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Cell physiology1

Cell physiology1






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    Cell physiology1 Cell physiology1 Presentation Transcript

    • In the name of GOD
    • Physiology of the cell by H. Khorrami Ph.D. http://khorrami1962.spaces.live.com khorrami4@yahoo.com
    • Contents: • Plasma membrane • Some cellular organells • Transport across membrane • Membrane potential: resting & action potential • Refractory period • Chronaxie, rheobase, length constant, • Synapses, electrical & chemical • EPSP, IPSP • Adaptation, plasticity, post tetanus potentiation, long term potentiation • Lateral inhibition, synaptic fatigue, • Receptive field • Summation: temporal, spacial • Signal transduction • G-proteins • Apoptosis & necrosis • Muscle fiber, neuromuscular junction, contraction, twitch, motor unit, • Isometric & isotonic contraction • Muscle metabolism, fatigue
    • Cell membrane • Two layer phospholipids ( 45% of weight) • 2 × 1.7 + 0.1 nm • Proteins ( 55% of weight) • + 2 × 2nm • Structural • Integral • Channel • Pump • Enzymes • Receptors • Orphan • Non-orphan • Carbohydrates
    • Properties of membranes
    • Fluid mosaic model
    • Lipids
    • Phospholipids
    • Membrane lipids
    • Fatty acids
    • Phospholipids' head groups
    • Fatty acid tails
    • Glycolipids
    • Cholesterol
    • Membrane asymmetry
    • Organelle lipids
    • Lateral organization
    • Membrane curvature
    • Transport of lipids
    • Lipid synthesis
    • Non-vesicular lipid transport
    • Movements in membrane • Phlip-phlap • Rotation • Lateral diffusion ( 107 per second) • Flexion
    • Functions of carbohydrates • Negative surface charge • Attachment of cells together • As receptor • Immune recognition
    • Lysosomes Lysosomal storage Enzyme involved Problem disease(LSD) Pompe α-glucosidase Glycogen in hepatocytes MPS Glycosaminoglycans Tay-Sachs Hexosaminidase A Gangliosid Hypoxanthine-guanine- Gout Uric acid phosphoribosyl-tansferase Leprosy, silicosis,
    • Na: 15 Na: 145 Cl: 4 Cl: 104 K: 150 K: 5 Mg Ca: 10-3 - PO4+ Hco3 AA Glucose Fat Po2 Pco2 PH: 7.40 Protein PH: 7.00
    • Osmosis • Osmolarity • Osmolality • Isotonic, hypotonic & hypertonic
    • Osmosis
    • Osmotic pressure • Based on decrease in freezing point • A one molar solute -1.86⁰ C • Plasma… -0.52 • 280mmol • pv=nRT, p×1=1×62.63×310 • A one molar solute 19200mmHg • Osmotic pressure of plasma? • 5600mmHg
    • Could a hyperosmolar solution be isotonic? • Yes • Because tonicity depend on permeability of the membrane
    • Membrane transport • Diffusion • Facilitated diffusion • Active transport
    • Simple & facilitated diffusion Simple diffusion Facilitated diffusion No saturation Saturation(Vmax) Fast Low velocity Chemical gradient Carrier protein Linear correlation Non-linear correlation Competition
    • Diffusion • Fick’s law: • J = - DA(dc/dx)
    • Secondary active transport • Symport – Intestine – Kidney – Glucose & AA • Antiport – Heart – Rbc – Calcium, H+, HCO3, Cl- …
    • Ion Channels • Leak channels • Voltage-gated channels • Ligand-gated channels – Intracellular – Extracellular • Mechanically-gated channels
    • Sodium channel
    • Glucose transporters transporter tissue function insulin stimulation • Facilitative glucose transporters • GT-1 BBB, Rbc, fibroblast glu uptake + • GT-2 liver,β cell, intestine low-affinity - • GT-3 brain, fibroblast glu uptake ? • GT-4 fat, skl. muscle, heart glu uptake +++ • GT-5 small intestine, sperm fruc. transp. ? • Active glucose transporters • SGT-1 intestine, kidney intes. renal reabs -
    • Resting potential
    • Resting potential
    • Action potential
    • Na-voltage gated channel
    • Action potential
    • Threshold
    • Na channel
    • Review
    • Falling phase
    • Undershoot
    • Refractory period
    • Resting state
    • Depolarising phase
    • Repolarising phase
    • Undershoot
    • Blocking the channel
    • Potassium channels in AP • Delayed rectifier K ch – In repolarization • Early K ch – Reduce the velocity of depolarization • Calcium-activated K ch – Preventing repetitive stimulation
    • Action potential equations • Nernst: – Ek= -RT/ZF Ln [K]i/ [K]o • Goldman-Hodgkin: – Ek= -RT/ZF Ln P[K]i+ P[Na]i+ P[cl]o/ P[K]o+ P[Na]o+ P[cl]i
    • Comparison of synapses Electrical Chemical Bidirectional Unidirectional No delay Delay (1-2ms) Fast Slow
    • Century 21st
    • Gap junction
    • Electrical synapse
    • Gap junction
