Premier MCAT PREP
Premier MCAT Prep
Cart Pricing Help Log in Work with us
Second Messengers

Second Messengers

4 min read Updated Apr 18, 2026

A second messenger is a small intracellular molecule produced in response to an extracellular signal. It carries the signal from the receptor into the cell and amplifies it. Five main ones dominate the MCAT.

Three ways a signal gets through the wall

Cell signalling
Outside Inside seven of them ligand G-protein coupled Ligand binds G protein swaps GDP for GTP Adenylate cyclase makes cAMP cAMP activates protein kinase A PKA phosphorylates its targets adrenaline, glucagon, most hormones
Seven membrane-spanning helices. The largest receptor family in the body.
 a pair, cross-phosphorylated ligand Receptor tyrosine kinase Ligand binds Two receptors pair up They phosphorylate each other Adaptors dock on the phosphates Ras and MAP kinase cascade insulin · growth factors
The receptor is the enzyme. Mutations that lock it on are a common cause of cancer.
 an open pore ligand Ligand-gated ion channel Ligand binds The pore opens Ions flow down their gradient Membrane potential changes No second messenger needed acetylcholine at the NMJ · GABA · glutamate
Milliseconds rather than seconds, because nothing has to be made.
 Why it is a cascade and not a relay 1 hormone 10 G proteins 100 cAMP 1,000 active PKA millions of phosphorylated targets Each step activates many copies of the next, so a nanomolar signal outside becomes a wholesale change inside. That is the point of a second messenger. Steroids skip all of it lipid-soluble, so they cross the membrane, bind an intracellular receptor, and act as a transcription factor. Hours, not seconds.
1

Scroll sideways to see the whole map.

G-protein coupled: slow, amplified Receptor tyrosine kinase: growth and metabolism Ion channel: fast, electrical Second messenger

Why amplification mattersOne hormone molecule activates one receptor, which activates many G proteins, each of which drives a cyclase making many cAMP, each activating a kinase that phosphorylates many targets. A handful of molecules outside the cell becomes millions of altered molecules inside it. That is why hormones work at nanomolar concentrations.

The other second messengerscAMP is not the only one. IP₃ releases calcium from the endoplasmic reticulum, DAG activates protein kinase C, calcium itself acts through calmodulin, and cGMP carries nitric oxide's signal. All do the same job: turn one event at the surface into many events inside.

Steroids skip all of itSteroid hormones are lipids, so they cross the membrane and bind receptors inside the cell. The complex then acts as a transcription factor directly. No second messenger, no amplification cascade, and a response measured in hours rather than seconds.

Water-soluble signals cannot get in, so they shout through the wall and something inside repeats the message. The receptor family determines how loud the shout gets and how fast: milliseconds for a channel, seconds for a kinase cascade, hours for a steroid.

The Five

| Second messenger | Made by | Activates | Receptor type |
|------------------|---------|-----------|---------------|
| cAMP | Adenylyl cyclase (from ATP) | Protein kinase A | Gs-coupled GPCR |
| cGMP | Guanylyl cyclase (from GTP) | Protein kinase G | Some hormones, NO |
| IP3 | Phospholipase C (from PIP2) | Opens ER Ca2+ channels | Gq-coupled GPCR |
| DAG | Phospholipase C (from PIP2) | Protein kinase C | Gq-coupled GPCR |
| Ca2+ | Released from ER by IP3 or entering via channels | Calmodulin, PKC, many enzymes | Various |

cAMP

Adenylyl cyclase converts ATP to cAMP (+ pyrophosphate). cAMP activates PKA, which phosphorylates many targets. cAMP is degraded by phosphodiesterase (PDE). Caffeine inhibits PDE, so caffeine raises cAMP indirectly.

Examples of pathways using cAMP:

  • Epinephrine → beta-adrenergic receptor → Gs → adenylyl cyclase → cAMP → PKA → phosphorylates glycogen phosphorylase kinase → glycogen breakdown.
  • Cholera toxin locks Gs in the active form, producing persistent cAMP in gut cells and massive watery diarrhea.

IP3 and DAG

Phospholipase C (PLC) cleaves PIP2 into IP3 (diffusible, cytoplasmic) and DAG (stays in the membrane). IP3 binds receptors on the ER and releases stored Ca2+. DAG, together with Ca2+, activates PKC. PKC phosphorylates a different set of substrates than PKA.

Calcium as Second Messenger

Cytoplasmic free Ca2+ is kept very low (~100 nM) by Ca2+ ATPases and Na+/Ca2+ exchangers. Small Ca2+ releases produce dramatic changes. Ca2+ binds calmodulin, activating many calmodulin-dependent kinases (CaMK). Ca2+ also activates PKC (with DAG), triggers muscle contraction (binds troponin C), and triggers neurotransmitter release at synapses.

Amplification Numbers

For a typical GPCR-cAMP-PKA cascade:

  1. 1 hormone → 1 active receptor
  2. 1 active receptor activates ~100 G proteins
  3. Each G protein’s Gα produces ~1000 cAMPs (over its active lifetime)
  4. Each PKA molecule (4 cAMPs activate 1 PKA) phosphorylates ~100 targets

Net: one hormone molecule → ~10,000-1,000,000 phosphorylation events, depending on kinetics.

Which second messengers does a Gq-coupled receptor produce, and how?
Click to reveal answer
Gq activates phospholipase C, which cleaves PIP2 into IP3 and DAG. IP3 binds ER-membrane receptors and releases stored Ca2+ into the cytoplasm. DAG stays in the membrane and activates protein kinase C (which also needs Ca2+). Net second messengers: IP3, DAG, and Ca2+.
Why is cholera toxin so disruptive at the cellular level?
Click to reveal answer
Cholera toxin ADP-ribosylates Gα(s), locking it in its GTP-bound (active) state. Adenylyl cyclase stays continuously active, cAMP accumulates to pathologic levels, and in gut epithelial cells this causes massive fluid secretion by opening chloride channels. The result is severe watery diarrhea. Removing the toxin does not immediately reverse the damage because the G protein is chemically modified.
How does signal amplification occur in a GPCR-cAMP cascade?
Click to reveal answer
Each step amplifies. One active receptor activates many G proteins. One Gα activates adenylyl cyclase to produce many cAMPs. Each PKA activated by cAMPs phosphorylates many targets. One hormone can produce tens of thousands to millions of downstream phosphorylation events. This multi-stage gain is why low hormone concentrations (nanomolar) produce strong cellular responses.
Scroll or pinch to zoom