaptic Inhibition
The process whereby the axo-axonic synapse reduces the amount of transmitter released
Presynaptic facilitation
The process whereby an axo-axonic synapse increases the amount of NT released
Presynaptic inhibition is thought to be mediated by
- The simultaneous closing of Ca++ channels and the opening of K+ channels
- An increased Cl- conductance
- Direct inhibition of NT release independent of Ca++
Presynaptic facilitation is mediated by
Enhanced Ca++ influx
Common features of chemical sensitive channels
- they are all membrane spanning proteins
- the region exposed to the external environment recognizes and binds neurotransmitter molecules
- they mediate an “effector” function of changing the conformation of an ion channel
Ionophoric channels
receptors that gate ions channels directly
Metabophoric channels
receptors that gate ion channels indirectly
Differences between direct (ionophoric) and indirect (metabophoric) chemical sensitive channels
- in receptors that gate ion channels directly, the recognition side and the channel are one unit; receptors that gate ion channels indirectly have there components separate, thus the presence of transmitter must be conveyed by a second system
- they have different overall functions
- structurally, the direct channels are made up of multiple independent subunits; indirect channels are made up of one long amino acid sequence
Direct channels function
they produce fast synaptic action (milliseconds)
Indirect channel function
they produce slow synaptic action (seconds to minutes) which can modulate activity is suited for “learning”
Typical Direct chemical sensitive channels are found
in nerve-muscles synapses that use ACh
in the CNS, insynapses that use glutamate, glycine, GABA, ACH, and 5HT
Typical Indirect chemical sensitive channels are found
in the CNS, in synapses that use norepinephrine (NE), dopamine (DA), and most synapses that use seritonin (5HT) (and ACh too, sometimes)
Types of Direct chemical sensitive channels
- Ach
- GABA
- Glutamate
ACh Direct Chemical Sensitive Receptor
Ach-nicotinic -
Ach-mescarinic -
Ach-nicotinic
nerve muscles
5 subunits - 2 alpha, beta, gamma, delta
Need 2 Ach to bind to each alpha unit
M2 subunit is responsible for forming the lumen
Has 3 rings of negative charge
Causes an EPSP and actually allows both Na+ and K+ to flow
GABA Chemical Sensitive Channel
5 subunits: 2 alpha, 2 beta, gamma
All 5 bind GABA, but alpha has the highest affinity
Allows Cl- flux - so causes IPSPs
Gamma - Benzo’s and Barb’s bind to it too
How do benzo’s and barb’s binding to GABA receptors affect the channel?
the presence of one ligand binding will influence the binding of the others - the binding of benzo’s increases the affinity/efficiency of the GABA receptor (easier for GABA to bind)
Similarities between GABA, glycine and Ach
- genes that encode them are from the same family.
- each subunit has 4 membrane spanning helical structures
- the M2 member of each subunit is the channel lumen
- GABA and glycine M2 has amino clusters that result in a selectivity for anions which is not present in Ach
4 types of Glutamate Receptors
- Kainate receptor
- quisquilate A
- quisquilate B
- NMDA receptor
Similarities between Kainate receptor and Quisauilate A
- especially in motor neurons
1. both are affected by AMPA
2. both are not affected by NMDA
3. both gated a low conductance cation channel that fluxes/allows flow of Na+ and K+ but not Ca++
“AMPA” Types
NMDA receptor special properties
- these receptors gate a high conductance cation channel that fluxes Na+, K+, and Ca++ ions
- these channels are plugged up by extracelluar Mg++ and the channel won’t operate unless the Mg++ is removed
- the VM must be sufficiently depolarized to blow out the Mg++
Pharmacological difference between AMPA and NMDA
NMDA receptors are blocked by APV and inhibited by phencylidine (PCP)
Diseases that may be influenced by too much Ca++
Excitotoxicity (maybe do to too much glutamate) Huntington's Parkinson's Strokes Maybe Alzheimer's
G-Protein
Recognition of NT is done on on structure and the activation of some effector is accomplished by an enzymatic cascade
Often involves 2+ enzymes
Types of G-Proteins
- cAMP
- phospho-inositol
- arachidonic pathway
