Exam 1 Lecture Notes PDF

January 14th: Excitable Cells (Chapters 3 & 4) What is the purpose of an action potential? Neurotransmitter release When a neuron releases a neurotransmitter, does it always release the same amount? No, more equates to a stronger signal, while less release equates to a weake...

January 14th: Excitable Cells (Chapters 3 & 4) What is the purpose of an action potential? Neurotransmitter release When a neuron releases a neurotransmitter, does it always release the same amount? No, more equates to a stronger signal, while less release equates to a weaker signal. o Dependent upon ions such as sodium, potassium, and calcium What depends on action potentials? o Muscle contraction, heartbeat, thoughts and memories, and much more… Input zone (dendrites) receives graded potentials which may or may not cause an action potential. o Input zone contains thermally-gated channels, light-gated channels, and ligand-gated channels. o The goal is to trigger an action potential that occurs at the axon hillock (where voltage-gated sodium and potassium channels are located). Resting membrane potential (RMP) is very much dependent upon one ion: POTASSIUM o Changes in potassium can cause changes in RMP. ▪ RMP moves up closer to threshold → Action potentials occur more readily → Spasms Caused by high potassium ▪ RMP moves down further from threshold → Action potentials do not occur as readily Low potassium causes fatigue What ion is in charge of threshold potential? CALCIUM o When donating plasma, they remove blood and centrifuge out the plasma cells. Then, they add a calcium chelator called citrate so that the blood does not clot. If they give too much citrate, it will begin to take out the calcium in your extracellular fluid. The clinical sign of this is convulsions. o Low calcium → Threshold goes down o High calcium → Threshold goes up Beta-blocker – Used for hypertension to lower blood pressure o Medications block the beta-1 receptors on the heart to slow the heart down and decrease the strength of contraction. o They change the way CALCIUM interacts with the heart. There is more potassium INSIDE the cell than out. Think of the cell as a “salty banana.” o Every time potassium leaves the negative charge inside the cell becomes stronger. o The cell is most permeable to potassium. [𝑂𝑢𝑡𝑠𝑖𝑑𝑒] Nernst Equation to calculate Equilibrium Potential 𝐸 = 61𝑙𝑜𝑔 [𝐼𝑛𝑠𝑖𝑑𝑒] o What happens if equilibrium potential changes? In reality, only extracellular or “outside” will be changing. o Hyperkalemia – If the extracellular concentration of potassium goes up, for example, the concentration gradient will become smaller (not 30:1 but maybe 15:1). Potassium is less likely to leave the cell's interior down its concentration gradient. We hit equilibrium sooner (for example, at -80 mV) because potassium is pulled in sooner by the electrical gradient. RMP is normally -70 mV (potassium’s equilibrium potential of -90 mV pulls it down). But in this case, RMP goes up – closer to threshold and more excitable (may go into muscle fasciculations). ▪ Diabetic cause of death is usually renal failure and hyperkalemia. ▪ The lethal injection for the death sentence is a potassium chloride overdose. o Hypokalemia – RMP is further from threshold, and therefore, the cells are less excitable (bradycardia and weakness). Clinic Minute – How can we make the seizure area of the brain less excitable? o We could increase threshold (usually done with calcium and the heart), induce potassium permeability (the weight of its influence on RMP becomes stronger so RMP moves down), and most often, decrease sodium permeability so that potassium rules RMP (RMP moves down). iClicker: To increase the excitability of a cell, we want to increase the influx of a positive ion (for example, sodium). Sending a signal across the synapse utilizes a neurotransmitter which can be excitatory or inhibitory.  