LG - Metabotropic Receptors I

Question 1

Q: What are the major types of neurotransmitters that activate metabotropic receptors? (5)

Answer 1

• Amino acids – Glutamate, GABA, Glycine
• Monoamines – Dopamine, Serotonin, Norepinephrine, Histamine
• Neuropeptides – e.g., Substance P, Endorphins
• Acetylcholine
• Purines – ATP, ADP, GTP

Question 2

Q: Give examples of neurotransmitters that act on both receptor types. (4 pairs)

Answer 2

• ATP – P2X (ionotropic), P2Y (metabotropic)
• Acetylcholine – nAChR (ionotropic), mAChR (metabotropic)
• GABA – GABA-A (ionotropic), GABA-B (metabotropic)
• Glutamate – NMDA/AMPA/Kainate (ionotropic), mGluRs (metabotropic)

Question 2

Q: How do ionotropic and metabotropic receptors differ? (3 key features)

Answer 2

• Speed: Ionotropic (1–100 ms), Metabotropic (100 ms–minutes)
• Mechanism: Ionotropic = ligand-gated ion channels, Metabotropic = GPCR-mediated signalling
• Function: Ionotropic = fast transmission, Metabotropic = neuromodulation

Question 3

Q: What therapeutic applications target metabotropic receptors? (3)

Answer 3

• Treatment for epilepsy, anxiety, schizophrenia, Rett syndrome, Parkinson’s, Alzheimer’s, OCD
• GABA-B agonists used for muscle spasms, alcohol dependence, narcolepsy
• mGluRs are potential drug targets in various CNS disorders

Question 3

Q: What are the general properties of metabotropic receptors? (3)

Answer 3

• Signal via G-proteins to modulate ion channels and biochemical pathways
• Act on sub-second to minute timescales
• Involved in excitability, synaptic plasticity, network function, and disease

Question 4

Q: What is the structure of mGluRs? (3)

Answer 4

• Large extracellular Venus Flytrap Domain (VFTD) for ligand binding
• Linked to 7-transmembrane domain (7TMD) for G-protein activation
• Require obligate dimerisation (homo- or heterodimers) to function

Question 4

Q: Which GPCR family includes metabotropic glutamate receptors (mGluRs)? (1)

Answer 4

• Class C GPCRs, along with GABA-B, Ca²⁺-sensing, and umami taste receptors

Question 5

Q: What are the three mGluR groups, and how do they differ? (4)

Answer 5

Group I

• Receptors: mGluR1, mGluR5
• Function: Excitatory
• Signalling: Activates PLC → ↑ intracellular Ca²⁺
• Location: Cortex, hippocampus, striatum

Group II

• Receptors: mGluR2, mGluR3
• Function: Inhibitory
• Signalling: Inhibits adenylyl cyclase → ↓ cAMP
• Location: Olfactory bulb, cerebellum, thalamus

Group III

• Receptors: mGluR4, mGluR6, mGluR7, mGluR8
• Function: Inhibitory
• Signalling: Inhibits adenylyl cyclase → ↓ cAMP
• Location: Brainstem, spinal cord, retina

Question 6

Q: What are examples of mGluR agonists? (3)

Answer 6

• Group I: 3,5-DHPG
• Group II: DCG-IV
• Group III: L-AP4

Question 7

Q: What determines receptor localisation in mGluRs? (1)

Answer 7

• The C-terminal domain controls targeting to specific cellular compartments

Question 8

Q: How do mGluRs exist structurally in native tissues? (3)

Answer 8

• Form homodimers (e.g., mGluR5–mGluR5)
• Also form heterodimers (e.g., mGluR2–mGluR4, mGluR1–mGluR5)
• Dimerisation via disulfide bridges in VFTD, and requires 2 glutamate molecules for full activation

Question 9

Q: What is allosteric modulation in mGluRs? (2)

Answer 9

• Modulators bind within 7TMD core, not at VFTD
• Can enhance or inhibit glutamate signalling

Question 9

Q: How is mGluR5 involved in neurodevelopmental and psychiatric disorders? (5 conditions)

Answer 9

Linked to:

• Autism spectrum disorder (ASD)
• Schizophrenia
• Parkinson’s disease
• Depression
• Fragile X syndrome (FXS) – excessive mGluR5 activity

Question 9

Q: Give examples of allosteric modulators of mGluRs. (2)

Answer 9

1) Negative Allosteric Modulators (NAMs):

• FITM for mGluR1
• Mavoglurant for mGluR5 (binds deep in 7TMD)

2) Positive Allosteric Modulators (PAMs):

• e.g., ADX47273, enhances Ca²⁺ oscillations

Question 9

Q: What distinguishes inactive and active conformations of mGluRs? (2)

Answer 9

• Inactive: VFTDs are open; dimer held by cysteine-rich domains
• Active: Both VFTDs bind glutamate → closed conformation → activates G-protein

Question 10

Q: Describe the Fragile X syndrome (FXS) model involving mGluR5. (3 stages)

Answer 10

• WT: mGluR5 triggers controlled protein synthesis
• FMRP Knockout: No FMRP → excessive mGluR5 signalling → dysregulated protein translation
• Genetic mGluR5 reduction: Restores normal protein synthesis, rescues FXS phenotypes

Question 10

Q: How is drug activity at mGluRs measured experimentally? (2)

Answer 10

• Intracellular Ca²⁺ imaging (e.g., in astrocytes or transfected cells)
• Detection of Ca²⁺ oscillations in response to agonists/modulators

Question 11

Q: What types of allosteric modulation can occur at mGluRs? (3)

Answer 11

• PAMs – increase receptor response to glutamate
• NAMs – decrease or block glutamate signalling
• Neutral allosteric ligands – bind without functional effect, but block PAMs or NAMs

Question 12

Q: What is an example of GPCR crosstalk involving mGluRs? (1)

Answer 12

• mGluR2/5-HT2A heterocomplex: Hallucinogens (e.g., LSD, DOI) require mGlu2 for effect
  • Disrupting mGlu2 prevents psychotic-like effects in mice

Question 13

Q: What are the key takeaways from this lecture? (4)

Answer 13

• Metabotropic receptors regulate neural activity via GPCR signalling
• mGluRs act as dimers, influencing excitability and plasticity
• Allosteric modulators offer a way to finely tune receptor activity
• mGluRs are important drug targets for neurodevelopmental and psychiatric disorders