(4) G-Protein-Coupled Receptors (GPCRs)

G-protein-coupled receptors

cell-surface receptors that transmit signals from extracellular ligands to intracellular signaling pathways through G proteins

What physiological functions are GPCRs involved in?

heart rate, neurotransmission, vision, smell, immune response

Why are GPCRs called “serpentine”?

they snake through the plasma membrane 7 times

Heterotrimeric G protein

in the cystoplasmic domain, composed of ⍺, β, and ɣ subunits

Ligand binding to GPCR

binds on the extracellular side, causing a conformational change

GPCR inactive state

⍺ subunit holds a guanosine diphosphate (GDP) molecule

GPCR activation

1. receptor binds G protein

2. GDP is replaced with GTP on the ⍺ subunit

3. G⍺ subunit separates from βɣ subunit

Effector activation of G⍺-GTP and Gβɣ

adenylyl cyclase, phospholipase C (PLC), and ion channels

Signal termination of GPCR

1. G⍺ subunit hydrolyzes GTP → GDP, deactivating itself

2. When GDP is back on the ⍺ subunit, it reassociates with βɣ, reforming to inactive trimeric G protein

On-off switching

cycle of GTP replacing GDP on the ⍺ subunit, then being hydrolyzed to GDP and being inactivated while the ligand remains bound, allowing for amplification of signal

Signal amplification

one activated receptor can activate many G proteins, each triggering a cascade amplifying the signal

Built-in shut-off

G⍺ subunit’s GTPase activity ensures the signal is short-lived

Lateral movement

G proteins can diffuse along the membrane to find effectors to activate

Receptor phosphorylation and β-arrestin binding

leads to receptor internalization (endocytosis)

Breakdown of which second messengers leads to signal attenuation of GPCRs?

cAMP and IP₃

Pharmacological significance of GPCRs

target of 1/3 of all drugs because they regulate physiological functions like blood pressure, heart rate, pain, mood, and immune response

Beta blocker GPCR target

adrenergic receptors

Opioid analgesic GPCR target

opioid receptors

Antihistamine GPCR targets

histamine H₁ receptors

Angiotensin II receptor blocker GPCR targets

AT₁ receptor

Serotonin agonist/antagonist GPCR targets

serotonin receptors