Explain signal transduction.
RECEPTION - TRANSDUCTION - AMPLIFY - RESPONSE
An extracellular first messenger signal molecule activates a receptor which activates intracellular second messenger molecules to be transduced via a specific pathway, to activate a cellular response.
Enzyme-linked receptors general mechanism.
- Ligand binding
- Protein conformational change
- Transmitted via TM helix
- Activation of intrinsic enzymes
- Signalling cascade.
Enzyme-linked receptor guanylyl cyclase
2 guanylyl cyclase domains convert GTP -> cGMP which activates downstream kinases.
Enzyme-linked receptor serine/threonine kinase.
Ser-Threo kinase domains phosphorylate target proteins,
Enzyme-linked receptor tyrosine-kinase
Tyr kinase domains phosphorylate self or other proteins
Tyrosine kinase-association enzyme-linked receptor
NO KINASE DOMAINS.
Tyr kinase proteins associated non-covalently with cytoplasmic domains.
Enzyme-linked receptor tyrosine phosphatase
Receptor contains tyrosine phosphatase domains & dephosphorylate target proteins.
What are cell surface receptors.
Hydrophilic signalling molecules activate intracellular signal transduction pathways.
What are nuclear (intracellular receptor).
Hydrophobic signalling molecules act as TRANSCRIPTION FACTORS in nucleus to regulate GENE TRANSCRIPTION.
Compare steroid and non-steroid hormones (as first messengers)
Steroid:
- lipid soluble (derived from cholesterol)
- small; pass through plasma membrane to bind to intracellular receptors & activate genes.
- Slower acting (mins-hrs)
Non-steroid:
- Water soluble (derived from aa)
- bind to cell surface receptors -> activate signal transduction pathway.
- Activate existing enzymes.
- Faster acting (s-min)
Describe the mechanism of cytoplasmic receptor activation.
- Ligand binds to receptor & dislodges repressor protein
- Ligand-receptor complex enters nucleus & binds to Hormone Response element in promoter region of DNA.
- Gene expression.
Describe the mechanism of nuclear receptor activation.
- Lipid soluble hormones diffuse through plasma membrane
- bind to cytoplasmic (& migrate to nucleus) or nuclear receptors
- Hormone-receptor complex binds to hormone response element (Acts as TF).
- mRNA synthesis
- mRNA migrates & binds to ribosomes - protein synthesis.
Compare ionotropic & metabotropic receptors.
Ionotropic: ionic ligand-receptor binding opens ion channels.
Metabotropic: ligand-receptor binding -> cascade of reactions via G protein linking.
Briefly describe how a ligand-gated ion channel works.
First messenger binds to receptor -> conformational change -> molecule enters via ion channel.
State the 4 GPCR families & their functions.
- Gα(s) stimulate AC»_space; cAMP
- Gα(i) stimulate AC «_space;cAMP
- Gα(q/11) stimulate PLC-β»_space; IP3 & DAG
- Gα(12/13) activate Rho family of GTPases.
What are enzyme-linked receptors responsible for?
Mediate actions of multiple growth factors, cytokines & hormones.
Regulate cell growth, proliferation & differentiation.
For each receptor state ligand examples & their signal transduction pathway/target.
- Ligand-gated ion channels
- GPCRs
- Enzyme linked receptors
- Nuclear receptors
- EC: GABA, (Cl-), ACh (Na+, K+, Ca++), ATP (Ca++, Na+, K+), glutamate (Na+, K+, Ca++).
IC: sAMP (K+), IP3 (Ca++) - Neurotransmitters ACh & peptides (βy subunits activate ion channels)
odorants, cytokines, lipids ( α subunit activates enzymes - cyclases, phospholipases) - ANP - receptor guanylyl cyclase
TGF-β - ser/threo kinase
insulin, EGF - tyrosine kinase
IL-6, erythropoietin - tyrosine kinase-associated receptor - Steroid hormones: mineralocorticoids, glucocorticoids, androgens, estrogens, progestins.
Miscellaneous hormones: thyroid, Vit D, retinoic acid, prostaglandins.
Bind to regulatory sequences in DNA - alter gene expression.
