THE PROCESS – PART 1: RECEPTION

• Signaling Molecules: small molecules that bind to larger receptors of specific target cells

1. Hydrophilic ligands: cannot cross membrane and bind to membrane receptors                                                     

• Ex: proteins that are both large and polar

2. Hydrophobic ligands: non-polar signaling molecules that can cross membrane and bind to intracellular receptors

• Receptors: specific proteins that receive ligands and trigger transduction

1. Membrane receptors: transmembrane & amphipathic; consists of an extracellular ligand-binding site and an intracellular domain that initiates transduction pathway
2. Intracellular receptors: proteins in cytoplasm or nucleus

• When a ligand binds to the cell-surface receptor, the inside part of the receptor “changes”
  • Usually means it changes shape, which may make it active as an enzyme or let it bind to other molecules

G Protein-Coupled Receptors

• GPCRs: amphipathic, transmembrane protein that activates a G protein → which activates another membrane protein → triggers cellular response or activates second messenger
• G protein inactive with GDP and activated when GDP is replaced with GTP

Process Summary

1. GPCR receives signal: specific messenger ligand binds to outward surface of receptor
2. GPCR activates G protein: ligand binding activates GPCR → GPCR exchanges a GTP for the GDP on a nearby G protein → activates G protein
3. G protein binds to and activities [membrane] effector protein:
4. Effector protein initiates cellular response:

• Enzymatic activity: effector protein may be enzyme that catalyzes specific substrate → ex: protein kinase and initiate kinase cascade
• Produce second messenger cAMP:
  • If effector protein is adenylyl cyclase, enzyme makes cAMP
    • Pathway activates cytoplasmic protein (ex: protein kinase)
    • Response may be stimulatory or inhibitory
  • Produce second messenger IP3 and DAG:
  • Produce second messenger CA2+:

1. GPCR signaling/pathway is deactivated when GTP is hydrolyzed:

Receptor Tyrosine Kinases (RTKs)

• Kinases: Enzyme activated through phosphorylation and can activate a protein by catalyzing transfer of terminal phosphate from ATP to amino acid — tyrosine with this kind
  • Protein Kinase A: ser/thr kinase activated by elevated cAMP levels
• Can receive growth factor → cell division → malfunctions = cancer

Process summary

1. RTK receives signal: ligand binds to its outer surface
2. RTK forms a dimer: two RTKs associate → form a pair (dimer)
3. RTK is activated by autophosphorylation: many phosphates can attach
4. Relay proteins are phosphorylated by RTK
5. Relay proteins initiate transduction pathway: activated relay proteins are released → each relay protein can activate cellular response or initiate protein kinase transduction pathway → each cause different response
6. RTK pathway deactivated by dephosphorylation or receptor protein packaged in vesicle (endocytosis)

GPCRs vs RTKs Pathways

1. RTK directly responsible for initiating transduction pathway; GPCR indirectly activates transduction pathway via G protein and effector molecule
2. RTK can trigger multiple transduction pathway  → direct lots of coordinated responses;

GPCR triggers single pathway → single response

Ligand-Gated Ion Channels

• Gated Ion receptor: transmembrane channel protein that opens/closes in response to ligand binding to allow ions to pass thru

1. Ligand-gated ion receptor receives signal: ligand binds to outward face
2. Receptor channel opens and ions pass through: Ligand binding caused 3D shape of receptor to change → open or close channel → allows a specific ion to pass thru
3. Ions initiate chemical response:
4. Ligand-gated ion receptor deactivated when ligand detaches or enzymatically degraded: Ligand binding site can be blocked by allosteric ligand or channel blocker

• There are also voltage-gated ion receptors that open or close in response to voltage differences across the membrane
  • Transmission of nerve impulse along neuron; Na+ enters → cell more + → if strong enough stimulates voltage-gated Na+ channel and then a voltage-gated K+ channel to open
• Some controlled by electrical signals, some in organelle membrane (ER)
• Ligand can block binding to stop diseases or open channel to allow flow of CA+, NA+, or K+

Example:

• Acetylcholine: neurotransmitter that transmits nerve impulses between nerve cells (neurons)
  • Does not enter cytoplasm
• Acetylcholine binds to ligand-gated receptor molecules → opens gated channel → allows Na+ to enter cell → cells become more positive → change in membrane voltage (active potential) initiates nerve impulse → can stimulate muscle contraction