PSL300 Michelle French.docx

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Michelle French

1. Gap Junction – Direct cytoplasmic connection between adjacent cell - Formed by connexons (have different isoform/specificity). When open = syncytium (multiple nuclei) - Small molecule can pass (ATP, cAMP) ; electrical signals pass directly 2. Contact Dependent Signal – Interaction between membrane molecule of 2 cells - Cell Adhesion Molecules (CAM) link to cytoskeleton transfer signals in both side of cell membrane 3. Local Commmunicate = chemical in extracell fluid ; limited by distance - Autocrine – Signal acts on same cell that secreted it - Paracrine – secreted by one cell, diffuse to adjacent. i.e. Histamine ; @injury, make capillaries permeable - i.e. cytokine > peptides ; i.e. eicosanoids peptide auto + paracrine 4. Long Distance Communicate = electrical signal by nerve cells Electrical Signal – Changes cell membrane potential Chemical Signal – Secreted by cell to extracellular fluid Hormone – Secreted by endocrine cells in blood > circulation. Only target cell w/ receptor. - Peptide hormones made in advance. (1) Control Enzyme Rate (2) Control cell transport (3) Control gene expression - i) Hormone deficient, remove gland ; ii) Replacement therapy, put gland back ; iii) Hormone Excess ; implant additional ; iv) Purify Extract ; isolate active - Low concentration exerts effect on distant target Neurotransmitter - Diffuse across small extracell space, rapid effect Neurohormone – Neurocrine enter the blood. Act on distant targets - Major groups (1) Catecholamine (from Adr. Med) ; (2) Made @ Hyp > Post Pit ; (3) Hyp controls Ant. Pit Neurocrine – Secreted by neurons under influence of action potential Neuromodulator – Slower effect, can be auto or paracrine Cytokines – Secreted by all nucleated cells ; control develop, diff. Can be auto/paracrine. Can travel distance (imm) - made on demand. Functionally, EPO is a cytokine (defined as hormone) Receptor – Local signal binds. NO response if no receptor. (1) Ligand binds receptor = first messenger. (2) Receptor activates one+ intracell molecules. (4) Last molecule generally initiates target proteins Lipophillic – Diffuse the bilayer of membrane. Has cytosolic or nuclear receptors. Often activate gene transcription Lipophobic – Cannot diffuse through CM. Receptor Channel – Ligand binding will activate channel, ions can flow across Receptor Enzyme – Receptor = extracellular ; Enzyme = intracellular. i.e. Tyr Kinase (insulin) ; JAKinase (cytokine) GPCR – 7Tm segments. GProtein Transducer. GTP = ON > Adenylyl Cyclase or Phospholipase C Integrin – Ligand binding alters cytoskeleton. Blood clotting, cell adhesion/recognition. Attach to cytoskeleton via anchor protein. i.e. platelets have integrin receptor Signal Transduction – Extracell molecule activates receptor > intracel effect. Ligand = 1 messenger ; Intracell = 2 nd - (1) Extracell > Receptor; (2) i. protein kinase > +P OR ii. 2 message sent ; (3) a. 2 message alters potential OR nd nd b. 2 message Inc Ca OR c. 2 change phosphatase activity ; (4) Alter protein, contraction, gene, cell transport Transducer- Converts signal from one to another Signal Amplification – One signal into multiple second messengers Amplifier Enzyme – Receptor + Ligand complex. (1) GPCR > Adenyl Cyclase > cAMP (From ATP) > PKA (2) NO > Guanylyl Cyclase (can be membrane/cytosol) > cGMP (From GTP) > PKG (3) GPCR > Phospholipase C > IP3 soluble (ER > release Ca) + DAG lipid (PKC > +P) - Ca can bind Calmodulin Leukotriene – From Arachidonic Acid via lipoxygenase. Secreted by WBC, cause anaphylaxis (cannot breathe) Prostanoids – From Arach Acid via cyclooxygenase. i.e. Prostaglandin (imm) + Thromboxane Nor/Epinephrine – Bind to adrenergic receptors. a-receptor > Norepi. b2-receptor > Epi. - Epi + a receptor = vessel constriction (gut/kidney ; smooth muscle) - Epi + b2 receptor = vessel dilation (skeletal muscle) Down-regulate – Decrease membrane receptor. Endocytose receptor or desensitize via chemical modulation i.e. +P turns off b-adrenergics. Can cause drug tolerance. Up-Regulate – Add more receptor to amplify signal. i.e. SSRI = serotonin reuptake inhibitor ; extends Serotonin NT i.e. ARB = Angiotensin blocker. Ca Channel Blocker = decrease blood presure Diabetes Insipidus – shorter half life of ADH/Vaso receptor 1. Nervous System > Internal Environment – Blood volume, osmolarity, pressure, temp, etc. maintained 2. Tonic Control – The frequency of release controls a system. i.e. high freq = vessel constrict 3. Antagonistic Control - i.e. insulin vs. glucagon. SNS fight/flight vs, PSNS rest/digest 4. One signal, Multiple Effect – i.e. Epi on a/b2 receptors Local Control – isolated change in cell. Cause auto/paracrine reaction. - i.e. O2 in nearby tissue managed by paracrine (CO2, Lactic Acid) > dilate vessel = more blood + O2 to area. Reflex Control – widespread systemic change. i.e. nervous system + endocrine system release cytokines - Response loop + Feedback loop. (1) Stimulus (2) Sensor (3) Aff. Signal (4) Integrate Center’s setpoint (5) Eff. Signal (6) Effector/Target Receptors – Central> Eye/Ear/Nose/Tongue, Chemo > pH, Gas, Chem, Osmo > osmolarity, Thermo > Temp, Baro>pressure, Propio> body position, Mechano> touch, pain Threshold – Minimum stimulus needed for reflex. Afferent Pathway – In neural reflexes only, not in endocrine cell. Endocrine Cell = both sensor + integrator Integrating Center – In neural reflex, integrator = CNS (spine + brain) Efferent Pathway – i.e. vagus nerve > heart and phrenic nerve > diaphragm. Endocrine = hormones > blood Response – Cellular = target cell. Systemic = i.e. Epi > b2 = smooth muscle relax Acclimatization – Physiological adaptation due to natural environment. i.e. biorhythms Acclimation – Adaptation induced artificially Neg. Feedback Loop – Homeostatic. End result oscillates around setpoint. Cannot prevent initial disturbance Pos. Feedback – Reinforces stimulus. Need intervention outside of the loop. i.e. oxytocin on cervix stretching Feedforward Control – In anticipation of an event. i.e. salivation, HCl in stomach before food Circadian Rhythm – i.e. body temp peaks late afternoon, declines early morning. Cortisol peaks morning, low night Goiter – From lack of Iodine or thyroid tumor Pheromone – Ectohormone > external environment. Act on other organisms. i.e. in danger, for sex Axillary Gland – armpits, sweat gland. Growth Factors – Can be auto/para/systemic. Cholecystokinin CCK – Cause contraction of gallbladder, also controls hunger Peptide Hormone – Made in advance, exocytosed, dissolves in blood, short halflife, membrane receptor, often has secondary messenger, affect protein synthesis, made from AAs i.e. PTH Steroid Hormone –Made on demand (from cholesterol), simple diffusion, carrier in blood, longer half life, cyto/nuc/membrane receptor, often affect gene transcription + protein synthesis. Also non-genomic responses - i.e. VitD, insulin (muscle/fat = glut4 ; liver = glycogen synthesis) - Catecholamine – Tyr derivative, made in advance, stored in vesicle, exocytosed, dissolve in blood, short half life, membrane receptor, second messenger, modify existing protein ie. Nor/Epi + Dopa > are neurohormones ; +Tyr Thyroid Hormone – Tyr derivative, made in advance, stored in vesicle, diffuse to blood, need carrier, long half life, nucleus receptor, gene transcription + protein synthesis i.e. T3/4 = Tyr + I. Acts like a steroid hormone (nuc receptor) Half Life – How long enzyme is active in body. Longer = steroid hormone/TH Preprohormone – Pre = signal sequence to lumen of rough ER ; Pro = need to be further cleaved by proteolytic vesicle (via the Golgi). If all fragments secreted together = co-secretion i.e. Prohormone = pro-opiomelanocortin > ACTH > y-lipotropin + b-endorphin + a-MSH = pro-insulin > insulin (SS bonded) + C peptide i.e. Preprohormone = pre-pro-TRH > 6 TRH + signal sequence + peptides >> TH Carriers – Specific ie. Corticosteroid-globulin or General i.e. albumin - Are lipophobic, cannot pass CM. Only unbound hormone can enter target. But only need few steroids to have effect Melatonin – From pineal gland, derived from Tryptophan ; imm function, antiox, circadian Parathyroid Hormone – Thyroid Ca-sensing GPCR, coupled to Ca. HIGH Ca = NO PTH. Inc Bone resportion ; Inc Kidney reabsorb Ca ; Inc Calcitriol = Inc intestine absorb Ca. Negative feedback by High Ca levels. Posterior Pituitary – Extension of brain. Secretes neurohormones made @ Hypothalamus ; aka neurohypophysis 1. Vasopressin/ADH – Inc water reabsorb @ Kidney DCT 2. Oxytocin – Inc milk ejection (letdown) and positive feedback on uterine contraction @ birth Anterior Pituitary – Differ from post, derived from epithelial cells ; aka adenohypophesis 1. Prolactin – Breast milk production. Controlled by inhibiting + releasing hormones 2. TSH – Thyroid to release TH. 3. ACTH – Adr. Cortex to release DHEA ; Cortisol ; Aldosterone 4. GH – Liver to release IGF1. Controlled by inhibiting + releasing hormones. Overall Bone growth, Protein Catabolism, Na retention 5. FSH – Granulosa to release Estradiol + AMH. Sertoli for sperm growth + Inhibin + Androgen Bind Protein 6. LH – Thecal to make Androstenedione ; Leydig to release Testosterone Trophic Hormone – hormone controls the release of another hormone. Hyp > Ant Pit i.e. ACTH Somatostatin - Inhibits GH release ; aka SRIH and GHIH Short Neg Feedback – Pituitary hormone inhibits hypothalamus. i.e. ACTH inh CRH Long Neg Feedback – i.e. cortisol inhibits CRH (far downstream) Hyp-Hypophyseal Portal – Tropic hormones made in Hyp transported directly to Ant Pit Portal System – Circulation of two capillary sets. i.e. (1) Kidney, (2) Digestive, (3) Brain Low Pressure/Volume – Aortic + Carotid Baroreceptors. Atrial volume receptor. (1) Inc Cardiac Out + Vasoconstrict ; (2) Inc Thirst > Inc ICF/ECF Volume ; (3) Kidney conserved H2O Water Balance – 50% of body weight, balanced daily. Gain via food (most) + metabolism. Lost via urine (most) + lungs + feces + activity (sweating, etc). Replenish water = infusion or injection Diuresis – Removal of excess water in urine, i.e. due to excess urine glucose (DM). Leads to polyuria + polydipsia. Kidney – Cannot replenish water, can reabsorb water (via aquaporins) and Na in the DCT and CD. Medulla = higher osmolarity vs cortex. Osmosis – Water from less concentrated to more concentrated Nocturnal Enuresis – ADH not released at night (normally high levels released) ADH/Vasopressin peptide Pathway From Post Pit > Collecting Duct Basolateral membrane receptor > GPCR Effect Increase aquaporin-2 vesicles to the apical face of CD = more water enter bloodstream (1) Lower osmolarity (2) Higher blood volume (3) Higher blood pressure Stimulus (1) High osmolarity = Osmoreceptors stretch = more firing = ADH release (2) Low blood volume = Lower