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3A

Andrew Susilo Part 1-3 None Inglés 49 fichas

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  1. 1Development of brain structures from embryo: prosencephalon -> telencephalon (cerebral hemispheres) + diencephalon ((hypo)thalamus) // mesencephalon (midbrain + SN) // rhombencephalon -> metencephalon (pons + cerebellum) + myelencephalon (medulla).
  2. 2Cranial nerves - exit skull to periphery, 12 pairs; spinal nerves - arise from spinal cord, mixed nerves come together from afferent + efferent neurons @ nerve root, 23 pairs Basic functions of nervous system: motor (including tone + posture) / sensory / automatic reflexesInformation processing @ cerebellum: motor plan (which muscles + intensity + duration) -> position sense (via somatosensory information) -> feedback (correction from cerebellum)
    Reticular formation - scattered gray matter @ brainstem; other nuclei (distinct) connects with cranial nerves
  3. 3Subcortical areas: internal capsule (subcortical white matter, contains corticospinal UMN) // BG (collection of subcortical nuclei, help motor areas of cortex, also for cognition / emotion etc) // corpus callosum // diencephalon.
  4. 4UMN usually decussate to LMN @ brainstem /x/ spinal cord intersection -> synapse @ spinal cord (corticospinal); corticobulbar tracts may / not decussate @ brain stem UMN signs: hyperreflexia / clonus (rhythmic contraction of antagonists) / hypertonia / extensor planar (Babinski)LMN unit = 1 LMN (from brainstem // spinal cord) + all skeletal muscles under it; typically many NMJ for a LMN (may be fewer if more precision required)
    LMN signs: atrophy / fasciculation (involuntary twitch) / hypotonia / hyporeflexia (usually when rapidly flexing)
  5. 5Categories of somatosensation: mechanoreceptors (detect position / vibration / touch) // nociceptors // thermoreceptors; latter two have bare nerve endings Large (A) vs small diameter (C) neurons: for position / vibration / fine touch vs for pain / temperature / gross touchPain / temperature / gross touch usually conveyed from spinal cord to brain via specific tracts (those from face usually go down via brainstem to body -> cross -> go up again)
  6. 6Types of cells controlled by ANS: smooth muscle // cardiac // gland cells SNS vs PSNS: first neuron from middle spinal cord vs brain stem / bottom, short -> long vs long -> short Sympathetic chain = ganglia from first axons.
  7. 7Neurotransmitters projected diffusely towards cortex: Glu (eg by RAS, for consciousness) / histamine (from some hypothalamus neurons) / NE (eg from locus coeruleus @ pons) / 5-HT (from raphe nuclei @ all levels of brainstem) / DA (eg from midbrain VTA) / ACh (eg from basalis / septal nuclei)DA projections to other areas: SN @ midbrain -> striatum @ BG // hypothalamus -> pituitary (regulates PRL release) // VTA -> (via NAcc) limbic system
    ACh projections to other areas: LMN -> muscle // most ANS neurons (fewer uses NE)
  8. 8Early methods of studying brain: phrenology (bumps x specific tasks / characteristics @ brain area) / autopsy (\ limited in showing brain function) / via brain injury (cerebral localisation, eg from Gage); generally limited in time span / nature of control over injuriesAblation methods: surgical (\ only for surface) / sever nerves with scalpel / RF lesions (high frequency current destroys only around tip) / neurochemical (eg kainic acid for destroying cell bodies only / oxidopamine for DA and NE neurons) / cryogenic (using cryoloop, reversible)
  9. 9Structural methods for studying brain: CT (use X-ray) / MRI (use radiowaves + strong B field, more detailed picture) Functional recording of brain: EEG / MEG (better resolution \ very expensive) fMRI gives structural images + active areas \ poorer temporal resolution than PET, PET must be combined with others.