    • K channel
    • Nernst equation
    • Goldman equation
    • Functions of the electrical transmission 1.Electrical synapses are more reliable, less likely to fail. 2.Greater speed –important in rapid reflexes involving escape reactions. 3.The synchronization of electrical activity of groups of cells. 4.Intracellular transfer of molecules such as Ca, ATP and cAMP. 5.The activity of gap junctions between cells in the retina can be modulated by dopamine. Thus the gap junctions can be dynamic components of neuronal circuits. 6. Mutations in the genes encoding gap junction proteins cause diseases: •Peripheral neuropathy –Charcot-Marie-Tooth disease •Abnormal cardiac development •Congenital deafness Charcot-Marie-Tooth disease –inherited peripheral neuropathy -degeneration of peripheral nerves -Foot deformities, muscle wasting, distal sensory loss, decreased tendon reflexes Gap junction is necessary for radial migration in the neocortex
    • Chemical synapse
    • Chemical synapse • neurotransmitter • Depolarization of the presynaptic nerve terminal • Triggers the release of molecules Interact with receptors on the postsynaptic neuron • Excitation or inhibition of the postsynaptic neuron.
    • Neurotransmitters: Definition: • Synthesized by presynaptic neuron • Released by stimulation • Microapplication of NT. Mimic the presyn. stimulation • Presynaptic & microappl. Stim. Must be blocked by pharmacologic agent • High affinity uptake mechanism for the substance in synaptic terminal release of NT, synapsin 6/9/2010 91
    • Neurotransmitters • Small molecules • Neuropeptides  Opioid peptides  Ach Leucine enkephalin  Biogenic amines Methionine enkephaline b - endorphin Dopamine Dynorphins Norepinephrine  Pituitary peptide Epinephrine Oxytocin 5-HT Vasopressin ACTH Histamine TSH  Amino acids  Gastrointestinal peptides Aspartate CCK GABA Sub-P Glutamate Neurotensin Glycine Homocystein Gastrin Taurine Insulin  Nucleotides Glucagon Adenosine Somatostatin ATP  Others  Retrograde gases Angiotensin Nitric oxide Bradykinin Carbon monoxide Neuropeptide Y 6/9/2010 92
    • Receptors of NTs • Ionotropic: • Metabotropic: ligand gating i.e. nicotinic work by second receptor (inhibited by messenger curare) (G protein) 6/9/2010 93
    • Neuropharmacology of some receptors Neurotransmitter Receptor subtype Agonist Antagonist Acetylcholine(Ach) Nicotinic receptor Nicotine Curare Muscarinic Muscarine Atropine receptor Glutamate AMPA AMPA CNQX NMDA NMDA AP5 GABA GABAA Muscimol Bicuculine GABAB Baclofen Phaclofen
    • Acetylcholine
    • Catecholamines
    • Serotonin synthesis
    • Glutamate receptor • Non-NMDA; • NMDA; • kainate receptor & • Gating channel is • AMPA permeable to Na, K, Mg – permeability  to Na & & Ca2+ K • Magnesium block – Excitatory • Act on this receptor – Act on this receptor at when depolarized rest (voltage-dependent) N-Methyl-D-Aspartate , α-amino-3-OH-5-methyl-4-isoxasole propionate 6/9/2010 98
    • Glutamate receptors
    • Calcium can trigger • Enzymatic activity • Opening of a variety of channels • Gene expression • Cell death • Long-term memory
    • Glutamate receptors • Activation of AMPA • Na+ inward & K+ outward • Depolarization • Pop out of Mg2+ from the pore of NMDA
    • Voltage-dependent NMDA
    • Excitotoxicity • High demand of brain cells to oxygen & glucose • Cardiac arrest, stroke, ….. • Limits of ATP • Depolarizing the membrane • Calcium leak into cells • Glutamate release • Depolarization • More calcium • …………… • Cell death
    • TTX
    • Length constant
    • Components of a second messenger cascade
    • Nicotinic receptor
    • Acetylcholine
    • Acetylcholine receptors Name Location Blocked by Agonists Muscarinic End of postgang. Atropine Metacholine parasym Carbachol Betanechol Pilocarpine Nicotinic Autonomic ganglia Scopolamine Nicotine Adrenal medulla Hexamethonium N-M junction Tubocurarine
    • Ach (muscarinic receptor)
    • Norepinephrine
    • Inhibitory neurotransmitter
    • Cell-to-cell communication by extracellular signaling usually involves six steps • Synthesis of the signaling molecule by the signaling cell • Release of the signaling molecule by the signaling cell • Transport of the signal to the target cell • Detection of the signal by a specific receptor protein • A change in cellular metabolism, function, or development triggered by the receptor-signal complex • Removal of the signal, which usually terminates the cellular response
    • Signaling molecules operate over various distances in animals