atrial stretching (3) Low blood pressure = carotid/aortic baro-receptor Salt Balance – High osmolarity leads to vasopressin release + thirs > Inc BP and ECF volume Aldosterone Steroid, nuclear receptor Pathway CRH > Ant Pit > ACTH > Adr. Cortex > Primary Cells @ DCT/CD Effect (1) Increase K secretion– Na/K ATPase basolateral (2) Increase Na retrieval – Na/K ATPase basolateral (3) Increase blood pressure Stimulus (1) High extracell K concentration (2) Angiotensin II (3) Low blood pressure = carotid/aortic baro-receptor AngII peptide Pathway Renin > Angtesen (Liver) > AngI (ACE) > AngII Effect (1) Inc vasopressin = Inc blood volume + Inc blood pressure (2) Inc thirst = Inc blood volume + Inc blood pressure (3) Vasoconstriction = Inc blood pressure (same blood volume) (4) Inc cardio output = inc blood pressure Stimulus (1) Kidney granular cell @ Low BP > renin (2) Low flow @ macula densa = paracrine renin release (3) Low BP by sympathetic neuron = renin release ACE Inhibitor – dec AngII conversion, but inc bradykinin (normally suppressed) > cough Renin Inhibitor – Dec active renin = fewer AngI Natriuresis – Inc Na loss and water loss through urine Atrial Natriuretic Peptide – (1) Inc Na excretion = lower BP. (2) Inc GFR (3) Dec water reabsorb (4) Inhibit renin, aldosterone, vasopressin Insulin Peptide, anabolic for everything, at fed state Pathway @ pancreatic beta cells. Glu enter cell > inc glycolysis > more ATP:ADP > inhibit K-channel > depolarize > Ca enter > exocytosis insulin vesicles Effect (1) Dec blood glucose – more GLUT2 transporter at s. intestine, GLUT4 at muscle, hexokinase @ liver (MORE glucose entry). Insulin receptor = Tyr kinase (2) Inc glycogen synthesis (glycogenesis) (3) Inc fat synthesis (lipogenesis) (4) Inc protein synthesis (5) Inhibit glycogenolysis, lipolysis, b-oxidation, gluconeogenesis, protein breakdown Stimulus - Circadian release. Low at night (1) High blood glucose (hyperglycemia) (2) GLP-1 and GIP (and CCK + gastrin) – anticipatory release w/ food intake (3) Inc plasma amino acid (4) ParaSympathetic NS – stimulate beta cells Inhibit (1) Low blood glucose (2) Sympathetic NS – Epi and norepi inhibits Too little DM Glucagon Peptide, in fast state Pathway @ pancreatic alpha cells Effect (1) Inc glycogenolysis (2) Inc gluconeogenesis (3) Inc ketogenesis (4) Inc blood glucose (5) Inc blood amino acid – to counteract insulin effects Stimulus (1) Low plasma glucose (hypoglycemia) Inhibit (1) High plama glucose DM Type I – destruction of insulin producing beta cell. High ketones (b-oxidation), muscle/fat breakdown (no glucose for energy), hyperglycemia (no insulin), polyphagia (satiety center unable to absorb glucose), polyuria (high glucose in filtrate), glucosuria (high glucose in urine), polydipsia and ADH (low BP + water), acidosis (due to anaerobic + ketones). Treatment = insulin injection DM Type II – Insulin resistance due to genetics, diet, age. Not as severe symptoms. Some responsiveness to insulin. Treatment = stimulate beta cell, slow digestion of carbs, inhibit gluconeogenesis, exendin-4 Metabolic Syndrome – High BP, Type 2 DM, atherosclerosis Adrenal Cortex – Outer > Inner = Z. glomerulosa (aldosterone), Z. fasciulat (cortisol), Z reticularis (sex hormone) Adrenal Medulla – Secretes Epi + Dopa - Cholesterol > (or Aldosterone) DHEA > Androstenedione > Estrone OR Testosterone > (aromatase) Estradiol Crossover effect – Aldosterone + cortisol binds same receptor. Aldosterone cells must convert cortisol > cortisone. HPA Path – Cortisol feeds back to inhibit ACTH and CRH Cortisol
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