  10. 10CNS mainly derived from neural stem cells; PNS - mainly from neural crest cells; both arise early from ectoderm Neurites = projections (axon // dendrite) Axon hillock = point of leaving soma; initial segment (trigger zone) = first part of projection after hillock; axon collaterals branch along length of axonCNS neuronal development: neural stem cells (unipolar) -> differentiate into neuroblasts (*can only become neural cells) -> migrate -> extend axon with growth cone towards target (follow guidance cues) -> can become multipolar (motor) // pseudo-unipolar (sensory) // bipolar (interneuron)
  11. 11Astrocytes - most common type of cell @ CNS, end feet found @ end of branched processes forming BBB Functions of astrocytes: scaffold / gliosis (divide -> migrate to injury -> glial scarring with hypertrophied projections) / ion homeostasis / release lactate / clear neurotransmitters @ synapseOligodendrocytes - similar to astrocytes \ fewer projections, extend towards nearby axons (produce myelin, many oligodendrocytes to 1 axon / vice versa)
    Schwann cells vs oligodendrocytes: shapeless, not all have myelin (only large ones have), each Schwann to 1 axon only, from neural crest
  12. 12Microglia - derived from monocyte from mesoderm Resting microglia (small soma + highly branched processes, just monitoring interstitial fluid at first) convert to active (larger, blob) -> act like macrophages to scavenge CNS.
  13. 13Ependymal cells - derived from neural stem cells, simple cuboid / columnar epithelium, line CSF-filled ventricles @ brain and spinal cord Apical (luminal) side of ependymal cells have microvilli + cilia Functions of ependymal cells: shield CSF /// interstitial fluid, secrete CSF via tufts.
  14. 14Na+ / Cl- / Ca^2+ mostly outside neuron \ K+ and organic anions (eg proteins) mostly inside Forces acting on ions @ neurons: electrical potential + diffusion potential Contributors to resting potential: Na+/K+ pump + K+ diffusion via leaky channelsDriving forces on other ions: Cl- driven by membrane potential (usually out unless concentration gradient otherwise, can be via Cl-/K+ symport) \ negligible for resting potential (equilibrium ~-70mV), Ca^2+ driven by Ca^2+/Na+ exchanger \ low permeability even though equilibrium ~+120mV
  15. 15Na+/K+ ATPase function: Na+ and K+ must be present for ATP hydrolysis to take place -> forms p-Asp intermediate (P-type ATPase) -> Na+ / K+ gradient -> controls cell volume + promotes active transport of glucose and amino acids (secondary active transport)Other types of P-type ATPase: Ca^2+ (transports Ca^2+ from cytoplasm into ECF / mitochondria / sarcoplasmic reticulum) / H+/K+ (pump H+ by parietal cells to stomach) / P4-ATPase (moves membrane lipids from outer to inner)
    V-type (eg H+ pump) uses ATP without phosphorylated intermediate
  16. 16Action potential mechanism: trigger zone having greatest density of Na+ channels -> action potential with opening of Na+ and K+ channels (more slowly) -> Na+ channels close and inactivate @ +40mV, K+ continues to go out -> repolarisation -> K+ slowly close -> some K+ causing hyperpolarisationAbsolute refractory period: Na+ close and won't open even in strong potential; relative refractory period: Na+ functional but membrane hyperpolarised
    Effects of myelination: decrease capacitance @ nodes vs sheath (charges closer vs further) / prevent escape / maintain resting potential easier
  17. 17Basis of K+ channel selectivity: pore constricts to smaller cavity from inside-out (K+ can still fit in) -> more constricted along the way, K+ must give up water and interact with carbonyl groups of selectivity filterHard-knock model: subsequent K+ moving into selectivity filter repels nearby K+ -> shift K+ further up \ repulsion too great for close contact in the first place?