oThat neurotransmitter can make sodium enter the cell = excitatory oThat neurotransmitter could make potassium leave the cell OR chloride enter the cell = inhibitory ▪ Lorazepam (benzodiazepine) – This medication causes chloride to enter the cells associated with anxiety to stop them from firing which lowers anxiety. TAKEAWAYS o RMP is most influenced by ECF K+ ▪ RMP moves in the same direction as ECF K+ o Threshold potential is most influenced by ECF Ca++ ▪ Threshold moves in the same direction as ECF Ca++ ▪ Calcium related to hydrogen (pH) levels → Hiccups (pH outside the stomach goes down, ionized calcium levels go down, then the diaphragm is too close to threshold and begins to fire) o RMP uses leak channels o Graded potentials use ligand, mechanically, thermally, etc. gated channels o Action potentials use voltage-gated channels January 16th: CNS Control: Autonomics (Chapter 7) Peripheral nervous system (PNS) lies outside the brain and spinal cord o Afferent division – input to CNS from periphery o Efferent division – input to periphery from CNS Efferent division is divided into two systems: o Somatic nervous system – motor neurons o Autonomic nervous system (ANS) – basically everything else (sympathetic, parasympathetic, and enteric divisions) iClicker: Blood flow to which structure or organ is not innervated by the sympathetic nervous system? Brain The control center of the CNS is the hypothalamus. o Regulates body temperature, hunger, and the ANS o Receives high-brain input (emotion, fear, etc.) The endocrine system also plays a role in ANS input. o Thyroid hormone is responsible for beta-1 receptors on the heart. ▪ If someone is hyperthyroid, they will have increased beta-1 expression, high HR, and high BP. Put on beta-blockers to lower HR and BP ▪ If someone is hypothyroid, they will have decreased beta-1 expression, low HR, and low BP. o Cortisol is responsible for alpha-1 receptors on arterioles. ▪ “Ones are excitatory” – Alpha-1 excites smooth muscle which causes arterioles to constrict. ▪ Addisonian crisis – People do not have cortisol; therefore, they do not have alpha-1 expression. They encounter a fight-or-flight situation, and their arterioles do not constrict. Their BP does not go up, so they tend to go into shock. The treatment is fast-acting cortisol, but it can be hard to recognize quickly. o Estrogen is responsible for beta-2 expression on coronary arteries in biological women (not in biological males) and muscarinic expression in certain vessels. ▪ “Twos are inhibitory” – Beta-2 and M2 cause dilation. o Androgens and estrogens are responsible for different patterns of ANS receptors in the brain. ▪ Ex. Somebody is terrified by something vs. somebody enjoys something (adrenaline-junky). This is due to a difference in receptors in the high brain. ANS Output o Most effector organs are innervated by both sympathetic and parasympathetic nerve fibers → Dual innervation ▪ Generally have opposite effects (but not always antagonistic) o Sympathetic or parasympathetic tone – both systems are partially active, but the activity of one can dominate over the other o Not all organs are dually innervated (most innervated by sympathetic but not everything innervated by parasympathetic)  ▪ Sweat glands, adrenal medulla, kidneys, skin, and uterus are only innervated by sympathetic fibers ▪ Lacrimal glands are only innervated by parasympathetic fibers (questionable) ▪ Salivary glands are dually innervated by sympathetic and parasympathetic activities are not antagonistic ▪ Bladder is dually innervated but has NO TONE (Tone is not always present). Parasympathetic is not always telling the bladder to contract (only once the bladder gets to a certain volume). The only time sympathetic inhibits bladder contraction is if there is a stressor. o Sympathetic CAN BE excitatory and CAN BE inhibitory (depends on the system) ▪ Ex. Excites the heart but inhibits digestion o Parasympathetic CAN BE excitatory and CAN BE inhibitory (depends on the system) INCORRECT Assumptions o Every system is dually innervated. FALSE o Sympathetic is excitatory; parasympathetic is inhibitory. FALSE ▪ Stomach growling is parasympathetic preparing for digestion (excitatory). o Both systems are always antagonistic. FALSE ▪ No, reproduction is synergistic. o Tone is always present. FALSE ▪ Not in the bladder. o Parasympathetic is “good,” and sympathetic is “bad.” FALSE ▪ Parasympathetic can kill you almost instantly; sympathetic may kill you over a period of months. o Respiratory rate is affected by sympathetic and parasympathetic. FALSE The heart becomes more irregular under parasympathetic tone; the heart becomes more regular under sympathetic tone. o Canine hearts are very irregular due to high parasympathetic tone. Sympathetic helps us focus on images far away (ex. Screen), but parasympathetic helps us focus on images right in front of us (ex. Laptop). o Systems can be very specific. o Ex. It is not like we get all these other responses like increased HR, dry