Lecture 16: NT Receptors and Signal Transduction

What are ionotropic glutamate receptors?

iGluRs are ion channels that mediate fast excitatory transmission.

What are iGluRs classified as?

NMDA (N-methyl D-aspartare) and non-NMDA receptors such as AMPA, kainate, and quisqualate

Quisqualate has the capacity to do what?

to activate both ionotropic and metabotropic glutamate receptors

What are iGluRs composed of?

They are heterotetramers, meaning they are composed of 4 subunits mostly as 2 different dimers

What families are included in Non-NMDA receptors?

GLuR1-R4 (AMPA)
GluR5-R7
KA1/KA2 (Kainate)

What is KA1 and KA2? What is their affinity?

KA1 and KA2 are high-affinity kainate-binding receptors

What does the different assembly of Non-NMDA subunits do?

Different assembly of Non-NMDA receptors can cause different properties including Ca permeability

What are NMDA receptors more permeable to compared to non-NMDA receptors?

Ca2+

What subunits compose NMDA receptors?

GluN1 (NR1)
GluN2A-2D (NR2A-2D)
GLuN3A,B (NR3A, 3B)

What does each iGluR subunit possess?

4 membrane-associated segments

How many iGluR membrane-associated segments completely go through the lipid bilayer?

3

What determines Ca permeability in non-NMDA receptors and where does it reside?

Glutamine in the TM2 determines Ca permeability in non-NMDA receptors

Is Aspargine involved with NMDA or non-NMDA receptors and where is it located?

NMDA receptors in the TM2

What is the function of Aspargine in NMDA receptors?

Aspargine is the site for Mg block

What are NMDA receptors channels dependent on?

They are Mg2+ dependent voltage-sensitive ion channel block as it regulates the voltage-dependent opening of the channel.

What amino acid is required for effective opening of NMDA receptor channels?

Glycine is required for effective channel opening

Are NMDA receptors permeable to Ca2+?

Yes

What plays a role in glutamate receptor clustering at excitatory synapses?

Postsynaptic densities
AKAP150
SynGAP
GKAP

How does glutamate receptor clustering at excitatory synapses occur?

NMDA receptor interacts with PSD-95 (postsynaptic density) through PDZ domains

What is AKAP150?

A kinase anchoring protein

what is synGAP?

synaptic-associated Ras GTPase activating protein

What is GKAP?

Guanylate cyclase associated protein

What receptors are metabotropic?

GPCRs, GPCR desensitization, muscarinic, dopamine, noradrenergic, serotonergic, mGLu GABA-B receptors

What does the activation of GPCRs leads to?

The activation of GPCRs leads to the coupling of the receptor with G-Protein

What does the coupling of GPCRs and G-Proteins initiate?

This initiates the exchange of GDP for GTP activated G-Proteins

What are the two types of structural classifications of G-proteins?

1. Monomeric small GTPases
2. Heterotrimeric complexes involving α, β, and γ subunits

What are the functional classifications of G-proteins?

1. Gs: stimulatory
2. Gq: activate PLC pathway
3. Gi: inhibitory

What does Gs activate?

Gs activate adenylate cyclase

What does Gi inhibit?

Gi inhibits adenylate cyclase or activates guanylate cyclase

What do classical transmitters mostly bind to?

Classical transmitters mostly bind to both ionotropic and metabotropic receptors

What doe peptidergic transmitters mostly bind to?

Peptidergic transmitters mostly bind to GPCRs

What are the 3 subfamilies that make up the GPCR family?

1. Rhodopsin-adrenergic receptor family
2. Secretin-VIP receptor family
3. Metabotropic glutamate receptor (mGluR) family

What are the differences between the subfamilies of the GPCR family?

They differ based on the agonist/ligand, binding site of the ligand, GPCR activation mechanism, and downstream signaling

Where does the NT binding site for many GCRPs (excluding mGLuRs, GABA-B, and peptides) reside?

within the pocket formed in the center of 7 TM structure

What determines G-protein coupling with receptors?

3rd intracellular loop (not TM domain)

What are the two mechanisms behind GPCR desensitization?

1. decreases in response by covalent modification (receptor phosporylation)
2. Physical removal of receptors from membrane

What does desensitization mean with GPCR desentization?

Desensitization means a decrease in response to a signaling molecule

What is the rapid phase of GPCR desensitization mediated by?

Rapid phase of GPCR desensitization is mediated by receptor phosphorylation

What is associated with the slower phase of GRCR desensitization?

intracellular pathways

What role does beta-arrestins play in the desensitization of GPCRs?

GPCRs undergo sequestration with beta-arrestins, which is loss of receptors at the surface membrane

What could happen with phosphorylated receptors with GPCR desensitization?

Phosphorylated receptors could be dephosphorylated and returned back to the plasma membrane, or they could be degraded

What receptors are associated with GPCRs?

Muscarinic ACh Receptors
Adrenergic Receptors
Dopamine Receptors
Purinergic receptors
Serotonin Receptors (except 5HT3)
Glutamate GCPRs
GABA-B Receptors
Peptide Receptors

What NT is associated with muscarinic receptors?

ACh

Muscarinic ACh receptors consist of five subtypes (M1-M5).
What are these subtypes coupled to?

M1, M3, and M5 are coupled to Gs (stimulatory G-protein)

M2 and M4 are coupled to Gi (inhibitory G-protein)

What NTs are associated with adrenergic receptors?

NE and Eph

What 3 families are adrenergic receptors classified as?

alpha1, alpha2, and beta (β1,β2,β3)

What are adrenergic α2 receptors presynaptic or postsynaptic?

α2 receptors are mostly presynaptic

How do adrenergic α2 receptors modulate NT release

via activating PLC, Ca channels, and adenylate cyclase (AC)

What do all adrenergic β agonists do?

All β agonists activate adenylate cyclase (AC)

What is the β adrenergic receptor agonist?

Isoproterenol

What is the β adrenergic receptor antagonist?

Propanolol

What dopamine receptor subtypes (D1-D5) are grouped within D1-like?

D1 and D5

What is the role of D1-like DA receptors?

Activate adenylate cyclase via Gs (D1/D5)

What dopamine receptor subtypes (D1-D5) are grouped within D2-like?

D2, D3, D4

What is the role of D2-like DA receptors?

inhibit adenylate cyclase via Gi (D2/D3/D4)

What do purinergic receptors bind to?

Bind to ATP (P1) or adenosine (P2)

All serotonin receptors (5HT1-5HT7) are GPCRs except…

5HT3

What are the GPCR serotonin receptors involved in?

sleep regulation, mood/anxiety regulation, cognition, circadian rhythm, eating, and arousal

What are glutamate GPCRs (mGluRs) classified as?

mGluRs are classified as mGluR1-mGluR8

Do mGluR1-5 activate or inhibit? What is do they activate or inhibit?

mGluR1-5 activate Phospholipase C

What does mGluR2 do?

inhibits adenylate cyclase (AC)

What is the function of GABA-B presynaptic autoreceptors?

produce inhibition of NT release

What is the function of GABA-B postsynaptic receptors?

activate K conductance via Gi