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Midterm 1 - Review Notes (Lec 1-13); PSYCH 2NF3

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Gautam Ullal

PSYCH 2NF3 2013 Quick Notes Tetrodotoxin (TTX)  Poisonous vertebrate toxin  Concentrated in liver, gonads, gut and skin of puffer fish o Not synthesized by puffer fish – fish is a host for symbiotic bacteria that synthesizes it o Puffer fish Na+ channel is resistant due to single point mutation  Blocks permeability of Na+ channel of neuronal membrane at the rising phase of the action potential in the central and peripheral nerves o TTX gains access to Na+ ion channel by masquerading as hydrated Na+ and attaches to it o TTX binds to channel for longer than Na+ (TTX several seconds vs. Na+ nanoseconds)  Only supportive treatment; no specific treatment  1 mg of TTX can kill an average adult human  Different Na+ channels in humans have different levels of sensitivity – cardiac and skeletal muscle Na+ channels are resistant  Paralysis occurs due to blockage of neuron that’s stimulates muscle (not due to blockage of Na+ channels on muscle)  Progressive grades of poisoning with TTX Signs and Symptoms Onset Grade 1 Perioral (around lips) numbness 5-45 mins Paraesthesia = feeling funny/tingling/numbness – occurs when sensory nerve fibers are involved With or without gastrointestinal symptoms (mainly nausea) Grade 2 Lingual (tongue), face, distal (terminal anatomical regions of body; fingers toes) numbness 10-30 mins Early motor paralysis and incoordination Slurred speech Normal reflexes Grade 3 Generalized flaccid paralysis – muscles that are paralyzed are flabby; no tension 15 min – several hours Respiratory failure Aphonia – inability to produce sound in the voice Fixed or dilated pupils Unconsciousness Grade 4 Severe respiratory failure and hypoxia (lack of oxygen) 15 min – 24 hr Hypotension – low blood pressure Bradycardia – slow heart rate Cardiac dysrhythmia – irregular heartbeat Unconsciousness – may be due to lack of oxygen in the brain  Neurophysiology – for motor and sensory nerves; patients with TTX poisoning compared to control o Threshold – minimum stimulus to elicit response  higher threshold; takes more stimulation to elicit response o Amplitude  lower amplitude; compound action potentials (AP) but smaller amplitude o Latency – response time to stimulus  higher latency; sensitivity has decreased  Can use low does of TTX to treat neuropathic pain (pain caused by damaged neurons) Ion Channels  Purpose o To selectively conduct various ions across cell membranes  excitation and conduction o Vary the excitability of the cell based on various external and internal signals (eg/ voltage, chemicals)  Gated Channels – significant for action potentials and transmission of nerve impulses 1) Voltage Gated – regulated by voltage changes; axon hillock, channels along axons 2) Ligand Gated – regulated by chemical transmitters, ions, second messengers etc binding to channel; dendritic terminals 3) Mechanically Gated – regulated by stretch, vibration etc; stretch receptors in muscles and skin, hair cells of internal ear  Muscles spindles keep sending pulses to central nervous system  important for muscle contraction  Hair cells in cochlea are sensitive to vibrations  hearing 4) Light/Photon Gated – regulated by photons; channel rhodopsin (light receptor), rod and cone receptors in retina 5) Temperature Gated – thermal receptors in skin (“free nerve endings” bring information from body’s periphery to the brain)  Non-Gated (Resting) – significant for resting membrane potential o Always open; there is still selectivity  Selective Permeability a) Diameter – pore diameter vs. ion diameter; diameter of hydrated state of ion > crystal size b) Biochemical/Charge-determined selective filter – ion permeability is also determined by specific charge configuration of the pore  Hydrated K+ ion is smaller than hydrated Na+ ion o Non-gated channels readily allow K+ but not Na+(due to size) o Na+ channels do not readily allow K+ ions to enter (due to charge) – K+ does not make same bonds as Na+ to channel  Can paralyze channel by blocking depolarization or repolarization o Depolarization prevention – “not to trigger” – paralyze NA+ channels; prevent ion entry because same size as Na+  Tetrodotoxin (TTX) – puffier fish  Saxitoxin – some shell fish o Repolarization prevention – “to keep the trigger in”; paralysis by selective increase in Na+ permeability and sustaining