Outline

• Basic Logic,

• Receptor/ligand & Receptor/effector specificity
• Hormones
• Types
• Syn/release/degradation
• Circuits
• Receptors
• Binding to hormones
• 2^nd Messengers
• intracellular signaling molecules (effectors)
• pathways

Basic Logic

• Importance, Extracellular signals used for:
• Unicellular interactions
• Multicellular physiol, growth, devel.
• Steps
• Synthesis
• Release
• Transport
• Detection by receptor
• Cellular response
• degradation
• Types
• Pheromones
• Hormones
• Paracrine
• Autocrine

Hormones

• Types
• Lipophilic: intracellular receptor
• Steroids
• Thyroxine
• Retinoic acid
• Slow acting (hrs to days)
• Syn on demand, released directly through PM
• Stable due to binding to plasma transport proteins
• Water soluble: cell surface receptor
• Peptides
• Small charged molecules, eg catecholamines
• fast acting (secs to mins)
• stored & released rapidly by regulated exocytosis
• degraded rapidly
• Lipophilic: cell surface receptor
• Prostaglandins (eicosanoid super family)
• All types regulated by positive & negative feedback circuits often involving many hormone types

Receptors

• Types of surface receptors (intracellular not discussed here)
• G-protein coupled receptors (GPCR):
• Ligandbinding alters receptor conformation
• receptor interaction w/ GTPase stimulates loading w/GTP
• GTP form stimulates or inhibits effector
• Ion channel:
• ligand gated channel
• Tyrosine-kinase linked (cytokine receptor super family):
• Receptor dimer formation upon ligand binding
• binding & activation of cytoplasmic kinase
• phosphorylation of substrate
• Intrinsic enzyme (eg receptor tyrosine kinases (RTKs))
• Ligand binding alters conformation
• conformational change leads activation of cytoplasmic enzymatic domain
• modification of substrate and/or receptor
• Receptor/ligand & Receptor/effector specificity
• Binding to hormones:
• R+H<->RH, Kd= [] giving 50% occupancy
• Response typically begins w/ few % occupancy, maximal near Kd, broad linear range
• Identification by grind & bind or expression & detection

2^nd Messengers

• cAMP, cGMP
• DAG, IP3, phosphoinositides
• Ca++

Intracellular signalling molecules (effectors)

• GTPase switch proteins
• Trimeric
• Monomeric
• Protein kinases
• Y
• S,T
• Adaptor proteins
• Phospho tyrosine binding (SH2, PTB)
• Proline binding (SH3, WW)
• Phosphoinositide binding (PH, FYVE)
• Sequence binding (PDZ)

Pathways

• Common themes for each class of receptor e.g:
• GPCR: ligand-receptor-trimeric G-effector enzyme-second messenger-SM dep. Kinase-substrate
• RTK: ligand-receptor-adaptor-ras-MAPK-substrate