Signal transduction

Abstract

In signal transduction, extracellular signals are converted into intracellular signals: A signaling molecule (ligand) reaches its target cell and binds to a specific receptor. This activates a signaling cascade involving intracellular enzymes and molecules (second messengers), which again leads to a specific reaction. Via signal amplification, the number of signaling molecules is increased at every step of the signal cascade.

Terminology

Receptors

Extracellular messengers have to bind to a receptor to exert their effect. Lipophilic messengers can pass through the cell membrane and bind to intracellular receptors, while hydrophilic messengers cannot due to the lipophilic properties of the cell membrane. Therefore, hydrophilic messengers typically act on integral membrane receptors, which translate the signal of the extracellular messenger into an intracellular signal.

Overview of receptor types

Receptor types Examples of ligands
Intracellular receptors Glucocorticoids
Cell surface receptors G protein-coupled receptors Catecholamines
Receptor tyrosine kinases

Insulin

Receptors with associated kinases

Growth hormones
Receptor protein serine/threonine kinases TGF-β (cytokine)

Other enzyme-linked receptors

Atrial natriuretic peptide (ANP)

Ligand-gated ion channels Acetylcholine

Intracellular receptors

Cell surface receptors

G protein-coupled receptors

G protein-coupled receptors (GPCRs); are the largest family of membrane receptors. The action of GPCRs depends on three elements: the receptor, the G protein, and the effector molecule

  • Examples of ligands: catecholamines, anterior pituitary hormones (ACTH, LH, FSH, TSH), glucagon
  • Receptor structure
    • Receptor with seven transmembrane helices
    • Binding sites for ligands are found in extracellular regions or between helices.
    • Has an intracellular binding site for the G protein
  • G protein
    • A heterotrimeric protein composed of three subunits
      • α subunit
        • Binds GDP in the inactive state and GTP in the active state
        • GTPase activity: hydrolyzes GTP to GDP and phosphate, thereby terminating α subunit activity
      • β subunit: stable complex with the γ subunit
      • γ subunit: complex with the β subunit with a lipid anchor in the cell membrane
    • Activation principle
      1. The binding of an extracellular ligand causes a conformational change in the receptor.
      2. The receptor binds intracellularly to G protein.
      3. Activated G protein binds GTP instead of GDP.
      4. Three subunits of the G protein dissociate in a complex composed of β and γ subunits and the α subunit.
    • GTPase: a small G protein composed of only an α subunit that functions independently to hydrolyze GTP to GDP and phosphate
  • Effector molecules
Receptor types and their connected G proteins
Gq proteins Gs proteins Gi proteins
Sympathetic α α1 α2
Sympathetic β β1, β2, β3
Parasympathetic muscarinergic M1, M3 M2
Histamine H1 H2
Dopamine D1 D2
Vasopressin V1 V2

Gs proteins activate adenylyl cyclase, whereas Gi proteins inhibit adenylyl cyclase!

Receptor tyrosine kinases (RTKs)

Receptor tyrosine kinases are transmembrane receptors that are generally activated by ligand-induced dimerization and autophosphorylation of cytoplasmic tyrosine residues, which triggers activation of downstream signaling cascades.

  • Examples of ligands: insulin , growth factors (e.g., EGF, IGF)
  • Receptor structure:
    1. Extracellular domain
    2. Single transmembrane domain
    3. Intracellular domain with tyrosine kinase activity
  • Activation principle
    1. Ligand binding to the extracellular domain results in receptor dimerization.
    2. The two adjacent tyrosine kinase domains phosphorylate one another to tyrosine residues (autophosphorylation).
    3. Increased kinase activity through autophosphorylation
    4. A number of different signal transduction molecules with SH2 domains bind to the phosphorylated tyrosine residues and are activated → activation of various effectors of different signaling pathways
  • Examples of effectors
    • Phospholipase C
    • Ras

Non-receptor tyrosine kinases

Receptor serine/threonine kinases

Ligand-gated ion channels

Since most ligands of ligand-gated ion channels are neurotransmitters, only a short overview is provided here.

Second messengers

Second messengers are small molecules that mediate the intracellular response to an extracellular stimulus.

cAMP (cyclic adenosine monophosphate) and protein kinase A

cGMP (cyclic guanosine monophosphate)

Soluble guanylate cyclase is activated by nitric oxide!

The second messengers cAMP and cGMP are degraded and inactivated to AMP and GMP by various phosphodiesterases (PDE). A decrease in cAMP or cGMP causes contractions in smooth muscles. PDE inhibitors are used in the treatment of pulmonary hypertension (PDE-4 inhibitor roflumilast) and erectile dysfunction (PDE-5 inhibitor sildenafil).

Nitric oxide

  • Structure
    • Volatile gas: half-life of 2–30 s in the blood
    • Can freely diffuse across cell membranes → can act as an intracellular and extracellular signaling molecule
  • Synthesis: produced from L-arginine in two NADPH-dependent reactions, catalyzed by endothelial nitric oxide synthase (eNOS) in the endothelial cells of blood vessels
    • eNOS is stimulated by:
      • Physical effects such as arterial wall shear stress
      • Increase in intracellular calcium concentration in endothelial cells
  • Function: causes smooth muscle relaxation and subsequent dilation of blood vessels

Nitric oxide (NO) has a half-life of only a few seconds. It is not stored by the body but is synthesized as a result of activation. Nitrate drugs stimulate the formation and release of NO. Relaxation of smooth muscle cells in vessel walls leads to dilation of coronary arteries and peripheral veins. Peripheral vasodilation leads to a decrease in cardiac preload.

IP3 and DAG

Gq proteins activate phospholipase C, which cleaves the second messengers IP3 and DAG from PIP2. These, in turn, activate PKC!

Ca2+ as a second messenger

Ca2+ mediates the effect of other second messengers such as IP3 and DAG via PKC activation. It also functions as a second messenger by acting directly, i.e., without activating another signaling molecule!

last updated 12/10/2018
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