Common features of G-Proteins
- they all belong to the same gene family
- they all consist of a single subunit that have seven membrane spanning regions
- NT bound to the receptor site on the 7-spanning structure that activates a guanosine nucleotide-binding protein known as the g-protein to initiate the process
2 Phases in the G-Protein system
- Phase one: the 1st effector enzyme is activated producing a “Second messenger”
- Phase two - the second messengers lead to changes in specific proteins within the neuron
Subunits of the G-Protein
alpha, beta, gamma
Alpha unit is not very tightly bound
G-Protein Alpha subunit
high affinity for GDP
Subclasses of G-Protein
- Gs / b-adrenergic receptors - stimulate adenylate cyclase
- Gi / a-adrenergic receptors - inhibit adenylate cyclase
- G-other/Go - not clear what they do
Activate a G-Protein Systems
- the process begins when an agonist interacts with the receptor
- agonist-receptor complex draws the G-Protein and forms an agonist-receptor-G-Protein complex
- this agonist-receptor-G-Protien complex causes the alpha subunit to exchange its GDP for a high energy GTP, the G-Protein dissociates (explodes)
This charged up alpha subunit will activate the 1st effector
Phase One Summary
- receptor binds NT
- receptor/NT complex draws and binds the G-Protein with its attached GDP
- the receptor/NT/G-Protein complex causes the exchange of GDP for high energy GTP
- the whole complex explodes
- the alpha subunit has the GTP and can now activate the 1st effector enzyme
1st effector enzymes
cAMP - adenylate cyclase
inositol - PLC
arachidonic - phospholipase A
What does 1st effector enzymes do?
they produce the second messenger
“second messenger-induced changes in specific proteins”
Phase 2 Summary
Lasts for seconds or minutes
duration is limited by other enzymes
- inactivate the second messengers
- remove the phosphate groups
They are a constant counter
Phase 2 Summary
changes in specific proteins can be accomplished by either
- the second messenger directly binds to the target protein OR
- the second messenger directly activates the 2nd effector enzyme
Phase 2 Summary
Consequences of adding phosphate groups
- altering the conformation of an enzyme which will then modify the function of that enzyme
- altering the cytoskeleton - changing the shape of the structural protein
- altering those particular proteins that regulate DNA transcription!!!!
cAMP system will
convert ATP to AMP or cAMP
Protein Kinases
cAMP activates it
- cAMP-dependent protein kinase
- protein kinase C
- Ca++/calmodulin-dependent protein kinase
Functional similarities between Protein Kinases
- “catalytic” subunit which essentially is the portion of the enzyme that does work
- there is a regulatory subunit that prevents the catalytic part access
Protein Kinase Regulatory Subunit
regulates by globbing onto and thereby covering the active sites of the catalytic subunit
Must remove the regulatory subunit to get to the catalytic subunit
Activated cAMP-dependent protein kinase will
add phosphate groups to the channel
de-activating the G-Protein Systems
- one enzymes will remove the phosphate group that the activated protein kinase added - the phospho-protein phophatase
- Phosphodiesterate will comvert cAMP to AMP
- the alpha unit will convert its GTP to GDP
- alpha unit re-associates itself with the beta and gamma units
- NT is removed from the receptor site
Inositol G-Protein System
Phosphatidyl inositol (PI)
1st effecotr is PLC
two second messengers
- DAG
- IP3
IP3 Inositol G-Protein System
- PLC causes the release of IP3 in the postsynaptic side, IP3 moves into cytoplasm, binds to endoplasmic reticulum
- IP3 binds to ER receptors
- Ca++ sensitive protein kinase
- when activated, this protein kinase will then add phosphate groups to target proteins
DAG branch
- Stays in the membrane
2. Protein kinase C in the cytoplasm has to be relocated to contact the membrane and have DAG open the enzyme
Special Issues
- G-Protein systems can interact with one another
- G-Protein often will open OR close ion channels
- G-Protein can sometimes act directly on ion channels (not via phosphorylation)
- G-Proteins can alter the properties of transmitter receptors (desensitization)
- G-Proteins can regulate gene expression