mouth, etc. that come with the sympathetic response (same for parasympathetic). There are no parasympathetic hormones. Divisions of the Autonomic Nervous System (ANS) o Sympathetic Nervous System (Fight-or-Flight) ▪ Nerve fibers originate in the thoracic and lumbar regions of the spinal cord. ▪ Preganglionic fibers are short. Cholinergic (release Ach) ▪ Postganglionic fibers are long. Mainly adrenergic (release norepinephrine) o Exception: Some release Ach (cholinergic) – those responsible for thermoregulatory sweat Have nicotinic receptors that bind Ach from preganglionic fibers o Parasympathetic Nervous System (Rest and Digest) ▪ Nerve fibers originate in the cranial and sacral regions of the spinal cord. ▪ Preganglionic fibers are long. Cholinergic (release Ach) ▪ Postganglionic fibers are short. Often originate near or in the effector organ Cholinergic (release Ach) Have nicotinic receptors that bind Ach from preganglionic fibers  Cholinergic vs. Adrenergic o Cholinergic: Acetylcholine (Ach) ▪ Cholinergic fibers release Ach ▪ Ach binds to: Nicotinic receptors on postganglionic cell bodies and on adrenal medulla Muscarinic receptors on effector organs o Adrenergic: norepinephrine (NE) ▪ Adrenergic fibers release NE ▪ NE binds to: Alpha-1, alpha-2, beta-1, and beta-2 adrenergic receptors Adrenergic receptors can also bind epinephrine released from adrenal medulla o Exceptions… ▪ Adrenergic receptors bind NE and cause nervous sweat (adrenergic) ▪ Muscarinic receptors bind Ach and cause thermoregulatory sweat (cholinergic) All sympathetic postganglionic fibers are adrenergic except this one! Thermoregulation is sympathetic ONLY. Sympathetic Response o Heart – increased rate, increased force of contraction ▪ Prefers fatty acids (burns lactate better than glucose) o Blood vessels (talking about arterioles and veins) – skin and organs constricted, muscles and heart dilated ▪ Arteries do have sympathetic receptors, but the pressure is so high that nothing happens. With arterioles, sympathetic can constrict/dilate. Same neurotransmitter (NE) but two different effects… How is that accomplished? Different receptor. o Lungs – bronchodilation, inhibition of mucus secretion o Gall bladder, urinary bladder, digestive system – relaxation, cessation of digestion o Fat – lipolysis (breakdown of fat to increase energy availability) o Exocrine glands – increased sweat, increased salivary mucus ▪ Two forms of sweat: (1) Thermoregulatory/Whole-Body Sweat – cholinergic; (2) Nervous Sweat/Palm & Armpit – adrenergic iClicker: Which of the following is not a sympathetic response? Bronchoconstriction January 21st (Class Canceled): ANS Part II (Chapter 7) Sympathetic Response o Endocrine glands – decrease insulin, increase glucagon, increase epinephrine and norepinephrine ▪ Decreasing insulin and increasing glucagon INCREASES blood glucose (useful to skeletal muscle and the brain) o Brain – increased alertness ▪ Adderall (amphetamine) increases norepinephrine in the brain; too much norepinephrine → loss of alertness o Reproduction – orgasmic contractions ▪ Synergistic – sympathetic nervous system responsible for all smooth muscle contractions; sympathetic also triggers skeletal muscle contraction ▪ Sympathetic neurons synapse with motor neurons in the brain that cause contraction Thermoregulation (Sympathetic Response) o High Temperature ▪ Increase blood flow to the skin – arteriolar dilation (graded) ▪ Increase cholinergic sweat ▪ Relaxation of skeletal muscles (CNS effect) – “spa or hot tub;” the brain uses sympathetic neurons to inhibit the motor neurons in the brain ▪ Movement of blood to the periphery ▪ Behavior adaptation – maximize our surface area by sprawling muscles o Low Temperature ▪ Restrict blood flow to the skin – arteriolar constriction (graded); ALPHA-1 ▪ Piloerection – “goosebumps;” also alpha-1 ▪ Fasciculation of muscles (CNS effect) – shivering ▪ Movement of blood to the central compartment – digestive system, lungs, heart ▪ Behavioral adaptation – decrease our SA so we do not lose as much heat Parasympathetic Response o Heart – decreased rate ▪ No parasympathetic innervation to the ventricles, so really cannot change the strength of contraction o Blood vessels – dilation to reproductive organs only o Lungs – bronchiolar constriction; stimulation of mucus secretion o Digestive – increased motility; relaxation of sphincters; stimulation of secretion o Gall & Urinary bladders – emptying