1. Intracellular signaling – the all important sibling of membrane potential signaling!a. Second messenger systems;b. Effector pathwaysEssential components of Signaling Systems1. A molecular signal;2. A receptor molecule;3. A target effector molecule (response).Often involves “cascades”the neurotransmitter glutamate (signal)↓Acts on glutamate receptor protein (receptor)↓Opens an ionic membrane channel (target effect-or)Molecular signals1. Cell impermeant molecules: includes neurotransmitters (do not readily cross membranes);2. Cell permeant molecules: includes steroid-based molecules, thyroid hormone (thyroxins), and retinoids (related to vitamin A);3. Cell-associated molecules: cell membrane proteins to cell membrane receptor interactions of closely apposed cells.Receptor molecules1. Channel-linked receptors (ionotropic);2. Metabotropic receptors (G-protein-coupled receptors);3. Enzyme-linked receptors;4. Intracellular receptorsTarget Effector “Cascades”G-proteins and their targets: both heteromeric (alpha/beta/gamma small proteins) and monomeric (small G-proteins) forms generally activate enzymes that regulate the production of “second-messengers”;5. Second messenger targets: second messengers regulates several target enzymes (e.g., PKA);6. Nuclear messenger targets: protein modification induced in transcription factor targets can translocate to nucleus and modify gene transcription (CREB).Major G-proteins targets1. Cyclic nucleotide cascades:A. Adenylyl cyclase: is targeted by several types of activated alpha subunits (GTP) leading to increases (alpha stimulatory or Gs) or decreases (alpha inhibitory or Gi) in [cAMP]i.B. Guanylyl cyclase: similar for [cGMP]i.C. cAMP/cGMP cascades: cAMP/cGMP regulates the cAMP/cGMP-dependent protein kinases (PKA and PKG, respectively).Kinases and Phosphatases – the Yin and Yang!Phosphorylation and DephosphorylationPhosphate groups added to or removed from a proteinChanges conformation and biological activityThe Function of Signal CascadesSignal amplification by GPCRsCyclic nucleotide cascades:Phosphorylation Targets of PKA (and PKG):Enzymes;Neurotransmitter receptors;Ion channels;Structural proteins;Transcription factors (CREB);More usual targets: serine and threonine amino acids;Thousands of protein targets even in neurons!NRSC 2100 1st Edition Lecture 11 1. Intracellular signaling – the all important sibling of membrane potential signaling!a. Second messenger systems;b. Effector pathwaysEssential components of Signaling Systems1. A molecular signal;2. A receptor molecule;3. A target effector molecule (response).• Often involves “cascades”the neurotransmitter glutamate (signal)↓Acts on glutamate receptor protein (receptor)↓Opens an ionic membrane channel (target effect-or)Molecular signals1. Cell impermeant molecules: includes neurotransmitters (do not readily cross membranes);These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.2. Cell permeant molecules: includes steroid-based molecules, thyroid hormone (thyroxins), and retinoids (related to vitamin A);3. Cell-associated molecules: cell membrane proteins to cell membrane receptor interactions of closely apposed cells.Receptor molecules1. Channel-linked receptors (ionotropic);2. Metabotropic receptors (G-protein-coupled receptors);3. Enzyme-linked receptors;4. Intracellular receptorsTarget Effector “Cascades”G-proteins and their targets: both heteromeric(alpha/beta/gamma small proteins) and monomeric(small G-proteins) forms generally activateenzymes that regulate the production of “second-messengers”;5. Second messenger targets: second messengers regulates several target enzymes (e.g., PKA);6. Nuclear messenger targets: protein modification induced in transcription factor targets can translocate to nucleus and modify gene transcription (CREB).Major G-proteins targets1. Cyclic nucleotide cascades:A. Adenylyl cyclase: is targeted by several types of activated alpha subunits (GTP) leading to increases (alpha stimulatory or Gs) or decreases (alpha inhibitory or Gi) in [cAMP]i.B. Guanylyl cyclase: similar for [cGMP]i.C. cAMP/cGMP cascades: cAMP/cGMP regulates the cAMP/cGMP-dependent protein kinases (PKA and PKG, respectively). • Kinases and Phosphatases – the Yin and Yang!– Phosphorylation and Dephosphorylation• Phosphate groups added to or removed from a protein– Changes conformation and biological activity – The Function of Signal Cascades• Signal amplification by GPCRsCyclic nucleotide cascades:Phosphorylation Targets of PKA (and PKG):Enzymes;Neurotransmitter receptors;Ion channels;Structural proteins;Transcription factors (CREB);More usual targets: serine and threonine amino acids;Thousands of protein targets even in