Hormone Signaling

BCH 120 — Metabolic & Endocrine Biochemistry · Dr. Radi

build Jul 17 · 11:10 · CC BY-NC-SA 4.0 · owned figures (RDKit / matplotlib / PyMOL)
Dr. Radi

By the end of this unit, you can…

  • Explain how a hormone message crosses the membrane, and classify hormone actions (endocrine, paracrine, autocrine, cell-contact) and chemical classes (peptide, amine, steroid, thyroid)
  • Apply the five features of signal-transducing systems, and read receptor-binding data (Kd, affinity, dose-response)
  • Walk GPCR signaling — the β-adrenergic/epinephrine cascade, cAMP/PKA, amplification, GTPase self-inactivation, and βARK/β-arrestin desensitization
  • Compare the second-messenger systems (cAMP, IP₃/DAG, Ca²⁺/calmodulin, cGMP) and the receptor tyrosine kinases (insulin receptor, RTK family, JAK-STAT)
  • Explain membrane polarization and gated ion channels (Na⁺/K⁺ ATPase, the acetylcholine receptor, voltage- vs ligand-gated), sensory GPCR signaling (sight, smell, taste), and nuclear-receptor gene regulation
Dr. Radi

Today's route 🗺️

  1. Signaling — The Big Picture
  2. Hormone Chemistry & Two Mechanisms
  3. Five Features & Reading Kd
  4. GPCRs & the Epinephrine Cascade
  5. Switching the Signal OFF
  6. More Second Messengers — IP₃, DAG & Calcium
  7. Receptor Tyrosine Kinases & Insulin
  8. Guanylyl Cyclases & Ion Channels
  9. Your Senses Run on GPCRs
  10. Nuclear Receptors — Signaling to the Genes
Dr. Radi

1 · Signaling — The Big Picture

"In BCH 100 you lived inside one cell. Now we zoom all the way out — to a whole body of tissues that have to talk to each other. That conversation is endocrinology, and it all runs on one four-part relay."

Dr. Radi

Welcome — now zoom OUT

All of BCH 100 lived inside one cell: enzymes, pathways, feedback. This whole course lives at the level of the body. Your brain demands glucose, your liver ships fuel, muscle and adipose store and burn it, and the endocrine pancreas sets the rules. Nobody's in charge of the whole thing — so how do organs that never touch coordinate a meal, a fast, a sprint? Hormones. That's the story.

Dr. Radi

Every signal is the same four-part relay

Here's the pattern you'll see over and over for ten weeks, so learn it now. A signal (hormone, light, a neurotransmitter) hits a receptor that's specific for it; the receptor triggers a second messenger inside the cell; the messenger drives a response — enzymes flip, genes turn on, the cell acts. Signal → receptor → messenger → response. It's a doorbell: finger, button, wires, chime.

Dr. Radi

Two ways the body sends a message

The body has two messaging systems. Neuronal signaling is wired — fast (milliseconds), short-range. Hormonal signaling broadcasts into the bloodstream — slower but body-wide. The punchline: the same molecule can be either — epinephrine is a neurotransmitter and a blood-borne hormone.

Dr. Radi

Four classes of hormone action

We classify hormones by how far the message travels from release to target. Endocrine: into the blood, to a distant organ (insulin, glucagon). Paracrine: diffuse to the neighbor cell (eicosanoids — we'll spend a whole lecture on those). Autocrine: right back onto the same cell (growth signals — and cancer loves this one). Cell-contact: the messenger stays fixed to the membrane and one cell literally touches another (your immune system).

Dr. Radi

One binding event — several possible answers

When a hormone lands on its receptor, the cell can respond in more than one way, and which one tells you a lot about the hormone. It can release a second messenger that switches enzymes; fire a receptor tyrosine kinase that reprograms gene expression; open an ion channel and change the membrane's voltage; signal the cytoskeleton through an adhesion receptor; or — for a steroid — walk into the nucleus and rewrite transcription directly. Keep this menu handy; the rest of the unit is these five, one at a time.

