Signal Transduction Dr. Nasim

Ligands & Receptors Ligand Receptor proteins Binding site Affinity Neurotransmitters & drugs Receptor proteins ligand binds to multiple receptors Binding site specific point of ligand & receptor Affinity attraction physical & electrical fit~

Receptor Activation Lock & Key Model Structure-activity relationship Physical & electrical fit Affinity Activation  excitation or inhibition Drugs Change structure  change affinity Agonists  activate Antagonists  no activation ~

Chemical Signaling Mechanisms Synaptic Paracrine Medium range intercellular signaling Endocrine Hormones via blood Pheromones Via air ~

Signaling Pathways Cell impermeant Cell permeant Requires receptors in membranes Cell permeant Lipid soluble Steroid hormones Cell-associated signaling molecules e.g., CAMs ~

Receptor Types Channel-linked receptors Enzyme-linked receptors Ionotropic Enzyme-linked receptors Protein kinases mostly Neurotrophin-R G-protein-coupled receptors Metabotropic Intracellular receptors Activation by cell-permeant signals ~

Metabotropic receptors G protein-coupled receptors requires GTP Receptor indirectly controls channel G protein-gated ion channels 2d messenger systems neuromodulation slower action changes in sensitivity of neuron ~

G protein-gated Ion Channels NT binds to receptor protein activates G protein G protein binds to channel opens or closes relatively fast compared to 2d messenger systems ~

G protein: direct control GDP

G protein: direct control GTP * GDP

G protein: direct control GTP Pore

2d Messenger Systems NT = 1st messenger Membrane-associated components Receptor Transducer Primary effector Intracellular 2d messenger Secondary effector ~

2d Messenger Systems Slower & enduring changes Signal amplification Multiple effectors Signal amplification 1 NE  1000s cAMP 1000s cAMP  10,000s phosphates Effects Control channel Alter properties of receptors regulation of gene expression ~

2d Messengers Calcium (Ca2+) Cyclic nucleotides Target: calmodulin Calmodulin  protein kinases & phosphatases Cyclic nucleotides cAMP & cGMP Target: protein kinases ~

2d Messengers: Membrane Lipids Precursor: PIP2 Phosphatidylinositol biphosphate Cleaved by phospholipase C Diacylglycerol DAG  Protein Kinase C (membrane) Inositol triphosphate IP3  Ca2+ (endoplasmic reticulum) ~

2d Messenger Targets Enzymes Protein Kinases Protein Phosphatases Modulate phosphorylation Protein Kinases activated by: Ca2+ , cAMP, DAG, etc. Increase phosphorylation Protein Phosphatases Decrease phosphorylation activated by Ca2+/calmodulin ~

Nuclear Signaling Modulates protein synthesis Slow: 30-60 min Transcriptional activator proteins DNA  RNA  Proteins ~

b-adrenergic 2d Messenger System external signal: nt external signal: nt norepinephrine b adrenergic -R Receptor trans- ducer primary effector Receptor trans- ducer primary effector GS adenylyl cyclase 2d messenger 2d messenger cAMP secondary effector secondary effector protein kinase

b-adrenergic 2d Messenger System NT: Norepinephrine Membrane-associated components Receptor: b-adrenergic Transducer: Gs protein Primary effector: Adenyly cyclase Intracellular components 2d messenger: cAMP Secondary effector: Protein kinase ~

G protein: Protein Phosphorylation C G GDP PK

G protein: Protein Phosphorylation C G GTP ATP cAMP PK

G protein: Protein Phosphorylation C G GTP ATP cAMP P PK

G protein: Protein Phosphorylation C G GTP Pore ATP P cAMP PK