📡Cell Signaling
Cells constantly communicate with each other and respond to their environment through sophisticated signaling pathways. Understanding signal transduction is essential for physiology, pharmacology, and understanding disease.
Ninja Nerd Endocrinology Library
Hormone receptor pathways, hypothalamic–pituitary axis, thyroid, adrenal, pancreas, pineal, and reproductive endocrinology — the clinical companion to the cell-signaling theory below.
Receptor Pathways & Hypothalamus-Pituitary
Receptor Pathways
Hypothalamus: Posterior Pituitary Connection
Hypothalamus: Anterior Pituitary Connection
Oxytocin
Antidiuretic Hormone (ADH)
Growth Hormone
Prolactin
Thyroid & Parathyroid
Synthesis of Thyroid Hormone
Target Organs of the Thyroid
Thyroid Overview
Parathyroid Gland | Calcitonin
Adrenal Glands
Adrenal Gland: Aldosterone
Adrenal Gland: Cortisol
Adrenal Gland: Gonadocorticoids
Adrenal Medulla: Catecholamines
Adrenal Gland Overview
Pancreas & Pineal
Pancreas: Glucagon Function
Pancreas: Insulin Function
Pancreas: Overview
Pineal Gland
Reproductive Endocrinology
Female: Ovulation
Female: Menstrual Cycle
Female: Ovulation & Menstrual Cycle Overview
Male: Spermatogenesis
Male: Erection & Ejaculation
🔗 Signal Transduction: The Basics
Signal transduction converts an extracellular signal into an intracellular response through a cascade of molecular events. This process involves signal amplification, allowing a few signaling molecules to produce a large cellular response.
🎯Major Receptor Types
| Receptor Type | Structure | Mechanism | Speed | Examples |
|---|---|---|---|---|
| Ion Channel (Ionotropic) | Ligand-gated channel | Direct ion flux | ~ms | nAChR, GABAA, NMDA |
| GPCR (Metabotropic) | 7-TM helix | G-protein cascade | ~sec | β-AR, mAChR, opioid |
| Tyrosine Kinase | Single-pass TM | Phosphorylation | ~min | Insulin-R, EGF-R, PDGF-R |
| Nuclear Receptor | Intracellular | Gene transcription | ~hours | Steroid-R, Thyroid-R, VDR |
| Cytokine Receptor | Single-pass TM | JAK-STAT pathway | ~min | IL-R, IFN-R, GH-R |
📡G-Protein Coupled Receptor (GPCR) Signaling Simulator
Cascade Status:
β2-adrenergic receptor in complex with Gs protein
The first structure of a GPCR caught in the act of activating its G-protein (Rasmussen, Kobilka et al., Nature 2011). Earned the 2012 Chemistry Nobel. β2AR (yellow region) couples to the heterotrimeric Gs (αβγ) — the molecular event modelled in the simulator above.
🔄G-Protein Subfamilies
Gαs
Stimulates AC → ↑cAMP
β-adrenergic, glucagon, TSH
Gαi/o
Inhibits AC → ↓cAMP
M2 muscarinic, α2-adrenergic, opioid
Gαq/11
Activates PLC → IP₃ + DAG
α1-adrenergic, M1/M3 muscarinic
Gα12/13
Activates Rho → cytoskeleton
Thrombin, LPA
Gαs · GTPγS bound to adenylyl cyclase (C1·C2 catalytic core)
Tesmer et al., Science 1997. Shows how activated Gαs docks onto adenylyl cyclase to switch on cAMP production — the mechanistic step downstream of GPCR activation. Forskolin and the GTP analogue are shown as orange sticks.
💬Second Messengers
cAMP
Cyclic AMP
cGMP
Cyclic GMP
IP₃
Inositol 1,4,5-trisphosphate
DAG
Diacylglycerol
Ca²⁺
Calcium ions
PKA catalytic subunit + ATP + PKI inhibitor peptide
Knighton et al., Science 1991 — the prototype protein kinase structure. cAMP binding to the regulatory subunits releases this catalytic subunit, which then phosphorylates Ser/Thr substrates. The ATP and the bound substrate-mimic peptide are shown as orange sticks.
Inositol 1,4,5-trisphosphate receptor (IP3R) — full-length tetramer
Cryo-EM structure of the human IP3R1 channel (Fan et al., Nature 2018). IP3 generated by Gαq → PLC binds the four cytoplasmic IP3-binding cores, opening the central Ca²⁺ channel in the ER membrane.
📈Signal Amplification Cascade
A key feature of signal transduction is amplification. One hormone molecule can trigger production of thousands of product molecules.
🔬Receptor Tyrosine Kinases (RTKs)
Mechanism
- 1.Ligand binding causes receptor dimerization
- 2.Trans-autophosphorylation of tyrosine residues
- 3.Phosphotyrosines recruit SH2-domain proteins
- 4.Activation of downstream pathways (Ras/MAPK, PI3K/Akt)
Clinical Significance
- •Insulin receptor: Diabetes mellitus
- •EGFR: Cancer target (Herceptin, gefitinib)
- •VEGFR: Angiogenesis, cancer therapy
- •Bcr-Abl: CML (Gleevec/imatinib)
Insulin-receptor tyrosine-kinase domain (active, tris-phosphorylated)
Hubbard, EMBO J. 1997 — the active conformation showing the activation loop displaced after autophosphorylation, exposing the substrate-binding cleft. Three phosphotyrosines (orange sticks) stabilise the active fold.
EGFR kinase domain bound to erlotinib (Tarceva)
Stamos, Sliwkowski & Eigenbrot, J. Biol. Chem. 2002. Erlotinib (orange sticks in the ATP cleft) is a first-generation EGFR inhibitor used in NSCLC. The structure shows why activating mutations in the kinase domain (e.g. L858R) sensitise tumours to this drug.
Chapter Topics
Receptor Types
Classification and mechanisms of cellular receptors
G-Protein Signaling
GPCR structure and G-protein activation cycles
Tyrosine Kinases
RTKs, JAK-STAT, and phosphorylation cascades
Second Messengers
cAMP, cGMP, IP₃, DAG, and calcium
Signal Integration
Crosstalk, feedback, and pathway convergence