    Knock-on model: K+ and water occupies adjacent sites, still allowing repulsion to be driving force
  18. 18Synapses occur most often @ dendrites; can have some @ soma / axon (especially terminal) CNS synapses mostly covered by feet of astrocytes Neurotransmitter release: Ca^2+ influx -> activate synaptotagmin to release complexinAmino acid neurotransmitters: Glu / GABA (inhibitory @ brain) / Gly (inhibitory @ spinal cord)
    Opioids (eg endorphin) - type of peptide neurotransmitters, important in pain perception
    Monoamines = amino connected to aromatic via 2C chain
  19. 19Ionotropic vs metabotropic receptors: ligand gated ion channels vs second messenger linked (direct or indirect), brief / quick / local vs larger (due to amplification) and widespread Neurotransmitter removal: passive (diffusion) / enzymatic / reuptake / astrocyte end-feet (metabolise / recycle)Common neurotransmitter receptors: nicotinic (ACh binds to cation channel -> Na+ in, Ca^2+ in, K+ out) // muscarinic (ACh binds to GPCR -> activate K+ channel -> K+ out) // GABA (GABA binds to Cl- channel -> Cl- in for GABA_A/C // K+ out for GABA_B) // NMDA / AMPA (Asp / Glu binds to cation channel)
  20. 20Cholinergic receptors: N1 (NMJ) / N2 (postganglionic / chromaffin) / M1/3/5 (smooth muscle / glands, G_q) / M2/4 (smooth muscle / glands / heart, G_i) Adrenergic receptors: a1 (G_q) / a2 (digestive system, G_i) / b1 (heart / kidney, G_s) / b2 (airways / blood vessels / bladder, G_s) / b3 (adipose, G_s)SNS vs ANS: all cholinergic (excitatory) vs some adrenergic and/or inhibitory, one-neuron vs two-neuron
    NMJ events: ACh binds N1 @ motor end plate -> net Na+ in -> end plate potential (much larger than EPSP) -> local current flow to adjacent region -> muscle action potential propagated both directions
  21. 21Neuromodulators = alter strength of response \ do not generate E/IPSP Neuromodulators of GABA_A: benzodiazepines (increase frequency of Cl- channel opening) / barbiturates (increase duration of Cl- channel opening) / ethanol (enhance activity of GABA_A)Common neuropeptides: enkephalin (suppress substance P release) / opioids (dynorphin / endorphin) / substance P (from peripheral pain receptors to CNS) / hypothalamic hormones / angiotensin II (-> vasoconstriction + aldosterone release) / CCK (stop eating) / peptide Y (stimulate food intake / stress response)
  22. 22GPCR characteristics: eukaryotes only, 7 alpha helices, 3 subunits (beta not anchored to lipid) RTK most useful for growth / survival Other types of ion channels: voltage gated // stretch activated (open or close in response to deformation / stretching of membrane, eg cardiac cell).
  23. 23PKA consists of 2 R + 2 C subunits GTP-G_as associates with adenylate cyclase -> produce cAMP -> bind to R subunits of PKA -> C subunits released -> phosphorylate Ser/Thr; cAMP cascade turned off by cAMP phosphodiesterase, G_a.s re-assembles via GTP hydrolysis (slow)Phosphoinositide cascade: hormone eg ADH binds GPCR -> activate G_a.q -> activate PLC -> hydrolysis of PIP2 phosphodiester into DAG + IP3 -> IP3 binds to IP3 receptor for rapid release of Ca^2+ -> works with DAG to activate PKC (Ser/Thr kinase)
  24. 24RTK activation: hormone binds to extracellular domain (1 membrane-spanning helix) -> dimerise -> brings together intracellular domains (JAK2) -> cross-phosphorylate @ Tyr -> phosphorylate substrates eg STAT5 for HGH / Grb2 for EGF / IRS for insulin (-> glycogen synthesis + glucose uptake)Ras family of GTPases: Ras (regulate cell growth via Ser/Thr kinase) // Rho (reorganise cytoskeleton via Ser/Thr kinase) // Arf (regulates vesicular trafficking / activate phospholipase D etc) / Rab (for endocytic / secretory pathways) / Ran (for nucleo-cytoplasmic transport)
  25. 25cGMP signaling pathways: NO (binds intracellular receptor -> activate guanylyl cyclase component -> cGMP -> activate PKG -> phosphorylate MLKC @ Ser/Thr -> prevent actin-myosin interaction -> smooth muscle relax) / RGC (can bind to ANP -> extracellular domains dimerise)JAK pathway: receptor dimerise -> JAK cross-phosphorylate @ Tyr -> STAT binds and gets activated -> go in nucleus to stimulate transcription of some genes
    Other effects of G proteins: regulate opening of ion channel via direct binding / second messenger
  26. 26Ions influencing neuronal excitability: extracellular K+ (increase in concentration abolishes concentration gradient --> depolarise) / Na+ (increase in concentration intensifies concentration gradient --> depolarise) / Ca^2+ (increase in concentration binds more Na+ channels to open).