o Eye – sets for near vision o Pancreas – digestive enzymes (insulin and glucagon) increase ▪ Increased insulin → shifts glucose from plasma into cells ▪ Increased glucagon → causes glucose to be broken down from the liver and come out of storage ▪ Considering these are antagonistic, why do both? The parasympathetic nervous system does not control digestion. It only prepares the digestive system for digestion. The nutrients in the consumed food determine the actual release. o Genitals – increased blood flow; increased secretions ▪ The only time we see parasympathetic affecting blood vessels and the skin ▪ Glands used for lubrication are modified sweat glands (not nervous OR thermoregulatory sweat) Neurotransmitters and Receptors o Sympathetic Preganglionic ▪ Release acetylcholine which binds to… Receptor in nicotinic NN (“nicotinic nerve”) o Sympathetic Postganglionic ▪ Release norepinephrine which binds to… α1  α2 β1 β2 β3 ▪ Release acetylcholine (thermoregulatory sweat) which binds to… Receptor is muscarinic M3 o Parasympathetic Preganglionic ▪ Release acetylcholine which binds to… Receptor in nicotinic NN (“nicotinic nerve”) o Parasympathetic Postganglionic ▪ Releases acetylcholine which binds to… M1 – on the stomach and promotes stomach acid production M2 – slows heart, relaxes smooth muscle M3 – most common M4 M5 Ex. Urination: Is that sympathetic or parasympathetic? Parasympathetic. What receptor is responsible for causing bladder contraction? M2 is relaxation/inhibitory; M1 is gut/stomach acid; It must be M3. o A parasympathetic response that involves excitation will almost always be M3. Ex. Increased rate and strength of contraction: Is that sympathetic or parasympathetic? Sympathetic. What receptor is responsible? “Ones are excitatory, twos are inhibitory.” We know it is a 1. Beta-1 is exclusively found on the heart; therefore, it is beta-1. o Any other excitatory sympathetic response (goosebumps, piloerection) would have been alpha-1. Ex. Sweaty palms: Is that sympathetic or parasympathetic? Sympathetic. Excitatory or inhibitory? Excitatory. Therefore, it is a 1. Is it on the heart? No, thus it is an alpha-1. SPECIAL CASE: α2 o Alpha-2 in the periphery has a weak effect on the smooth muscle of the GI tract o In the CNS, alpha-2 regulates sympathetic output o Drugs (alpha-2 receptor agonists; reduces sympathetic output) ▪ Clonidine – used to decrease BP in hypertension (also a heavy sedative) ▪ Xylazine ▪ Dexmedetomidine Incorrect Assumption: All receptors are functional in all tissues. o In a sympathetic response, where does blood go? ▪ α1 Receptor Location: All arteriolar smooth muscle except in the brain Chemical mediator: Norepinephrine from sympathetic fibers and the adrenal medulla; Epinephrine from the adrenal medulla (less affinity for this receptor) Arteriolar smooth muscle response: Vasoconstriction ▪ β2 Receptor Location: Arteriolar smooth muscle in the heart and skeletal muscles Chemical mediator: Epinephrine from the adrenal medulla (greater affinity for this receptor) Arteriolar smooth muscle response: Vasodilation Incorrect Assumption: Parasympathetic is body-wide; all organ systems are impacted during a parasympathetic response. Incorrect Assumption: Sympathetic is always body-wide. o Can just cause pupil dilation without racing heart, sweaty palms, etc. Clinic Minute: S.L.U.D.D. o Salivation – excessive drooling o Lacrimation – massive tear production  o Urination – uncontrolled urination o Defecation/diarrhea o Death – parasympathetic slows the heart so much it stops o If you see, immediately grab a drug called atropine to block the parasympathetic response. January 23rd: Endocrine – Hormones and Cell Signaling Across Endocrine Axes Different Classes of Hormones o Membrane Receptor Binding – norepinephrine, oxytocin, growth hormone ▪ Polypeptide hormones – built by rough ER ▪ Functional hormones cleaved from preprohormones (ex. Insulin; C-peptide is cleaved off) ▪ Hormones packed in the Golgi into vesicles that fuse with the membrane to make the hormone available on demand o Intracellular (and Membrane) Receptor Binding – cortisol, androgens, estrogens ▪ Derived from cholesterol ▪ Not typically stored within the cell ▪ Cholesterol diffuses across the cell membrane (phospholipids), goes to the mitochondria (into the outer membrane of the mitochondria using STAR protein, and then made into pregnenolone ▪ Pregnenolone – starting steroid for everything (estrogens, androgens, cortisol…) ▪ Depending on the enzymes present in the cell, pregnenolone is converted to specific steroids ▪ Steroids diffuse back through the plasma membrane and into circulation iClicker: Which of the following does not directly regulate the suprachiasmatic nucleus? Pineal gland o The SCN regulates the pineal gland. o Melanopsin-containing retinal ganglion cells, synthesis of clock proteins, and degradation of clock proteins ALL directly regulate the SCN. Cells Communicate via Extracellular Chemical Messengers in Multiple Ways o Autocrine – cell secretes a hormone that binds to self-receptor o Paracrine – cell secretes a hormone that binds to a local target cell o Endocrine – cell secretes hormone that travels through the blood and binds to distant target cell o Neurohormone – neuron secretes a hormone that travels through the blood and binds to a distant target cell (anything that comes from the posterior pituitary) o Neurotransmitter – neuron secretes a hormone that binds to a local target cell Nervous System o Speed of response – generally rapid (milliseconds) o Duration of action – brief (milliseconds) ▪ Neurotransmitters readily degraded in the synaptic cleft; SSRIs designed to extend the duration Endocrine System o Speed of response – generally slow (minutes to hours) o Duration of action – long (minutes to days or longer) ▪ Cyclicity in females Net signaling result is the integration of all signaling inputs. The same signaling molecule can induce different responses in different target cells, depending upon which receptor is expressed. o Ach causes contraction in skeletal muscle cells, relaxation in a heart muscle cell, and secretion in a secretory cell. o Response depends on what type of cell the signaling molecule is going to + what type of receptor is on that cell Hydrophilic hormones utilize membrane-bound receptors to cause cellular responses o (1) Ion-gated Receptor Channel – chemical messenger binds to receptor, causing it to open or close ▪ Regulate movement of particular ions across the membrane o (2) Receptor-Enzyme – chemical messenger activates intracellular protein kinase ▪ Usually act in a chain reaction (cascade) ▪ Tyrosine Kinase, JAK/STAT, G-protein coupled  More specific examples… o Receptor-enzyme signaling via Tyrosine Kinase Pathway (Dimer Unit) ▪ Two extracellular messengers are required for TK activation ▪ Activation of the receptor causes phosphorylation of tyrosines on receptor ▪ The designated intracellular protein is phosphorylated by active tyrosine kinase and carries out cellular response o Receptor-enzyme signaling via JAK/STAT Pathway ▪ Receptor and attached enzymes function as a unit, but they are separate pieces (JAK units are not part of the receptor like tyrosine is in the previous example) ▪ Binding of ONE extracellular messenger activates JAK x2 ▪ JAK phosphorylates STAT, which influences gene expression o Gs-protein Pathway (cAMP)  ▪ First messenger → G-protein → adenylyl cyclase → cAMP → pKA ▪ First messenger activates the G protein and a portion of it dissociates to activate the effector protein (adenylyl cyclase) ▪ Converts ATP into cAMP ▪ cAMP activates protein kinase A ▪ pKA activates designated intracellular protein which initiates cellular response ▪ Gi is basically the same idea, except it deactivates cAMP o Gq-protein Pathway (IP3-Ca2+) ▪ Activation of G-protein activates phospholipase C ▪ PLC converts PIP2 into IP3 and DAG ▪ IP3 mobilizes intracellular calcium to create an active Ca2+-calmodulin complex Complex activates CaM kinase which activates designated protein for cellular response ▪ DAG activates protein kinase C ▪ PKC activates designated protein for cellular response 2nd Messenger Systems allow for tremendous signal amplification. o One extracellular molecule bound to a receptor could activate multiple adenylyl cyclase proteins. Intracellular Receptors – “always slower than membrane-bound receptors” o Lipophilic hormones bind receptors inside the cell and primarily produce effects by modulating gene expression. ▪ Receptors always formed in DIMERS o Hormone diffuses through the membrane and binds to a portion of receptor specific to the molecule ▪ Other portion binds to DNA ▪ The hormone + intracellular receptor = Hormone response element (HRE) Estrogen and Testosterone o Lipophilic steroid hormones that use classical signaling o BUT they ALSO have extracellular membrane receptors (cascade responses) ▪ Estrogen – GPER, ER-α, and mER-α ▪ Testosterone – SHBG-R  Receptor Regulation – “for signaling thorugh cell membrane receptors only” o Receptor sequestration: “hiding” receptors intracellularly ▪ Happens in cells in the absence of insulin, insulin binding causes the rise of GLUT transporter to bind glucose and pull it into the cell, do not want to bind glucose all the time o Receptor down-regulation: intracellular destruction of receptors ▪ Lysozome destroys receptor, seen in uterus (whether we need estrogen or progesterone receptors on the endometrium) o Receptor inactivation: usually by phosphorylation or dephosphorylation o Inactivation of signaling protein: compromise of protein kinase ▪ Get the initial response, but a response downstream gets blocked o Production of inhibitory protein: blocks second messenger signaling Bioavailability – “free and weakly bound are considered bioavailable” o Steroid hormones like to bind to plasma proteins → Therefore, not many are free/weakly bound and “bioavailable.” o Albumin – the most abundant protein in the blood o Ex. Testosterone: 54% weakly bound to albumin, 44% tightly bound to sex hormone-binding protein (SHBG), 2% circulating free ▪ Low SHBG → More testosterone running free in the bloodstream (occurs in PCOS) ▪ High SHBG → Less testosterone in the bloodstream (obese men) Hormone Secretion Patterns o Pulsatile – secretion peaks and drops ▪ Diurnal rhythm, reproductive biology o Basal – normal, relatively constant secretion ▪ Insulin (in a fasted state) o Sustained – an increase that stays elevated for long periods ▪ Chronic stress (release of cortisol), fluctuations of estrogen in females, hormone-secreting tumors Cortisol has a diurnal rhythm. o Stress or your diurnal rhythm cause the hypothalamus to release CRH… Follow the flow chart below. o When it is dark, cortisol levels start to rise. At dawn, cortisol levels start falling. o People with anxiety may have worse symptoms in the evenings.  Neurohypophysis: hypothalamus and posterior pituitary o Hormones are synthesized in neuronal cell bodies within the hypothalamus o Hormones are released at the axon terminal into the posterior pituitary o Hormones are NOT synthesized in the posterior pituitary Adenohypophysis: anterior pituitary Posterior Pituitary o Supraoptic and paraventricular nuclei extend through the hypothalamic posterior pituitary stalk o Each nucleus produces either vasopressin or oxytocin, but not both simultaneously o Travels down the axon with kinesin Anterior Pituitary o Composed of glandular epithelial tissue o Connected to the hypothalamus via portal system ▪ Fancy vascular link between the two o Most AP hormones are tropic (a hormone that regulates the secretion of a different hormone from a different endocrine gland) ▪ Contrast with trophic hormones, which promote the growth of the target organ o Five cell types in AP: ▪ (1) Somatotropes secrete growth hormone (GH) ▪ (2) Thyrotropes secrete thyroid-stimulating hormone (TSH) ▪ (3) Corticotropes secrete ACTH cleaved from POMC ▪ (4) Gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) ▪ (5) Lactotropes secrete prolactin (PRL) o Hormones from the AP can be grouped into 3 distinct categories… ▪ (1) Glycoproteins (TSH, FSH, LH) – common alpha subunit, unique beta subunit ▪ (2) Pro-opiomelanocortin (POMC) (ACTH, β-endorphin) – POMC gets cleaved before it is activated ▪ (3) Growth hormone and prolactin Hypothalamic-Hypophyseal Portal System o Portal system: a vascular arrangement where venous blood flows directly from one capillary bed into another by a connecting vessel o Almost all blood supplied to the AP must pass through the hypothalamus, allowing exclusive movement of hormones between the two and bypassing systemic circulation o As a general rule, a hormone secreted by the target gland has a negative feedback on both the AP and hypothalamus  ▪ Oxytocin has a positive feedback loop during parturition (“is a feed-forward system”) Can only have its effects in the uterus when estrogen is also high; because estrogen modulates the receptor number and bioavailability for oxytocin in the myometrium (uterine muscle) Estrogen also increases the number of gap junctions between myometrium cells so that contractions move as a single unit Braxton Hicks – oxytocin is slowly increasing Given pitocin (synthetic oxytocin) for induced labor Suckling stimulates oxytocin release that stimulates myoepithelial cell contraction surrounding