0813 - Functional Excitation and Inhibition Flashcards
List a variety of neurotransmitters and receptors in the CNS
Excitatory - Glutamate is main transmitter. GluR receptors. Also ACh.
Inhibitory - GABA is main transmitter. GABA(a),(b) etc receptors. Also Glycine and ACh.
Outline the five steps of classical neurotransmission and their requirements.
1 - Synthesis of compounds (presynaptic). Requires synthesising enzymes.
2 - Storage of compounds (presynaptic). Requires vesicular transport proteins.
3 - Release into cleft. Requires exocytosis or a constitutive pathway
4 - Binding (post-synaptic). Requires iono-or metabotropic receptors.
5 - Termination - Depends on transmitter type and extracellular space (tortuosity).
What is the glutamate cycle?
Very simple synthesis, no specific degrading enzymes.
Receptor deactivation via diffusion and re-uptake.
What is the GABA cycle?
Synthesised by Glu decarboxylase, so depends on Glu synthesis.
Deactivation via diffusion, uptake into glia, and re=uptake as Gln.
How do iono- and metabotropic receptors differ in terms of the receptor type, activity, speed, action, and clinical use?
Receptor - Iono ligand-gated ion channel, metabo 7TM-receptor coupled to G-protein
Activity - Iono excitatory or inhibitory; metabo determined by signalling pathway
Speed - Iono less than 50ms; metabo more than 100ms-minutes (slow)
Action - Iono depends on NT concentration; metabo allows amplification and interaction with other NTs.
Clinical - Iono implicated in rare diseases; Metabo agonists often abused as drugs.
What is the difference between excitation and inhibition?
Excitation results in an increase in the rate of APs at the same current (i.e. always depolarises)
Inhibition results in a decrease in the rate of APs at the same current (often hyperpolarises, but can be depolarising).
What are the major ionotropic GluRs? What do they have in common?
AMPA, Kainate, and NMDA-type (based on agonists).
Evolved differently to ACh, GABA receptors.
Typically a heteromultimer between 4 subunits with 2 Glu binding sites.
Outline NMDA receptors.
Ionotropic Glu receptor. Allows Na+, K+ and Ca++
Important for synaptic plasticity - memory and learning.
Affected by most cell signalling pathways.
Agonised by NMDA, antagonised by Ketamine.
NMDARs
Outline AMPA receptors
Ionotropic, Glu receptor. Allows Na+, K+, some Ca++
Often located with NMDA receptors.
Workhorse - Undertakes most transmission in CNS.
Agonised by AMPA, antagonised by NBQX
GluR2 continually recycled, depending on activity.
GluR1-4
Outline Kainate receptors
Ionotropic Glu receptor. Allows Na+, K+, some Ca++
Controls pre-synaptic release, inhibition = anaesthesia.
Agonists - Kainic Acid.
GluR5-7, KA1, KA2
What are the metabolic Glu Receptors?
mGluR1-8.
Perisynaptic, coupled to G-proteins.
Gi/o (II/III) inhibits adenylyl cyclase, modulating K+ and Ca++ channels, and is inhibitory.
Gq (I) activates Phospholipase C and can be excitatory.
Role - Group II/III autoreceptors reducing NT release. Group I is postsynaptic.
Outline GABA(a) Receptors
Ionotropic GABA receptors. Allows Cl-, HCO3-
6 subunits(2 alpha, 2 beta, 1 other, often gamma), 2 binding sites for GABA on alpha. Large molecular and pharmaco heterogeneity, but only a few dozen expressed.
Agonists - Muscimol, antagonists Picrotoxin
Action - fast inhibition.
How can the GABA(a) receptor be modulated?
Barbiturates, benzodiazepam.
Modulates opening time in the presence of GABA.
Also anaesthesia and steroids
Outline GABA(b) receptors
Heterodimer between 3 subunits (1a, 1b, 2). Permeable to nothing.
Couples via Gi/o to GIRK (G-protein K+) channels.
Action - Pre and post-synaptic inhibition in spine and cortex.
Agonist - baclofen, antagonists - saclophen, phaclofen.
What is the role of receptor-associated proteins, specifically TARPs?
TARPs - Transmembrane AMPAR regulatory proteins.
Modulate AMPAR activity by directly interacting with the channel and altering the number of receptors on the sub-synapse.
