Major CNS neurotransmitters and their receptors

type i synapse in the cns

• asymmetric

  • excitatory associated with L-glutamtergic synapse markers

    • antibodies to L glutamate

• round synpatic vesicles

• prominent dense presynaptic projections

• large active zone

• wide synaptic cleft

type ii synapse of the cns

• symmetric

  • inhibitory associated with GABAergic and glycinergic synapse markers

    • antibodies to GABA

• flattened vesicles

• small active zone

• narrow synaptic cleft

• less obvious dense projections

how do ionotropic neurotransmitter receptors work

• binding allows opening of the complex

• ions move in and out

how does metabotropic receptor work

• GPCR

• couples to G protein

• allows hydrolysis of GTP → GDP

• acts on effector enzyme to produce 2nd messenger 

what are the type of ionotropic iGluRs

• AMPA

• kainate

• NMDA

characteristics of ionotropic iGluRs

• tetramers

• 4 agonist binding sites

• non selective mixed cation channels therefore no Eion

is NMDA a heterodimer or homodimer

• heterodimer

• 2 glutamate binding sites

• dual agonism with glycine 2 binding sites 

At hyperpolarised membrane potentials, which major ionotropic glutamate receptor primarily mediates the postsynaptic current?

AMPA receptors (AMPARs) mediate the postsynaptic current at hyperpolarised levels.

Hint/NotesThis is because the NMDA receptor channel is blocked by a $\text{Mg}^{2+}$ ion at hyperpolarised potentials.

What is the immediate effect on the postsynaptic membrane potential when AMPA receptors are blocked, and which receptor is responsible for this remaining potential?

Blocking AMPA receptors causes a small depolarisation mediated by NMDA receptors (NMDARs).

Which ionotropic glutamate receptor is less voltage-dependent: AMPA or NMDA?

AMPA receptors are less voltage-dependent than NMDA receptors.

• because they do not have an intrinsic voltage dependent block

At significantly depolarised postsynaptic potentials, which receptor contributes a larger component to the excitatory postsynaptic current (EPSC)?

There is a larger NMDA-R receptor mediated component at depolarised potentials.

• depolarisaation moves the Mg2+ block

• resulting in large calcium and sodium current 

IV relationship for NMDA receptor mediated EPSC

• depolarisation to -30mV

• below -30mV non linear, non ohmic

• region of negative slope conductance 

  • channels are blocked or closed

what happens to IV plot if you remove magnesium

• no region of negative slope conductance 

group i mGLuR agonist

• DGPH

• direct depolarisation

• facilitates depolarisation

• actions postsynaptically

where do group ii and iii mGluR agonists act

presynaptically

group ii and iii agonist mGluR

• DCG-IV and L-AP4

• create depression of excitatory transmission

effector targets of group i mGluR

• postsynaptic - mediate via alpha subunit of g protein

• inc plc activation, inc pkc

• tandem 2 pore domain K+ channels and inward rectifiers close when phosphorylated

  • leads to depolarisation

• NMDA-R current enhances when phoshorylated - inc responsiveness

• enhances excitability

how do group ii and group iii mglur agonists decrease channel function

• inhibit P/Q and N type Cav channels, dec release

• direct interaction between membrane bound beta gamma dimer of g protein and the calcium channel

• or indreictly through alpha subunit, dec camp, dec PKA

• balance between protein kinases and phosphatases shifts dephosphorylation of calcium channels

• reduces excitability

which receptors are involved in early EPSP for L glutamate

• ionotropic

which receptor and channel is involved in early EPSP for L glutamate

• metabotropic receptor

• potassium channel

gaba/glycine receptors structure

• pentameric

• only 2 binding sites for agonists

GABA-A receptor

• ionotropic

• GABAB conformation

• gamma → alpha → beta → alpha → beta

ionotropic glycine receptor conformation

• BABAB

ionotropic electrophysiology

• selective anion channels - chloride

• Eion is -70mV

• hyperpolarisation if RMP is > -70mV

GABAb recpetors

• 2 subunits

• metabotropic

• heterodimer for g protein and agonist binding

effect of baclofen (GABA b receptor agonist) on postsynaptic membrane potential 

• direct hyperpolarisation 

how is the IPSP affected by GABA b receptor antagonists

• early IPSP remains intact

• late IPSP is blocked

effect of presynaptic GABAb receptor activation on IPSP and EPSP

• depression of inhibitory and excitatory transmission

• reduced amplitude

difference between GABA-b receptor agonists applied pre and post synaptically

• post synaptically - direct hyperpolarisation

• pre synaptically - depression of synaptic transmission 

postsynaptic effector targets of GABAb 

• direct interaction between membrane bound beta-gamma dimer g protein and GIRK channel

• activation of Kir3.1-4

• hyerpolarisation

• increased channel function 

• reduced excitability

presynaptic effector targets of GABA b

• P/Q and N type Cav channels dec release

• direct interaction between beta gamma dimer of g protein and ca2+ channel

• indirect via alpha subunit, dec camp, dec PKA

• dephosphorylation of Cav

• reduced excitability 

pyramidal neurons

• principal excitatory neurons in the cortex

• inc activity of other neurons