the alveoli of mammary glands. Vasopressin (ADH) – increases water reabsorption and causes vasoconstriction  Pineal Gland o The suprachiasmatic nucleus is responsible for setting the circadian rhythm ▪ SCN has input on the pineal gland and synthesis of clock proteins o Transcription factors CLOCK and BMAL-1 in SCN activate transcription for clock proteins PER and CRY o During the day, clock proteins accumulate and are transported into the nucleus at their critical level o In the nucleus, PER and CRY inhibit CLOCK and BMAL-1 o No more production of clock proteins and existing clock proteins start to degrade o As they degrade, less inhibition on transcription factors and the cycle starts over; the cycle takes ~1 day ▪ Actually it’s a lil slower than 24 hours, so SCN resets every day with environmental cues o Melanopsin is a protein found in the retina and transmits signals to SCN to keep the body’s time in sync with external time ▪ Once SCN has this input, it regulates the pineal gland for melatonin secretion ▪ Melatonin is “darkness hormone;” also helps to match circadian rhythm to light-dark cycle Janaury 28th: Adrenal – RAAS Axis Regulation Functional Zones of the Adrenal Glands o Adrenal cortex: outer layer; secretes steroids ▪ Zona glomerulosa secretes mineralcorticoids (aldosterone) – SALT ▪ Zona fasciculata secretes glucocorticoids (cortisol) – SUGAR ▪ Zona reticularis secretes sex hormones (DHEA) – SEX Also secretes a lil bit of cortisol Major source of sex hormones is gonads o Adrenal medulla: inner layer; secretes catecholamines (norepinephrine, epinephrine) ▪ Has chromaffin cells Steroidogenesis o Remember that steroids are lipophilic! o Need plasma proteins to travel in ECF ▪ Aldosterone binds to albumin ▪ Cortisol binds to transcortin ▪ DHEA binds to albumin o Each has a specific HRE (Hormone Response Element) - a specific sequence of DNA that is bound by intracellular receptors, such as steroid hormone receptors, to regulate gene expression ▪ Ex. Mineralcorticoid HRE is MRE Aldosterone o Mineralocorticoid – regulating ions in the body o Intracellular receptor and response element: MR and MRE o Plasma protein: albumin o Target cells: principal cells of distal and collecting tubules of the kidney  o Trigger for release: (indirect) low Na+ via RAAS, (direct) high K+ ▪ When ECF potassium is high, it will directly stimulate the adrenal cortex to produce aldosterone o Actions: Increase sodium retention, increase water retention, increase ECF volume and BP, increase potassium elimination ▪ “Save sodium, pee potassium” ▪ Remember that chloride follows sodium (chloride retention) and H+ is secreted into the urine (along with K+) Renin-Angiotensin-Aldosterone System (RAAS) o System is activated by low blood pressure (from low sodium and/or low ECF volume) o Kidneys release renin into the bloodstream, which converts angiotensinogen in the liver to angiotensin I o Angiotensin I is converted to angiotensin II in the lungs by ACE o Angiotensin II causes… ▪ Increase ADH release to reabsorb water ▪ Increase thirst to increase fluid intake ▪ Vasoconstriction of arterioles to raise BP ▪ Stimulates the adrenal cortex to release aldosterone to increase sodium reabsorption o Purpose is to correct low blood pressure How does aldosterone save sodium? o Inserts sodium leak channels on the luminal membrane of tubular cells o Inserts sodium/potassium pump on the basolateral membrane of tubular cells o Also indirectly promotes water retention because water follows salt Abnormal Secretion of Aldosterone o Hypersecretion – “Too much” ▪ Primary Hyperaldosteronism (Conn’s Syndrome) – hypersecreting adrenal tumor ▪ Secondary Hyperaldosteronism – inappropriate high activity of RAAS ▪ Causes exaggerated effects of aldosterone: edema (swelling), hypernatremia (high sodium in blood), hypokalemia (low potassium, muscle cramps/weakness), hypertension (high BP) o Hyposecretion – “Too little” ▪ Primary Adrenocortical Insufficiency (Addison’s Disease) – autoimmune destruction of the adrenal cortex Deficiency in ALL corticosteroids (aldosterone, cortisol, and DHEA) Potassium retention and sodium depletion → low BP Cortisol o Glucocorticoid o Intracellular receptor and response element: GR and GRE (also has low affinity for MR/MRE)  o Plasma protein: transcortin o Trigger for release: CRH → ACTH → Cortisol ▪ Negative feedback to the anterior pituitary and hypothalamus o Actions… ▪ Metabolic – increase blood glucose