Dr. Radi

2 · Hormone Chemistry & Two Mechanisms

"There are dozens of hormones, but only a few chemical families — and one physical property, solubility, decides how each one works. Get that, and you can predict a hormone's whole mechanism from its structure."

Dr. Radi

Sort hormones by their chemistry

Every hormone falls into one of a few chemical families, and the family tells you almost everything. Peptide/protein hormones (insulin, glucagon, ADH, growth hormone) and amines (epinephrine) are water-soluble — they're stuck outside the cell. Steroids (cortisol, aldosterone, the sex hormones) and thyroid hormone are lipid-soluble — they slip right through the membrane. One property, can it cross the membrane?, splits the whole endocrine system in two.

Dr. Radi

Meet three real hormones

Look at what you're actually dealing with. Epinephrine is a tiny amine — a catechol ring with a short amino tail (you'll build it from tyrosine soon). Cortisol is a steroid — that flat four-ring skeleton is pure cholesterol heritage, and it's greasy enough to cross any membrane. Thyroxine (T₄) is the oddball: an amino-acid derivative studded with four iodines, yet lipid-soluble enough to act like a steroid. Structure predicts behavior.

Dr. Radi

Two mechanisms, set by solubility

Now the payoff. A water-soluble hormone can't get in, so it knocks on a surface receptor and hands off to a second-messenger cascade — a response in seconds, no new protein required. A lipid-soluble hormone diffuses straight through, binds a receptor in the cytosol or nucleus, and the complex parks on DNA to change transcription — a response that takes hours to days but makes brand-new proteins. Fast switch versus slow rewiring.

Dr. Radi

Six ways across the membrane

Across the whole unit there are exactly six general types of signal transducer — this slide is your map. Five sit in the membrane: GPCRs and receptor tyrosine kinases (RTKs) are the heavyweights, alongside receptor guanylyl cyclases, gated ion channels, and adhesion receptors. The sixth, the nuclear receptor, works inside — a lipophilic hormone crosses on its own and the receptor acts on DNA. We'll meet each one; when a new receptor shows up, come back here and place it.

Dr. Radi

The glands that make it all

And where does all this hardware live? In the endocrine glands — the org chart for the whole course. The hypothalamus and pituitary are the master controllers up top; the thyroid and parathyroids set metabolic rate and calcium; the adrenals handle stress, salt, and steroids; the pancreatic islets run glucose; the gonads make sex steroids; even fat is an endocrine organ (it makes leptin). We'll tour these one gland at a time.

Dr. Radi

3 · Five Features & Reading Kd

"Every signaling system — from insulin to your sense of smell — shares five features. And the very first, specificity, is a number you can measure: the dissociation constant, Kd. Low Kd, tight grip."

Dr. Radi

Five features every signaling system shares

No matter which receptor, the same five features show up — so if you learn them once you understand them all. Specificity: a receptor fits one signal, lock-and-key. Amplification: one hormone triggers thousands of downstream molecules. Desensitization: keep the signal on and the system dials itself down. Integration: a cell adds up many signals into one decision. Modularity: the same protein parts get rewired into many pathways. Watch for these all unit.

Dr. Radi

Specificity is a number: Kd

Specificity isn't hand-waving — it's measurable, and it's the same math you learned for enzymes and substrates. Plot the fraction of receptors bound against [hormone] and you get a saturation curve. The concentration that gets you half-maximal binding is the dissociation constant, Kd. Here's the whole trick: a lower Kd means tighter binding — the receptor grabs its hormone at a lower concentration. High affinity = low Kd. Say it back to yourself; students flip it every year.

Dr. Radi

Sensitivity, on a log scale

Real dose-response curves are plotted on a log concentration axis, which turns that saturation curve into a tidy S. Three receptors with three different Kd values give three curves — each one crosses half-maximal response at its own Kd (the arrows). A high-sensitivity receptor (low Kd, left) responds to a whisper of hormone; a low-sensitivity one (high Kd, right) needs a shout. Same hormone, very different cells — that's how one signal does many jobs.

