PSIO 303A.docx

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Cindy Rankin

PSIO 303A: Review final Growth factors: in vitro and in vivo • responsible for proliferation and how they influence adulthood • REquired for 1. Proliferation - increase # • Fibroblast GF (FGF) + • Insulin -like GF (IGF-1) + • Hepatocyte GF (HGF) + • Transforming GF Beta - TGF-B from BMP's Family - • Myostatin - stop proliferation, stop muscle production. 2. differentiation - turn in to something specific • IGF-1 + • TGF - B - • Myostatin - stop differenciation 3. Quiescence - Mucsle nuclei replace itself every 6 months • Myostatin • TGF-B Where do all factors come into play in the Cell Cycle? • G1 - Growth, check point - proliferation - FGF • G0 - Leave cell cycle - neurons do not duplicate, muscle cells also can hang in here - Differentiation or quiescence (IGF) • G2 - preparation for division • S - synthesis of chromatin - proliferation - FGF • Mitosis - yeilds 2 daughter cells For developing babies/ muscles: • the cell cycle is rapid, differentiate fast. • After birth, the myonucleic lose the ability to divide - these are myogenic cells and they remain outside the fiber, unless otherwise activated. With the appropriate stimulus the satellite cells divide and contribute additional nuclei to the fiber - Hypertrophy, hyperplasia. • Satellite cell bonus - if the stimulation can duplicate the satellite cells they can undergo proliferation to regenerate damaged muscle, where the satellite cells are now sitting inside the membrane. • RELATIONSHIP - the more nuclei you have the more proteins are made, therefore the more cross bridges are formed, the more force is generated. Adult muscle: • Majority of time in G0 (or G1) in growth and differentiation. (satellite cells) • This is the primary cite for growth factors. Therefore the muscle can either get used or just sit there. Satellite cells: What stimulates activation to proliferate?? • Stretch • Injury • Exercise • Ultimate - HGF involved as an initiator, or nitric oxide - they then return to the cell cycle to proliferate and increase or regenerate muscle. • Trend - Fast fibers have less satellite cells, slow fibers have more satellite cells. Determination of muscle fiber type: • Prespecified - YES  Slow and fast types appear early, already differentiating  Myosin isoforms (slow and fast)  Both Myosin Heavy and Light heavy chains have fast and slow  Genetic signals also influence the prespecificity of the muscle fiber - via MRF • Determined over time - YES • Slow oxidative, fast fatigable are determined over time. Myoblast types Specified early: • Migration and location differ  environmental cues are important  Lateral fast fibers  medial fast fibers  superficial slow fibers What about later when the motor unit arrives? Do the muscles contraction at the beginning influence anything? Innervation and Activity affect muscle fiber type  Although prespecified early  Type is continued or supported by innervation. • Slow requires constant neural input, to stay slow talked to periodically • Fast appears independent ( of less dependent) Lecture #8: Cell signaling With Injury: • Inflammation • cell migration • removal of damaged tissue • sate cell proliferation and migration • New blood vessels (angiogenesis) • New connective tissue matrix • Local rise in growth factors: IGF, FGF, EGF, HGF, VEGF, PDGF... affects cell proliferation and differentiation. Growth and Trophic factors • EGF = Epidermal growth factor • FGF = fibroblast growth factor • PDGF =platelet -derived growth factor • HGF = Hepadocyte GF • VEFG = Vascular endothelial GF • IGF = insulin like GF  Ultimate goal is to affect gene expression!!!  Outcome - Mitosis, New protein synthesis, up/down regulation of ongoing synthesis, apoptosis  Primarily act locally - Paracrine (act on neighbors) and autocrine (act on itself) General characteristics Growth and trophic factors:  Require membrane receptors - specific to location and effect • Distribution widespread or could be localized • Can have multiple Receptor types and signaling mechanisms  Different # of GF R's types on different cell types - could have small # of receptors on a cell and have a small response  Effects are both short and long term • Short term - phosphorylation • Long term - transcription and translation Receptor Tyrosine Kinase (Trks, RTKs) • Primary for GF • Ligand binding (extracellular) causes dimerization which activates kinase • The complex (receptor and ligand (gf)) can phosphorylate itself and other proteins • Phosphotryosines serve as a binding site for multiple intracellular signaling molecules • Various downstream effects: both nuclear and intracellular • So many steps so that we can have sites of regulation and amplification Multi-step process to influence transcription or intracellular proteins • Building link between Ligand: receptor complex 1. Ligand binding - dimerization which activates kinase 2. Phosphorylates self and other proteins -allow for binding sites for intracellular signaling molecules • Ras signaling 1. Attract and bind proteins with SH2/SH3 motifs 2. Phosphotyrosine binding sites = SH2 3. Protein of choice: GBR2 - growth factor receptor bound protein 2 - contains SH2 protein recognizes the phosphotyrosine residues. 4. Binding of GRB2 complex recruits SOS 5. SOS enables RAS to bind GTP - replace GDP with GTP on ras 6. Activated GTP-RAS recuits raf-1 and activates it - simple protein-protein interaction 7. RAF-1 can now phosphorylate and activate MEK 8. MEK now phosphorylates and activates MAPK • Affect existing cytoplasmic proteins or transcription of new proteins 9. MAPK acts as an important effector molecule by phosphorylating many cellular proteins and initiates response. factors. Nerve Growth factor: • Rescues neurons from cell death (block apoptosis) • increases axonal and dendrite outgrowth (protein synthesis) • Improves synaptic transmission (increase efficacy) - presynaptic ruffling NGF family (neutrophins) also = Brain Derived Nerve factor, NT3 4/5 and 6 • location and function specific - dictated by the receptors that are expressed in cells. • Receptor subtype differs in : location , Ligand and downstream effect Lecture 9: NMJ - Switch properties of muscles with crossing nerves Mechanism? • Change in calcium concentration • contraction of stretch releases of GF • Mirco-damage or injury induces other factors • Essential - is it electrical (ion flux) or is it chemical (NT's, GF's, TF's) Neuromuscular junction: A. Synaptic transmission - B. Sythesis and packaging of neurotransmitter C. Action potential arrival D. Activation of V-gated Calcium channels - open with depolarization of membrane E. Increase in ca2+ in synaptic bulb causes vesicle mobilization F. Release of NT into synaptic cleft G. Transmitter binds to Post-synaptic receptor H. Activate post synaptic receptor effect I. NT inactivated by another molecule/enzyme Neurotransmitters: • Large peptides  substance P(info about pain), enkephalin (feels good)  Synthesized in Cell body - Golgi, ER  Trafficking - Large vesicles transported on the axonal
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