Biosignalling

Cell Signaling Pathways/Cascades

• Understand the participants

• first messengers versus second messengers

• Amplification

• variety of downstream outcomes

• complicated and intertwined

• Protein-protein interactions

• Typically stimulated with external ligand binding to GPCRs or receptor tyrosine kinases (RTKs)

• Pathways involve lots of kinases

Classes of Receptor Proteins in Eukaryotes

• G-protein coupled receptors → heterotrimeric G proteins

• receptor tyrosine kinases → phosphotyrosine adaptor proteins

• TNF receptor family → death domain adaptor proteins

• steriods → nuclear receptors → gene regulation

• Ligand-gated ion channels

Autocrine signalling

self-signalling

paracrine signalling

short range; growth factors

endocrine signalling

long range; hormones

First messengers

many diverse responses

Second Messengers

Small, nonprotein intracellular molecules that amplify receptor-generated signals

ex.

• Cyclic GMP (cGMP)

• cAMP

• Diacylglycerol (DAG)

• Inositol-1,4,5-triphosphate (IP3)

• Ca2+

Signal Amplification

50M fold

Modulating Cell Signaling Pathways Therapies

sildenafil citrate or ozempic

G Protein-Coupled Receptors

• involved in sensory perceptions such as: Vision, Taste, Smell

• Contain seven trans-membrane alpha helices

• Also called “serpentine” receptors or 7-transmembrane receptors

ex. rhodopsin (responds to photon)

G-protein Cycle

Sequential stimulation by GEFs: Guanine Nucleotide Exchange  Factor and GAPs: GTPase Activating Protein

Which enhances signaling?

Which dampens signaling?

GPCR Activation

Sensory Perception Mechanisms and GPCRs

miraculin

pH-dependent allosteric agonist/antagonist of a sweet taste receptor

miracle berry

Generalized Receptor Tyrosine Kinase Activity

ex. Epidermal Growth Factor Receptor (EGFR)

How can you tell EGFR is activated?

Ligand bound, receptor dimerized, phosphorylated

Guanine nucleotide exchange factor (GEP)

enhance G-protein signalling via GTP

GTPase activating protein (GAP)

diminishes G-protein signalling via GTPase activity

Nuclear Hormone Receptors

1. steroid (lipid) hormones/metabolites diffuse through membrane, enter cell and bind to receptor in cytoplasm/nucleus

2. changes conformation of receptors, dimerise, bind to regulatory regions called hormone response elements

3. regulates transcription

4. produce cellular response

ex. glucocorticoid, estogeb, angrogen, progesterone, aldosterone, retinoid X, vitamin D, retinoic acid, thyroid hormone, peroxisome proliferator-activated

Steps in Signal Transduction

1. Release of the primary messenger

2. Reception of the primary messenger

3. Delivery of the message inside the cell by the second messenger

4. Activation of effectors that directly alter the physiological response

5. Termination of the signal

• How do G-proteins get activated?

• What do they do in their activated states?

• How do they become inactivated?

• How do messages get amplified?

• How do messages get integrated?