Dr. Radi

Try this one: which grips tighter?

Two versions of a β-adrenergic receptor bind epinephrine. Variant A: Kd = 2 nM. Variant B: Kd = 50 nM. Which one binds epinephrine more tightly — and by how many fold?

Dr. Radi

Try this one: which grips tighter?

Two versions of a β-adrenergic receptor bind epinephrine. Variant A: Kd = 2 nM. Variant B: Kd = 50 nM. Which one binds epinephrine more tightly — and by how many fold?
Answer: Variant A. Lower Kd = higher affinity, so A grabs epinephrine at 25× lower concentration. Fold difference = 50 ÷ 2 = 25×. (Remember: the smaller Kd wins — it's the concentration you need to half-fill the receptor, so needing less means gripping harder.)

Dr. Radi

4 · GPCRs & the Epinephrine Cascade

"The GPCR is the most common receptor in your body and the target of a third of all drugs. Watch one — the β-adrenergic receptor — turn a whiff of epinephrine into a flood of blood glucose, amplifying the signal ten-thousand-fold along the way."

Dr. Radi

Meet the GPCR

The G-protein-coupled receptor is the workhorse of signaling — about 1000 of them in your genome, sensing hormones, light, smells, tastes, and neurotransmitters. The receptor snakes through the membrane seven times (it's α-helical, integral). Docked underneath is a heterotrimeric G-protein — three subunits, α, β, γ — and the Gα subunit is the business end: it holds GDP when off, GTP when on.

Dr. Radi

Epinephrine: the fight-or-flight hormone

Our star signal is epinephrine (adrenaline), fired from the adrenal glands on top of your kidneys. Its whole job is mobilize energy, now: in muscle and liver it triggers glycogen breakdown to glucose; in fat it drives lipolysis to free fatty acids; in the heart it cranks up rate and force. One hormone, a coordinated whole-body command — all through GPCRs.

Dr. Radi

The β-adrenergic cascade

Here's the relay, receptor to fuel. Epinephrine binds the β-adrenergic receptor; the receptor flips Gsα from GDP to GTP; active Gsα switches on adenylyl cyclase, which converts ATP → cAMP; cAMP is the second messenger that activates protein kinase A (PKA); and PKA sets off the cascade that turns on glycogen phosphorylase — ripping glycogen apart into glucose for the blood. Outside knock, inside surge.

Dr. Radi

Amplification: one whisper, a shout

Why route the signal through all those middle-men? Amplification. Each step is a catalyst making catalysts. One epinephrine activates hundreds of G-proteins; each turns on an adenylyl cyclase; each cyclase pumps out many cAMP; PKA fires thousands of downstream enzymes — and at the bottom, tens of thousands of glucose molecules pour out. A hormone at nanomolar concentration moves a mountain of sugar. That's the point of the cascade.

Dr. Radi

5 · Switching the Signal OFF

"A switch that only turns ON is useless — and dangerous. Epinephrine is meant to be brief, so a GPCR signal has two ways to stop: the G-protein times itself out, and the receptor itself gets muffled when the signal won't quit."

Dr. Radi

Self-inactivation: the GTPase switch

The G-protein is its own off-timer. Active Gα carries GTP — but Gα has a slow, built-in GTPase that hydrolyzes GTP back to GDP, flipping itself off and reassembling with Gβγ. How fast? That sets how long the signal lasts, and RGS proteins can speed it up. Epinephrine is supposed to be a short shout — the GTPase makes sure the alarm stops when the danger passes.

Dr. Radi

Desensitization: turning down a signal that won't quit

What if the hormone just keeps binding? The cell muffles the receptor itself. First, β-adrenergic receptor kinase (βARK) phosphorylates the receptor's cytoplasmic tail. Then β-arrestin binds that phosphorylated tail and caps it — physically blocking the receptor from reaching its G-protein. The receptor is still there, still binding epinephrine, but uncoupled. This is why a constant dose slowly loses its punch.

