Lecture 17: Metabotropic Receptors

What are the ionotropic and metabotropic receptors for acetylcholine?

• Ionotropic: Nicotinic ACh receptors (nAChRs)

• Metabotropic: Muscarinic ACh receptors (m1–m5 GPCRs)

What are the ionotropic and metabotropic receptors for glutamate?

• Ionotropic: AMPA, NMDA, and Kainate receptors

• Metabotropic: mGluRs (mGluR1–8)

What are the ionotropic and metabotropic receptors for GABA?

• Ionotropic: GABA_A and GABA_C receptors

• Metabotropic: GABA_B receptors

What are the ionotropic and metabotropic receptors for serotonin (5-HT)?

• Ionotropic: 5-HT3 receptor

• Metabotropic: 5-HT1, 5-HT2, and 5-HT4 receptors (all GPCRs)

What are the NTs that act exclusively through GPCRs?

• Dopamine: D1-D5

• Norepinephrine + epinephrine: adrenergic receptor a1, a2, b

• Neuropeptides

What are the main components of the G protein signaling cascade?

1) G protein-coupled receptor (GPCR): a 7 transmembrane-domain receptor.

2) Heterotrimeric G protein: composed of α, β, and γ subunits; it binds GDP/GTP and transduces the signal.

3) Effector proteins: enzymes or ion channels that generate second messengers (e.g., adenylyl cyclase, phospholipase C, or phospholipase A₂).

What does “G” in G protein stand for?

Guanine nucleotide-binding protein.

• Because the α-subunit binds GDP or GTP to control activation.

How many G protein subunits exist in humans?

• 27 α-subunits

• 6 β-subunits

• 13 γ-subunits

In the G protein signaling cascade, where does signal amplification occur?

• Receptor → G protein: One activated receptor can activate many G proteins ✅

• G protein → Effector: No amplification ❌ (1 G protein usually activates 1 effector)

• Effector → Second messenger: One effector enzyme (like adenylyl cyclase) can produce many second messengers (e.g., cAMP) ✅

What are the 3 major classes of GPCRs and their key features?

• Class I (A): Rhodopsin-like

  • Most common

  • Short N-terminus

  • Ligand binds within transmembrane domains

• Class II (B): Secretin receptor-like

  • Includes receptors for Secretin, Glucagon, Calcitonin, PTH, CRF

  • Long N-terminus, ligand binds at N-terminal region

• Class III (C): mGluR-like

  • Includes mGluRs, GABA_B, calcium sensors, and sweet/umami taste receptors

  • Very long N-terminus, ligand binds at N-terminal region

  • Often dimeric

What are the key structural features of a generic GPCR?

• Has 7 transmembrane helices (TM1–TM7)

• N-terminus extracellular, C-terminus intracellular

• N-terminal N-glycosylation for stability

• Conserved disulfide bond connects extracellular loops 2 and 3

• C-terminal cysteine acylation anchors receptor to membrane

• Ligand-binding residues (yellow) lie in a horizontal plane across the receptor

• Highly conserved residues (pink) found in most GPCRs