    • Cell-surface receptors
    • Signal transduction steps • Ligand binds to the receptor • Dissociation of a subunit from b & g • Exchanging GDP with GTP • Moving a subunit • Activation of adenylyl cyclase or GC • Second messenger( cAMP) • Binding cAMPs to R subunit of Protein kinase • Dissociation & activation of C subunit • Phosphorylation of target protein • Cell response
    • Cell-surface receptors
    • Second messengers
    • Other conserved proteins function in signal transduction: GTPase switch proteins
    • Other conserved proteins function in signal transduction: protein kinases
    • Other conserved proteins function in signal transduction: adapter proteins
    • Common signaling pathways are initiated by different receptors in a class
    • hormone signal outside GPCR plasma The a subunit of membrane a G-protein (Ga) a g g  a cytosol binds GTP, & can AC GDP b b GTP hydrolyze it to GDP + Pi. GTP GDP ATP cAMP + PPi a & g subunits have covalently attached lipid anchors that bind a G-protein to the plasma membrane cytosolic surface. Adenylate Cyclase (AC) is a transmembrane protein, with cytosolic domains forming the catalytic site.
    • hormone signal outside GPCR plasma membrane a g g  a cytosol AC GDP b b GTP GTP GDP ATP cAMP + PPi The sequence of events by which a hormone activates cAMP signaling: 1. Initially Ga has bound GDP, and a, b, & g subunits are complexed together. Gb,g, the complex of b & g subunits, inhibits Ga.
    • hormone signal outside GPCR plasma membrane a g g  a cytosol AC GDP b b GTP GTP GDP ATP cAMP + PPi 2. Hormone binding, usually to an extracellular domain of a 7-helix receptor (GPCR), causes a conformational change in the receptor that is transmitted to a G-protein on the cytosolic side of the membrane. The nucleotide-binding site on Ga becomes more accessible to the cytosol, where [GTP] > [GDP]. Ga releases GDP & binds GTP (GDP-GTP exchange).
    • hormone signal outside GPCR plasma membrane a g g  a cytosol AC GDP b b GTP GTP GDP ATP cAMP + PPi 3. Substitution of GTP for GDP causes another conformational change in Ga. Ga-GTP dissociates from the inhibitory bg complex & can now bind to and activate Adenylate Cyclase.
    • Identification and purification of cell-surface receptors Hormone receptors are detected by binding assays
    • KD values for cell-surface hormone receptors approximate the concentration of circulating hormones
    • G protein-coupled receptors and their effectors • Many different mammalian cell-surface receptors are coupled to a trimeric signal-transducing G protein • Ligand binding activates the receptor, which activates the G protein, which activates an effector enzyme to generate an intracellular second messenger • All G protein-coupled receptors (GPCRs) contain 7 membrane-spanning regions with their N-terminus on the exoplasmic face and C-terminus on the cytosolic face • GPCRs are involved in a range of signaling pathways, including light detection, odorant detection, and detection of certain hormones and neurotransmitters
    • G protein-coupled receptors
    • The structure of adenylyl cyclase
    • Trimeric Gs protein links b-adrenergic receptors and adenylyl cyclase
    • Some bacterial toxins irreversibly modify G proteins
    • Adenylyl cyclase is stimulated and inhibited by different receptor- ligand complexes
    • Types of G-proteins • Ras (growth factor signal cascades) • Rab (membrane vesicle targeting and fusion) • ARF (formation of vesicle coatomer coats) • Ran (transport of proteins into & out of the nucleus) • Rho (regulation of actin cytoskeleton)
    • Ras cycles between active and inactive forms
    • Receptor tyrosine kinases and Ras • Receptor tyrosine kinases recognize soluble or membrane bound peptide/protein hormones that act as growth factors • Binding of the ligand stimulates the receptor’s tyrosine kinase activity, which subsequently stimulates a signal- transduction cascade leading to changes in cell physiology and/or patterns of gene expression • RTK pathways are involved in regulation of cell proliferation and differentiation, promotion of cell survival, and modulation of cellular metabolism • RTKs transmit a hormone signal to Ras, a GTPase switch protein that passes on the signal on to downstream components
    • Ligand binding leads to autophosphorylation of RTKs
    • An adapter protein and GEF link most activated RTKs to Ras
    • Opening of ryanodine receptors releases Ca2+ stores in muscle and nerve cells
    • Signal transduction