depolarization; prevents further firing/pulse transmission; neuron open  Batrachotoxin – South American (Golden) Frog;  Scorpion Toxins - 1 PSYCH 2NF3 2013 Channelopathies – ion channels are disturbed  Tetrodotoxin – paralyzes muscles by blocking voltage gated Na+ channels along neurons that innervate the muscles; does not block influx of Na+ through Acetyl Choline (ACh)-gated channels  α-Bungarotoxin – snake venomprotein’ paralyzes muscles by tightly binding to acetylcholine receptors on muscle at neuromuscular junction; does not block voltage gated Na+ channels  Electromyography (EMG) – electrical recording of muscle activity; can be electrodes on skin or on muscles (pierce skin); contract and rest muscles, movement causes firing  Myotonia – unable to relax a muscle after it has contracted o Mutation in Na+ channel gene SCN4A of skeletal muscle membrane (nothing to do with neuron; to do with muscle – contrast to TTX) o Hyperexcitable Muscle – delayed inactivation of Na+ channel; once opened remains opened for long time o May be fatal when respiratory muscles involved o Cause – mostly genetic; runs in families o Extremely diverse presentations – nervous system, skeletal muscle, heart, lungs, kidneys (most common) o Episodic, sudden, paroxysms (rather than progressive degenerative pattern) o Incidence – rare; can be missed due to diverse manifestation  Nervous System Channelopathies – some epilepsies, migraines, neuromuscular disorders, pain syndromes, cerebellar ataxia and excessive startle  Febrile Seizures – epileptic seizures seen in children during rapid rise in body temperatures o When patient grows up – no longer experiences seizures o Can be genetic (runs in families)  Transgenically introduce (knock in) genes from patients to normal nice  made mice prone to seizure o Can be channelopathy  Mutations in certain Na+ channels – single nucleotide point mutation; Asp replaced by Tyr (results in single aa change)  Use sequence chromatogram of genomic DNA to see nucleotide frequencies  Wt channel closes quickly  Mutants have variations in how quickly the channel closes  leads to paralysis  Myoclonic Epilepsy – Na channelopathy o Myoclonus – sudden, non-rhythmic involuntary movements o Certain severe myoclonic epilepsies in infants are associated with hundred of Na+ channel gene mutations o Epilepsy – excessively firing neurons o Can manifest itself physically and neurologically (structures in the brain)  Hemiplegic Migraine – Ca channelopathy o Migraine headache accompanied with transient hemiplegia (one-sided muscle paralysis) o Runs in families  Channelopathy not confined to nervous system – Na/K channelopathies of cardiac tissue are associated with several cardiac arrhythmias (ventricular fibrillation  Channelome – profile of all ion channels expressed in living system (akin to genome); channelomics – science that deals with channelomes (akin to genomics)  Prolonged QT syndrome – delayed repolarization; shows heart down; may lead to death o Sudden Infant Death Syndrome (SIDS) – may be caused by prolonged QT intervals o Cardioelectrogram – shows heart beat  Diseases caused by altered ion channels o Ca Channel  Familial hemiplegic migraine (FHM)  Episodic ataxia (lack of muscle coordination) (EWA)  Congenital stationary night blindness (CSNB)  Paralysis o Na Channel  Generalized epilepsy with febrile seizures (GEFS)  Myotonia  Paralysis o K Channel  Episodic ataxia (EA)  Benign familial neonatal convulsion (BFNC) - o Cl Channel  Myotonia  Cystic Fibrosis – Cl channelopathy o Cl channel protein does not get inserted in cell membrane of lungs, gut and pancreatic duct; Cl ions are not pumped across channels well  clogging of ducts or respiratory passage by thick secretions o Could be fatal o Most common inherited disease among Caucasians Nervous System  Large diameter of squid axons – 400x diameter of mammalian axon o Important for quick propulsion to escapes danger o Useful for studying membrane potentials etc o Axoplasm can be easily squeezed out and replaced by fluid of interest 2 PSYCH 2NF3 2013 o Non-myelinated but compensates with large diameter  Voltage Clamp Technique – clamp voltage at different levels and studying ion flow (current); study ion channels, most open due to voltage o Recording electrode inside axon, reference electrode outside axon in chemical (eg/ saline) o Record voltage by sending current across axon – causes voltage to change o Fix voltage and determine current  Patch Clamp Technique – single ion-channel study; isolate segment of cell membrane; recording micropipette that offers vacuum suction on cell membrane causing electric seal around electric tip; isolate a cup of membrane (“patch”) – microelectrode can study single ion-channel currents at different predetermined “command voltages” o Observe persistently open Na+ channel in myotonic patient  Uncaging Techniques – offer single dendrite-spine resolution of neural activity o Glutamate (or other compound) bound to X chemical – glutamate is inactive, “caged” o Glutamate-chemical is floating freely but inactive o Absorption of a photon from a laser “breaks the cage” and activates glutamate – shine laser close to dendrite of choice o Glutamate will act on nearby dendrite  Two Photon Uncaging Technique – study high resolution biochemical events o Two laser beams (photons) in rapid succession o Both lasers hit caged compound – know it is stationary and can localize region o First laser hits compound but second misses – know compound is moving around and may activate on another dendritic spine Tools in Molecular Biology (used to investigate nervous system)  There is different channel-related gene expression at different locations of a nerve network  Identify gene for particular function – know structure and proteins involved in channel; can find gene responsible and see whether it is being expressed more or less; see at genetic level o PCR – amplify a targeted (suspected) gene  Denature DNA to separate strands (high T)  Anneal primers  Extend strand (using heat resistant polymerase)  Polymerase must be heat resistant; often use Taq polymerase; E. coli polymerase needs to be replaced each cycle  Eg/ increase in particular glutamate receptor subtype gene expression with increased synaptic plasticity  PCR amplify suspected gene  express gene  see effect gene has on expression of tissue  Eg/ Expose animal to learning procedure; see whether process involves glutamate and NDMA (receptor) o DNA Microarray – identify thousands of genes at a time  Probes – silicon chips made of arrays of microscopic DNA spots of different DNA  Sample tissues with fluorescently labeled cDNA are allowed to hybridize with DNA on chips  Laser-driven scanners read hybridized sites  Identify the location of the gene in tissue – see if particular protein is expressed more or less in a certain tissue o In situ (in original location) hybridization  Uses labeled DNA or RNA probes to hybridize against a tissue to study the distribution of a particular DNA or RNA o Immunohistochemistry  Uses antibody against specific protein to study its distribution in a tissue o Autoradiography  Detecting a particular protein, RNA or DNA by radiolabelling  Transgenic Techniques – knockout or knockin the gene to establish function o Conditional (Targeted) Knockout/in – tissue specific; effects the particular gene in cells of one particular organ o Constitutive (Random) Knockout/in – done at stem-cell level; effects the particular gene in cells in the entire organism o In vivo – gene knockouts (transgenics)  Silence some genes (knockout)  introduce into blastocyst of surrogate mother  mother gives birth to chimeric mice (chimeric = single organism that is composed of two or more different populations of genetically distinct cells that originated from different zygotes involved in sexual reproduction)  Can have skin marker – distinguish total (brown), no- (dark) and partial-knockout (spots)  Eg/ Obsessive Compulsive Disorder – mouse scratch face continuously  Mice with gene for glutamate receptor scaffolding-protein knocked-out in the striate nucleus of basal ganglia to reduce function of glutamate receptor o Scaffold protein – anchor receptor onto cell membrane absence causes receptor to sink into membrane  Knock in gene – mouse returns to normal; stops scratching  Protein structure-function and principles of proteomics – what to know which protein is synthesized; gene doesn’t mean protein will be synthesized (transcription/translation may not occur, post-translational modifications make proteins more complex) o Proteomics – analysis of 1°, 2°, 3° structure of proteins and protein-protein interactions  Proteins are more directly related to function and disease than genes  Same genes can give different proteins  Genes are identical in all the cells in ones body, but the proteins synthesized are different depending upon the cell type o MALDI (Matrix-Associated Laser Desorption Ionization Imaging) – different