Can you teach me g coupled receptor proteins and 2nd messenger
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G protein-coupled receptors (GPCRs)
A G protein-coupled receptor is a cell-surface receptor that converts an outside signal, such as a hormone or neurotransmitter, into an intracellular response.
They are also called:
- Metabotropic receptors
- Seven-transmembrane receptors, because the receptor protein crosses the cell membrane seven times
Examples include adrenergic receptors, muscarinic acetylcholine receptors, dopamine receptors, histamine receptors, opioid receptors, glucagon receptors, and many more.
The core pathway
Think of the sequence as:
First messenger → GPCR → G protein → effector enzyme/ion channel → second messenger → cellular response
-
A signaling molecule binds the extracellular part of a GPCR.
- This extracellular signal is the first messenger.
- Example: adrenaline binds a beta-1 adrenergic receptor.
-
The activated receptor interacts with a nearby heterotrimeric G protein on the intracellular side of the membrane.
-
The G protein has three subunits: alpha (α), beta (β), and gamma (γ).
-
In its inactive state, the α subunit holds GDP.
-
GPCR activation causes GDP to leave and GTP to bind α.
- α-GTP is active.
- The α subunit, and sometimes the βγ pair, can activate an effector.
-
The effector generates a second messenger, which amplifies the signal and changes cell function.
-
The α subunit has intrinsic GTPase activity. It converts GTP back to GDP, switching the pathway off. The three subunits reassociate.
This GDP/GTP switching mechanism is described in Costanzo Physiology, p. 66.
The high-yield G proteins
| G protein | Main effector | Second messenger / pathway | Major action |
|---|---|---|---|
| Gs | Activates adenylyl cyclase | ↑ cAMP → activates PKA | Stimulation |
| Gi | Inhibits adenylyl cyclase | ↓ cAMP → ↓ PKA | Inhibition |
| Gq | Activates phospholipase C | IP3 + DAG → Ca²⁺ + PKC | Contraction, secretion |
| Gt | Activates phosphodiesterase in retina | ↓ cGMP | Visual transduction |
Mnemonic
“QISS”
- Q = Gq
- I = Gi
- S = Gs
- S = special G proteins, such as Gt
Or memorize the pathways:
- Gs: “Stimulates cAMP”
- Gi: “Inhibits cAMP”
- Gq: “Quts PIP2”
1. Gs pathway: cAMP and PKA
Sequence
Receptor → Gs → adenylyl cyclase ↑ → cAMP ↑ → protein kinase A (PKA) ↑
- Adenylyl cyclase converts ATP into cAMP.
- cAMP activates protein kinase A.
- PKA phosphorylates proteins, changing enzyme activity, ion-channel opening, contractility, metabolism, or gene transcription.
Important Gs-coupled receptors
“B2, D1, H2, V2, MSH, CRH, ACTH, FSH, LH, TSH, PTH, glucagon”
Common clinical examples:
- Beta-1 receptor in heart: ↑ cAMP → increased Ca²⁺ availability → increased heart rate and force of contraction.
- Beta-2 receptor in bronchial smooth muscle: ↑ cAMP → smooth-muscle relaxation → bronchodilation.
- Glucagon receptor in liver: ↑ cAMP → glycogen breakdown and glucose release.
- V2 receptor in kidney collecting ducts: ↑ cAMP → insertion of aquaporin-2 water channels.
2. Gi pathway: decreases cAMP
Sequence
Receptor → Gi → adenylyl cyclase ↓ → cAMP ↓ → PKA ↓
Important Gi-coupled receptors:
- Alpha-2 adrenergic
- M2 muscarinic
- D2 dopamine
- Many opioid and somatostatin receptors
Example: M2 receptor in the heart
Vagal acetylcholine activates M2 receptors in the SA node:
- Gi lowers cAMP, decreasing pacemaker activity.
- The Gβγ subunit can also directly open potassium channels.
- Result: membrane hyperpolarization and slower heart rate.
That direct ion-channel effect is important: GPCRs do not always need a diffusible second messenger. They may alter ion channels directly. Principles of Neural Science distinguishes these slower metabotropic actions from fast ionotropic receptor actions, p. 348.