Dr. Radi

Agonists, antagonists, and β-blockers

The receptor doesn't care where the molecule comes from — only whether it fits and flips the switch. Epinephrine is the natural agonist. Isoproterenol is a synthetic agonist with higher affinity (lower Kd) — it turns the receptor on even harder. Propranolol is an antagonist: it sits in epinephrine's seat and does nothing — a β-blocker that slows a racing heart. Same pocket, opposite outcomes.

Dr. Radi

6 · More Second Messengers — IP₃, DAG & Calcium

"cAMP is famous, but it's not the only messenger a GPCR can make. Meet the phosphoinositide pathway — one enzyme, two messengers — and calcium, the ion the cell keeps almost empty so that even a whisper of it screams."

Dr. Radi

cAMP isn't the only messenger

You just watched a GPCR make cAMP — but that's one option, not the whole story. GPCRs are versatile: different ones activate different second messengers. cAMP (from adenylyl cyclase) fires PKA; cGMP fires PKG; IP₃ and DAG (both cut from a membrane lipid) split the signal two ways; and Ca²⁺ works through calmodulin. Same receptor architecture, a whole panel of inside couriers.

Dr. Radi

One enzyme, two messengers: PLC

Here's the elegant one. A GPCR turns on phospholipase C (PLC), which grabs a membrane lipid called PIP₂ and cuts it in two. One half, IP₃, drifts to the ER and opens Ca²⁺ channels — flooding the cytosol with calcium. The other half, DAG, stays in the membrane and switches on protein kinase C (PKC). One cleavage, two simultaneous messengers — and calcium is now in play as a third.

Dr. Radi

Calcium works through calmodulin

Calcium doesn't act alone — it works through calmodulin, a small protein with four Ca²⁺-binding sites (the "EF-hand" motif). When calcium rises, it clamps onto calmodulin, which changes shape and exposes greasy grooves that grab and switch on target enzymes — like CaM kinase II. So a calcium spike becomes a wave of enzyme activity. Calmodulin is the universal calcium reader.

Dr. Radi

Why calcium makes a perfect signal

Here's the trick that makes Ca²⁺ such a great messenger: the cell keeps its resting cytosolic calcium absurdly low, pumping it relentlessly into the ER and out of the cell. So when a channel finally opens and calcium rushes in, even a tiny amount is a huge relative change — a loud, unambiguous signal. That's how one ion triggers muscle contraction, neurotransmitter release, secretion, and even fertilization.

Dr. Radi

7 · Receptor Tyrosine Kinases & Insulin

"GPCRs hand off to a G-protein. The other great receptor family, the receptor tyrosine kinases, ARE the enzyme — they phosphorylate themselves and launch a cascade straight to your genes. The insulin receptor is the one you have to know."

Dr. Radi

Receptor tyrosine kinases: the receptor IS the enzyme

A receptor tyrosine kinase (RTK) doesn't need a middleman G-protein — its own cytoplasmic tail is a kinase. The logic: a growth factor binds, two receptors pair up (dimerize), and the paired kinases phosphorylate each other on tyrosine residues (autophosphorylation). Those new phosphotyrosines become docking sites that recruit adapter proteins, launching a kinase cascade toward growth and gene expression.

Dr. Radi

The insulin receptor

Insulin's receptor is the RTK you must know — and it's already a dimer: two α subunits outside, two β subunits spanning the membrane. Insulin binds the α subunits; that squeezes the β subunits so they phosphorylate each other on three tyrosines, snapping the tyrosine-kinase domain ON. No dimerization step needed — insulin just flips the switch on a receptor that's pre-assembled and waiting.

Dr. Radi

Phosphotyrosine is a docking plug

Why does autophosphorylation matter so much? Each phosphotyrosine is a docking plug, and specific protein modules — SH2 and PTB domains — are the matching socket. An adapter with an SH2 domain snaps onto the P-Tyr and brings the next enzyme into position. The beauty is modularity: the same plug-and-socket parts get mixed and matched across dozens of pathways, building a huge variety of circuits from a few interchangeable pieces.

