1. Lipid cascade:A. Phospholipase C (PLC): activated by G-alpha subunits (Gq);B. PLC activation: increases the cleavage of phospholipids (part of membranes – phosphatidylinositol-4,5-biphosphate) into diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3);C. IP3 then interacts with IP3 receptors on endoplasmic reticulum membrane, which opens Ca++ channels and increases cytosolic [Ca++].Targets of PKC phosphorylation (similar to those described for PKA above):Enzymes;Neurotransmitter receptors;Ion channels;Structural proteins;Transcription factors;More usual targets: serine and threonine amino acids;Long-term activation.3. Calcium (Ca++) cascade: cytosolic [Ca++] is usually kept very low (nanomolar range: 10-9 M), but much higher extracellularly and in organelle “reservoirs” such as endoplasmic reticulum and mitochondria (millimolar range: 10-3 M).A. Cytosolic [Ca++] regulated via:3. Voltage-gated Ca channels and other membrane Ca channels (e.g., NMDA);4. IP3 receptor channels in ER;5. Other cytosolic proteins (e.g., calbindin).3. Calcium (Ca++) cascade:B. ↑ cytosolic [Ca++]: activates Calmodulin - CALcium MODULated proteinC. (Ca++ calmodulin);Ca++calmodulin activates calmodulin-dependent protein kinases (CaMKII - prevalent in neurons);4. Mitogen-activated protein kinase (MAPK) cascades (also known as extracellular signal- regulated kinases (ERKs): extensive series of kinases that are activated by phosphorylation by other protein kinases or protein tyrosine kinase receptors through small monomeric G-proteins (e.g. ras family through trk receptors).Mediates multiple substrate phosphorylation;Some of these include protein phosphatases (dephosphorylation: PP1, PP2A, PP2B, best known).5. Nuclear signaling and gene expression:messengers such as cAMP and Ca++ can activate or inhibit transcription factors;exemple - cAMP response element binding protein (CREB) – regulates gene expressionExample: cAMP and its modulation of gene expressionDivergenceOne transmitter activates more than one receptor subtype greater postsynaptic responseConvergenceDifferent transmitters converge to affect same effector systemNRSC 2100 1st Edition Lecture 12 1. Lipid cascade:A. Phospholipase C (PLC): activated by G-alpha subunits (Gq);B. PLC activation: increases the cleavage of phospholipids (part of membranes – phosphatidylinositol-4,5-biphosphate) into diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3);C. IP3 then interacts with IP3 receptors on endoplasmic reticulum membrane, which opens Ca++ channels and increases cytosolic [Ca++].Targets of PKC phosphorylation (similar to those described for PKA above):Enzymes;Neurotransmitter receptors;Ion channels;Structural proteins;Transcription factors;More usual targets: serine and threonine amino acids;Long-term activation.3. Calcium (Ca++) cascade: cytosolic [Ca++] is usually kept very low (nanomolar range: 10-9 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.M), but much higher extracellularly and in organelle “reservoirs” such as endoplasmic reticulum and mitochondria (millimolar range: 10-3 M).A. Cytosolic [Ca++] regulated via:3. Voltage-gated Ca channels and other membrane Ca channels (e.g., NMDA);4. IP3 receptor channels in ER;5. Other cytosolic proteins (e.g., calbindin).3. Calcium (Ca++) cascade:B. ↑ cytosolic [Ca++]: activates Calmodulin - CALcium MODULated proteinC. (Ca++ calmodulin);Ca++calmodulin activates calmodulin-dependent protein kinases (CaMKII - prevalent in neurons);4. Mitogen-activated protein kinase (MAPK) cascades (also known as extracellular signal- regulated kinases (ERKs): extensive series of kinases that are activated by phosphorylation by other protein kinases or protein tyrosine kinase receptors through small monomeric G-proteins (e.g. ras family through trk receptors).• Mediates multiple substrate phosphorylation;• Some of these include protein phosphatases (dephosphorylation: PP1, PP2A, PP2B, best known).5. Nuclear signaling and gene expression:• messengers such as cAMP and Ca++ can activate or inhibit transcription factors;• exemple - cAMP response element binding protein (CREB) – regulates gene expressionExample: cAMP and its modulation of gene expression • Divergence– One transmitter activates more than one receptor subtype greater postsynaptic response • Convergence– Different transmitters converge to affect same effector