3. Gq pathway: IP3, DAG, calcium, and PKC
Sequence
Receptor → Gq → phospholipase C (PLC) ↑ → PIP2 splits into IP3 + DAG
PLC breaks membrane phospholipid PIP2 into two second messengers:
IP3
- IP3 diffuses through the cytoplasm.
- It binds receptors on the endoplasmic or sarcoplasmic reticulum.
- This releases stored Ca²⁺ into the cytoplasm.
DAG
- DAG stays in the cell membrane.
- Along with Ca²⁺, it activates protein kinase C (PKC).
So the pathway is:
Gq → PLC → PIP2 → IP3 + DAG → ↑ intracellular Ca²⁺ + PKC activation
Important Gq-coupled receptors
“H1, alpha-1, V1, M1, M3, AT1”
- Alpha-1 adrenergic: vascular smooth-muscle contraction → vasoconstriction.
- M3 muscarinic: glandular secretion and smooth-muscle contraction.
- H1 histamine: smooth-muscle and endothelial effects.
- V1 vasopressin: vasoconstriction.
- AT1 angiotensin II: vasoconstriction and aldosterone-related signaling.
4. Gt pathway: vision
Sequence in rods
Light → rhodopsin → Gt (transducin) → phosphodiesterase ↑ → cGMP ↓
Normally, cGMP keeps sodium channels open in photoreceptors. With light:
- Gt activates phosphodiesterase.
- Phosphodiesterase breaks down cGMP.
- cGMP falls.
- Sodium channels close.
- The photoreceptor hyperpolarizes, creating the visual signal.
This is an exception to the common “second messenger rises after activation” pattern. Here, cGMP falls.
Major second messengers
cAMP
- Produced by adenylyl cyclase from ATP
- Activates PKA
- Main association: Gs and Gi
IP3
- Produced from PIP2 by PLC
- Releases Ca²⁺ from intracellular stores
- Main association: Gq
DAG
- Produced from PIP2 by PLC
- Remains in the membrane
- Activates PKC
- Main association: Gq
Ca²⁺
- Released from intracellular stores or enters through membrane channels
- Binds proteins such as calmodulin
- Important in contraction, secretion, exocytosis, and enzyme activation
cGMP
- Produced from GTP by guanylyl cyclase
- Activates PKG
- Important in nitric oxide signaling and phototransduction
- Usually not the classic Gs/Gi/Gq GPCR pathway
Why use second messengers?
They allow:
- Amplification: one ligand-receptor interaction can activate many G proteins and produce many second-messenger molecules.
- Speed: enzymes and ion channels can be modified quickly.
- Different responses in different tissues: the same receptor can have different outcomes depending on the cell's enzymes and channels.
For example, beta-1 receptor stimulation raises cAMP in both the SA node and ventricular muscle, but it increases pacemaker firing in the SA node and contractility in ventricular muscle. Costanzo Physiology, p. 66.
GPCRs versus ligand-gated ion channels
| Feature | GPCR / metabotropic receptor | Ligand-gated ion channel / ionotropic receptor |
|---|---|---|
| Mechanism | Uses G proteins and intracellular pathways | Ligand directly opens a channel |
| Speed | Slower onset | Very fast onset |
| Duration | Often longer lasting | Usually brief |
| Amplification | High | Limited |
| Example | Muscarinic, adrenergic, dopamine | Nicotinic ACh, GABA-A, NMDA |
One-minute summary
- GPCRs are seven-pass membrane receptors.
- Ligand binding activates a G protein by replacing GDP with GTP on its α subunit.
- Gs increases cAMP and PKA.
- Gi decreases cAMP and PKA.
- Gq activates PLC, producing IP3 and DAG, increasing intracellular Ca²⁺ and PKC activity.
- Gt lowers cGMP in photoreceptors.
- Second messengers amplify the original extracellular signal into a cellular response.
Quick recall question
Which pathway does alpha-1 adrenergic receptor use?
Alpha-1 → Gq → PLC → IP3 + DAG → Ca²⁺ + PKC → smooth-muscle contraction.
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