  27. 27Neuroplasticity = nervous system change with experience; highest when developing / transiently after injury \ occurs throughout life Synaptic neuroplasticity = synaptic activity (transmitter / receptor / signaling); structural neuroplasticity = synapse strength (more long term).
  28. 28Hypothalamus - dual role in nervous and endocrine, signal to pituitary via paracrine + also produce hormones for posterior pituitary (ADH / OT) Hypothalamus hormones: GnRH / CRH / TRH / PIH (constitutive) Tropic hormones: FSH / LH / ACTH / TSH; direct hormones: PRL / endorphin / GHHormonal regulation: metabolism (via liver into bile) / excretion (via urine / feces / sweat) / negative feedback
    Steroid hormones - characteristic 4 ring (3 c-hex + 1 c-pent)
    Tyr derivative hormones can work intracellular (eg thyroid) / extracellular (eg catecholamines)
  29. 29Release of pancreatic endocrine hormones also influenced by ANS / GI hormones Alpha vs beta adrenergic receptors: peripheral blood vessel contraction + GI tract relaxation + platelet aggregation vs bronchi relaxation + skeletal muscle relaxation + heart actionSteroids transported @ blood by complexing with transcortin (or sometimes albumin)
    Anabolic steroids = androgens promoting muscle growth
    Testicular feminisation = genetic males with no functional cytosolic androgen receptors
  30. 30Gluokinase - rate-limiting step of glucose metabolism @ beta cells; G6P produced degraded to pyruvate -> oxidative respiration -> ATP closes K+ channels -> depolarisation opens Ca^2+ for influx -> exocytosis of insulin secretory granulesInsulin effects: glucose uptake (muscle / adipose) + glycogenesis (muscle / liver) + lipogenesis (adipose / liver) + inhibit gluconeogenesis (liver); glucagon effects: lipolysis (adipose) + glycogenolysis (liver); epinephrine effects: glycogenolysis (muscle / liver) + lipolysis (adipose) + gluconeogenesis (liver)
  31. 31GH mechanisms of action: direct (lipolysis @ adipocytes / glycogenolysis @ liver) // indirect (via IGF @ liver promoting uptake of amino acids for protein synthesis).
  32. 32Stress responses: short-term (E + NE stimulate glycogenolysis / increase HR / dilate bronchioles) // long-term (ACTH stimulates corticosteroid release -> lipolysis / glucose synthesis / anti-inflammation / stimulate Na+ and water reabsorption)Addison's disease: hypoglycemia / Na+ loss / K+ retention (-> impaired cardiac function) / increased stress susceptibility
    Cushing's syndrome: fatigue / hyperglycemia / edema
  33. 33Aldosterone vs ADH: promote Na+ reabsorption + K+ secretion vs promote water reabsorption RAAS system: JGA detects decreased BP -> release renin -> cleave angiotensin I (produced by liver) -> angiotensin II -> trigger release of aldosterone + vasoconstriction + increase in ADH.