Dr. Radi

The insulin cascade → GLUT4

Now trace the whole relay. Insulin activates its receptor; the receptor phosphorylates IRS-1; IRS-1 switches on Ras, which fires the classic MAP kinase cascade — Raf → MEK → ERK. ERK walks into the nucleus, phosphorylates the transcription factor Elk1, and turns on genes — including the GLUT4 glucose transporter that moves to the membrane so cells drink up blood sugar. This is how "I just ate" becomes "store the glucose."

Dr. Radi

A whole family — and the JAK-STAT shortcut

The insulin receptor has lots of cousins: EGFR, PDGFR, VEGFR, FGFR, TrkA — a whole family of growth-factor RTKs, each with a unique outside domain but the same inside kinase. And there's a variation worth knowing: JAK-STAT. Here the receptor has no built-in kinase — a soluble kinase, JAK, docks on, phosphorylates the receptor, and loads STAT proteins that dimerize and march to the nucleus. Same idea, different hardware.

Dr. Radi

8 · Guanylyl Cyclases & Ion Channels

"Two more transducer types round out the membrane. Guanylyl cyclases make cGMP — the messenger behind nitroglycerin and Viagra. And gated ion channels turn a signal into raw electricity: the polarized membrane, the nerve impulse, and the acetylcholine receptor."

Dr. Radi

Receptor guanylyl cyclases → cGMP

A third receptor type makes its own messenger: guanylyl cyclase converts GTP → cGMP, which activates protein kinase G (PKG). It comes in two flavors. A membrane receptor version detects ligands like ANF (which lowers blood pressure) and guanylin in the gut. A soluble version carries a heme and is switched on by nitric oxide (NO) — the pathway that relaxes blood vessels, and exactly where nitroglycerin and Viagra do their work.

Dr. Radi

Membranes are electrically polarized

Some signals don't use a chemical messenger at all — they use voltage. The Na⁺/K⁺ ATPase pumps 3 Na⁺ out for every 2 K⁺ in, and because it moves more charge out than in, it leaves the inside negative — a resting potential of about −60 mV. That charge separation is a loaded battery: the cell spends it to fire nerves, to pump nutrients, and — next slide — to send an impulse.

Dr. Radi

Nerve signaling: two kinds of gate

A nerve impulse is a channel relay. A stimulus opens voltage-gated Na⁺ channels, and the local depolarization pops the next one open — an action potential racing down the axon. At the tip, voltage-gated Ca²⁺ channels open; the calcium triggers release of the neurotransmitter acetylcholine; and across the gap, ACh opens a ligand-gated channel on the next cell. Voltage-gated carries it along; ligand-gated hands it across.

Dr. Radi

The acetylcholine receptor

That receiving channel is the nicotinic acetylcholine receptor — a beautiful machine of five subunits (α₂βγδ) arranged around a central pore. At rest the gate is shut. When two ACh molecules bind the α subunits, the pore twists open, and Na⁺ and Ca²⁺ pour through, depolarizing the muscle or neuron. It's a ligand-gated ion channel: chemical signal in, electrical signal out, in a millisecond.

Dr. Radi

9 · Your Senses Run on GPCRs

"Here's the payoff that makes signaling feel real: the same GPCR machinery that reads epinephrine also lets you see, smell, and taste. Rhodopsin is a GPCR whose 'hormone' is a single photon of light."

Dr. Radi

Rhodopsin: a receptor for light

The rod cells in your eye carry a specialized GPCR called rhodopsin, and its "ligand" is a photon. Tucked inside is a chromophore, 11-cis-retinal. When light hits it, the retinal isomerizes — the bent 11-cis form snaps straight to all-trans — flipping rhodopsin ON and activating its G-protein, transducin. Afterward the all-trans falls out (the receptor is bleached), and enzymes rebuild 11-cis to reset it for the next photon — the visual cycle.