proteins form separate peaks on a spectrometer (not on exam) o X-Ray Diffraction Crystallography – purified proteins are deep frozen and crystalized, subjected to X-rays, diffracted X-rays are detected, 3D map of electrons, atoms on the crystal is constructed using a computer  Ooctyes and Gene Expression – identified gene; how do we know it will activate a certain channel? o Xenopus has large oocytes (>1mm in diameter) 3 PSYCH 2NF3 2013 o mRNA or DNA for ion-channel proteins (eg/ K+ ions) microinjected into oocyte cytoplasm – oocytes synthesize ion channels o Voltage or patch clamp recording of ion currents confirm expression and insertion of ion channels into oocyte membrane Resting Membrane Potential  Resting Membrane Potential – membrane potential during resting state of a cell  Two factors favor equal distribution of ions 1) Random motion and concentration gradients 2) Electrostatic gradient  Two factors oppose equal distribution of ions 1) Ion Channels (Passive; no energy consumed); specific channels for Na+, K+, Cl- ions  Inside – K+, Polyanions (-)  negative  Outside – Na+, Cl-  positive  K+ and Cl- – can pass through channels readily due to small size  Na+ – cannot pass readily due to large hydrated diameter and charge (remain mostly outside)  Intracellular Polyanions (- proteins) – do not pass due to large size  Ions have concentration gradient that makes them diffuse across membrane  Concentration and charge can oppose each other  Eg/ K+ tends to leave cell (due to small size) but + charge is attracted to polyanion - charge  High concentration or charge – causes ions to diffuse down gradient 2) Na-K ATPase Pumps (Active – ATP hydrolysis, consumes 40-45% of energy) (more info below)  Electrogenic Pump – pumps 3 Na+ out and 2 K+ in  Absence of pump – membrane potential starts dying; irregular firing of neuron  Bilayer Lipid Membrane – functions like a battery, stores charge across membrane o Resistance (R) - ion conductance of channels o Capacities (C) - tendency of phospholipid bilayer cell membrane to store charges  Electrochemical Equilibrium – the point where Electrical Gradient is exactly balanced (of offset) by concentration gradient; there is no net flow of ions o Equilibrium Potential (for an ion) – voltage required to attain electrochemical equilibrium o Action potential does not cause significant change in cell composition because only a small number of ions needed to flow across channel  Nernst Equation – determines the equilibrium potential of a particular ion; only considers one particular ion o R (gas constant), T (absolute temperature), z (valence of ion), F (faradays coostant)I X and X (ion concentration, outside, inside)  Goldman Equation – determines membrane potential; accounts for permeability of multiple ions o P Knd P Na(permeability for K+ and Na+)  Na+/K+ Pump (Active, electrogenic pump) o Pumps ~100 times/sec in resting state o Throws out 3 Na+ ions and in 2 K+ ions  outside gets more positive o 3 sites on pump occupied by Na+  pump is phosphorylated(ATP activated, adds pho conformation change, throws Na+ out o 2 sites on pump occupied by K+  pump is dephosphorylated  conformation change, throws K+ in o Important to restore resting membrane potential (RMP) o Inactivated by oubain  Oubain – plant toxin that inhibits Na+/K+ pump o Inhibits Na/K pump  increases intracellular Na+  increases intracellular Ca++ (Ca++ is co-transported)  increases force in heart muscle o If too much Ca++ – can become poisonous o Results in reduced heart rate – effective in treating a failing or irregular heart o Produced in adrenal glands (near kidneys)  Digoxin – other plant derivative used by cardiologists  Oubain and Digoxin – dual mechanism in controlling abnormal and weak heart beat o Direct action on heart – increase intracellular Na+  increase in intracellular Ca++ o Indirect action on heart – increase activation of vagus nerve that controls heart beat Action Potential and Conduction of an Impulse in a Nerve  Threshold – minimum strength of current required to produce response  All-or-none phenomenon – either a complete response or none at all; once AP is generated, conducted without drop/gain in amplitude  Refractory Period – a period during which a second stimulus does not evoke a response; follows AP o Determined by channel dynamics (opening and closing) and Na+/K+ pump o Absolute – time period in which, no matter how strong t
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