  34. 34GnRH stimulates production of FSH + LH during puberty -> FSH stimulates sperm cell maturation // follicular development -> sertoli // follicular granulosa secrete inhibin (+ E2), LH stimulates androgen production by Lyedig cells // ovulation + androgen secretion from thecal cells + progesterone production from CLProlactin - produced by anterior pituitary, stimulates milk production from mammary glands following childbirth (ejected by contraction of myoepithelial cells); inhibited by DA
    Uterine smooth muscles only sensitive to oxytocin when oxytocin receptors peak during late pregnancy
  35. 35TSH binds to thyroid follicular receptors -> thyroglobulin released into colloid, I- actively transported into follicle (with Na+ symport) -> peroxidase attach I0 to Tyr of thyroglobulin -> T3/T4 released into bloodstream (T4 more abundant \ T3 more active, mostly attached to transport proteins)T3/T4 enter target cell via diffusion / carrier mediated transport -> mono-deiodinase removes 5' I -> T4 converted to T3 -> bind thyroid hormone receptor @ nucleus -> activate TRE transcription // bind mitochondrial receptors -> ATP production
  36. 36PTH released in response to low blood Ca^2+ / high PO4^3- -> stimulate resorption by osteoclasts + reduce deposition by osteoblasts + increase renal Ca^2 reabsorption + decrease PO4^3- reabsorption + increase PO4^3- excretion + stimulate calcitriol (increase intestinal Ca^2+ absorption)Calcitriol released in response to high PTH / low Ca^2+ and PO4^3- -> stimulate resorption + kidney reabsorption + intestinal absorption
    Calcitonin released from C cells in response to high Ca^2+ -> increase deposition + decrease resorption + increase excretion
  37. 37Secondary endocrine organs: heart (atria walls produce ANP in response to increased blood volume -> decrease Na+ reabsorption / decrease RAAS system) / GI (mucosa produces gastrin / secretin / CCK) / kidneys (produce renin / calcitriol / EPO) / thymus (produce thymosin) / adipose (produce leptin).
  38. 38Isoprene: 1C branch @ middle of 4C Steroid biosynthesis uses isoprene pyrophosphate (because pyrophosphate is weak base hence good leaving group); dimethylallyl + isopentenyl (head<->tail) -> geranyl, + another isoprene (head<->tail) -> farnesyl, x2 (head<->head, with reduction + release of PP) -> squaleneCholesterol synthesis: acetyl-CoA + acetoacetyl-CoA -> HMG-CoA -> (irreversible) reduced @ carboxylate by reductase (controlled by SREBP) to form mevalonate -> 2x phosphorylation @ terminal alcohol + 1 more @ tertiary alcohol (dephosphorylated with decarboxylation) -> isopentenyl-PP
  39. 39Classes of steroid hormones: progestagen (eg progesterone, from pregenolone, give rise to later three) / glucocorticoid / mineralocorticoid (via corticosterone) / androgen / estrogen (derive from androgen) Testosterone reduced by 5-alpha-reductase to yield DHTVit D synthesis: UV light breaks C9-C10 of 7-dehydrocholesterol -> previtamin D3 -> cholecalciferol (Vit D3) -> calcitriol (active hormone)
    All O atoms other than C3 @ steroid hormones introduced by hydroxylation (require NAPDH + O2 with cyt P450 mono-oxygenase)
  40. 40Other isoprenoids: ubiquinone (10 units) / Vit A (retinol, oxidised to retinal) / Vit K (synthesised as phylloquinone by plants // menaquinone by bacteria, carboxylate Glu residues in clotting proteins) / Vit E (nonspecific effects on redox).