Dr. Radi

The rod-cell cascade — with a twist

Follow the relay and watch for the surprise. Active transducin switches on a phosphodiesterase (PDE); the PDE destroys cGMP, so cGMP levels fall; and falling cGMP closes a Na⁺/Ca²⁺ channel that was held open in the dark. Closing the channel makes the rod hyperpolarize — it goes quiet — and that silence is the nerve signal for "light!" In the eye, darkness is the 'on' state; light shuts the cell up. Beautifully backwards.

Dr. Radi

Smell and taste, too

Once you see the pattern, your whole sensory world is GPCRs. Smell: odorant molecules bind olfactory receptors (hundreds of different GPCRs), which activate G-olf → adenylyl cyclase → cAMP, opening a channel. Taste: sweet and bitter tastants bind taste-receptor GPCRs coupled to gustducin, a close cousin of transducin. One receptor design — a GPCR, its G-protein, an effector — reused to build three senses. That's the power of modularity.

Dr. Radi

10 · Nuclear Receptors — Signaling to the Genes

"We opened the unit with two mechanisms. We've spent four lectures on the fast one — surface receptors and cascades. Now the slow one: lipid-soluble hormones that skip the middleman entirely and act as transcription factors themselves."

Dr. Radi

Nuclear receptors: no cascade needed

Steroids, thyroid hormone, retinoids, and vitamin D are lipid-soluble — so they skip everything you just learned. The hormone diffuses through the membrane, binds an intracellular receptor, and the complex goes to DNA as a transcription factor, switching genes on or off. No messenger, no cascade — slow (hours to days), but it builds brand-new proteins.

Dr. Radi

A modular receptor

Nuclear receptors are a family, and they're built from shared modules. The DNA-binding domain is the most conserved part — it's how they all grip DNA. The ligand-binding domain is what makes each one specific to its hormone. And the activation domain is the most variable — it's where the receptor recruits its helpers. Same three-part blueprint, swappable parts: that's how one gene family reads dozens of different hormones.

Dr. Radi

Where they bind: response elements

The DNA-binding domain is picky — it recognizes specific short sequences called response elements, parked in the control region upstream of target genes. These are usually paired six-base repeats (arranged as direct or inverted repeats). And receptors dock on them as dimers: sometimes homodimers (two of the same receptor), sometimes heterodimers (two different ones). Which pair sits down helps decide which genes respond.

Dr. Radi

Turning the gene up or down

Once bound, the receptor acts as a transcriptional activator or a repressor. Its activation domain reaches out and grabs co-activators (or co-repressors) — bridge proteins that connect the receptor to the RNA polymerase II machinery. Recruit coactivators and transcription goes up; recruit corepressors and it goes down. That single handshake is how one steroid can rewire a cell's entire protein output — and it's where we head next: the steroid hormones themselves.

Dr. Radi

Can you…?

  • ☐ explain how a hormone message crosses the membrane, and classify hormone actions (endocrine, paracrine, autocrine, cell-contact) and chemical classes (peptide, amine, steroid, thyroid)?
  • ☐ apply the five features of signal-transducing systems, and read receptor-binding data (Kd, affinity, dose-response)?
  • ☐ walk GPCR signaling — the β-adrenergic/epinephrine cascade, cAMP/PKA, amplification, GTPase self-inactivation, and βARK/β-arrestin desensitization?
  • ☐ compare the second-messenger systems (cAMP, IP₃/DAG, Ca²⁺/calmodulin, cGMP) and the receptor tyrosine kinases (insulin receptor, RTK family, JAK-STAT)?
  • ☐ explain membrane polarization and gated ion channels (Na⁺/K⁺ ATPase, the acetylcholine receptor, voltage- vs ligand-gated), sensory GPCR signaling (sight, smell, taste), and nuclear-receptor gene regulation?

If any box stays empty, the practice site has a drill for it. 🧪

Dr. Radi