  41. 41Triglyceride / phospholipid synthesis all start from phosphatidate (usually glycerol-3-phosphate first acylated by saturated acyl CoA to form lysophosphatidate -> acylated by unsaturated acyl CoA) Phosphatidate to triglyceride: dephosphorylation to DAG -> acylationPhospholipid synthesis requires combination of DAG + alcohol (either one activated, eg phosphatidate + CTP -> PPi + CMP-DAG-P -> react with inositol / phosphatidyl-glycerol etc // phosphoryl-ethanolamine/serine/choline + CTP -> PPi + CMP-ethanolamine/serine/choline-P -> react with DAG )
  42. 42Dipalmitoyl-DAG-P functions as lung surfactant Cardiolipin = diphosphatidyl-glycerol Phospholipases: A1 (cleave @ C1 ester) / A2 (@ C2 ester, generate lyso-phospholipid) / C (@ nearer phosphoester) / D (@ further phosphoester)Eicosanoid (20C) derivatives: arachidonic acid (FA, give rise to later three) / LTB4 / 15-LXA4 (lipoxin) / PGH2 (give rise to later three, PGH2 synthase inhibited by aspirin) / 6-oxo-PGF_1a (prostacyclin) / PGF_2a / TxB2 (thromboxane)
    Arachidonate stored as C2 ester of phosphatidylinositol
  43. 43Sphingolipid synthesis: palmitoyl-CoA + serine -> (with decarboxylation) 3-ketosphinganine -> reduced to dihydro-sphingosine -> acylated to dihydro-ceramide -> desaturated to ceramide (adjacent to tertiary alcohol C) Ceramide promotes tumour growthCeramide substitutions: sphingomyelin (phosphoryl-choline from PC, mostly @ outer, can modulate activities of kinase / phosphatase) / cerebroside (glucose / galactose from UDP-Glc / UDP-Gal, react with activated sugars of at least a sialic acid -> ganglioside)
  44. 44Lipoproteins solubilise hydrophobic molecules; apoprotein components contain cell targeting signals Plasma lipoproteins: chylomicron (for dietary fat) < VLDL (for endogenous fat) < IDL (precursor to LDL) < LDL (for cholesterol) < HDL (reverse transport to liver).
  45. 45Excess TG + cholesterol from liver exported in blood via VLDL -> hydrolysed by lipases @ capillary surfaces -> free FA taken into cells, IDL (cholesterol remnants) metabolised @ liver // converted into LDL (transport cholesterol to peripheral tissues); HDL esterifies cholesterol for returnLDL removal: ApoB-100 bind to receptor (non-liver) -> RME + lysosomal hydrolysis -> apoprotein hydrolysed to free amino acids, cholesteryl esters hydrolysed (must be re-esterified if stored inside), LDL receptor usually returns unchanged; cholesterol exert negative feedback on synthesis of LDL receptor
  46. 46Membrane skeleton: spectrin tetramer cross-linked @ both ends via attachments to other cytoskeletal proteins, also associate with ankyrin (bind to integral channel protein) Mehchanism of flip-flop: facilitated diffusion by flippase // active transport by membrane translocaseLateral organisation of membranes: eg apical (luminal) vs basolateral domain (remainder) in epithelial cell, microdomains enriched in some proteins / lipids (eg lipid rafts with closely packed glyco-sphingolipids + cholesterol, rapidly exchange protein / lipid with surrounding)
  47. 47Proteins entering RER: leading N-terminal signal peptides protrude beyond ribosomal surface -> SRP binds to signal peptide and ribosome, SRP-GDP replaced with GTP -> temporary arrest -> SRP binds to receptor @ translocon -> receptor-GDP replaced with GTP -> GTP hydrolysisPre-protein processing @ RER: membrane-bound signal peptidase cleave signal peptide -> nascent polypeptide folds with help of Hsp70 @ RER -> PTM eg glycosylation
    Translocon - heterotrimeric Sec61 for mammals // SecY for prokaryotes
  48. 48Mechanisms for protein transport in Golgi stack: anterograde (cargo vesicle bud off one compartment -> fuse with another in cis->trans) // retrograde (cisternal progression via retrograde transport of membrane compartment)Coated vesicles: clathrin (polyhedral framework assembled from triskelions, transport TM / GPI-linked / secreted proteins, also help in endocytosis) / COPI (fuzzy coatomer, can return escaped ER-resident proteins back) / COPII (transport from RER to Golgi)
  49. 49Proteins mediating membrane fusion: R-SNARE (usually vesicle membrane) / Q-SNARE (usually target) SNARE-mediated fusion process: SNARE zipping (docking) -> lateral tension induce hemifusion -> membrane breakdown to form fusion pore -> expand.

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None Part 1-3 Fichas sobre 3A, creado por Andrew Susilo el 19/12/2022.
Creado por
Andrew Susilo · dic 2022
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2 ene 2023
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