by increasing gluconeogenesis (liver produces glucose from non- carb sources) and decreasing glucose uptake; increase protein degradation (more amino acids in the blood); increase lipolysis (increase fatty acids in the blood) ▪ Cardiovascular – assists catecholamines in inducing widespread vasoconstriction ▪ Adaptation to stress – increases blood glucose/amino acids/fats for use in stressful situations ▪ Anti-inflammatory AND immunosuppressive– interferes with phagocytic activity, suppresses the production of inflammatory cytokines, inhibits the production of antibodies, etc. Ex. Dexamethazone, Prednisone, Prednisolone (Prelone) – dose must be weaned off, “adrenal cortex cannot come back from vacation quickly,” could cause an Addisonian crisis by suddenly stopping Abnormal Secretion of Cortisol o Hypersecretion (Cushing’s Syndrome) – “Too much” ▪ Primary – adrenal tumors ▪ Secondary – increased CRH/ACTH from the hypothalamus/anterior pituitary ▪ Tertiary – ACTH secreting tumor outside the pituitary (usually in the lungs) No negative feedback ▪ Exaggerated effects of cortisol Buffalo hump and moon face; fat deposits in abdomen, shoulders, and face common o Hyposecretion – “Too little” ▪ Primary Adrenocortical Insufficiency (Addison’s Disease) – autoimmune destruction of the adrenal cortex Hyperpigmentation from excessive secretion of ACTH (ACTH HIGH – AP keeps putting out ACTH to try and get cortisol) α-MSH (alpha melanocyte stimulaitng hormone) is cleaved from the same preprohormone as ACTH and promotes the dispersion of melanin (pathopneumonic – diagnostic feature) Potassium retention, sodium depeltion, low BP, hypoglycemia, and changes to body hair distribution, typically seen in 30-50-year-old female Aldosterone AND cortisol deficient ▪ Secondary Adrenocortical Insufficiency – insufficient ACTH secretion due to hypothalamic or pituitary abnormality Low ACTH & low cortisol (“affecting the whole pipeline”) ▪ Poor stress response, hypoglycemia (decreased glucose production by the liver and impaired glucose uptake by peripheral tissues)  Adrenal Androgens (DHEA) o Sex hormone o Intracellular receptor and response element: AR and ARE o Plasma protein: albumin o Trigger for release: ACTH ▪ Has negative feedback on GnRH, not CRH/ACTH o Actions… ▪ Female – growth of pubic and axillary hair, enlargement of pubertal growth spurt, sex drive ▪ Male – minimal effects since testosterone is stronger than DHEA Abnormal Secretion of DHEA o Hypersecretion ▪ Adrenogenital syndrome – caused by an inherited enzymatic defect that prevents the synthesis of cortisol No cortisol → Increased CRH/ACTH ▪ Female symptoms – hirutism (male pattern body hair), virilization (male secondary characteristics), smaller breasts, no menstruation, enlargement of clitoris ▪ Male symptoms – precocious pseudopuberty (premature development of secondary sex characteristics not associated with gonadal activity) No effect in adult males Adrenal Medulla o Modified portion of the sympathetic nervous system made up of chromaffin cells (modified postganglionic neurons) o Epinephrine and norepinephrine are catecholamines produced by chromaffin cells and secreted by exocytosis of chromaffin granules o Associated with short-term stress January 30th: Thyroid and Growth Axes and Integration Across Axes Thyroid Gland o Follicular cells are the major thyroid secretory cells and are arranged into functional units called follicles o Follicles are filled with an inner lumen called colloid ▪ Extracellular storage for TH (T3 and T4) ▪ Mostly made up of thyroglobulin (Tg) o Follicular cells produce tetraiodothyronine (T4, thyroxine) and tri-iodothyronine (T3) ▪ T3 and T4 collectively are thyroid hormones (TH) o Parafollicular C cells in interstitial spaces between follicles ▪ Secrete calcitonin  Synthesis of Thyroid Hormone o Follicular cells must take up tyrosine and iodine from the blood ▪ Iodine must be obtained from the diet (essential) o Thyroglobulin (Tg) is produced by the ER-Golgi complex in thyroid follicular cells with incorporated tyrosine o Tg transported to the colloid by exocytosis o Iodide is transferred from the blood into follicular cells via iodide trap ▪ Na/I symporter (secondary active transport) o Iodide is oxidized to its “active” form by thyroperoxidase (TPO) inside the follicular cell (on the luminal membrane) ▪ Active I- enters colloid o TPO attaches I- to tyrosine in a Tg molecule ▪ Attachment of one I- yields monoiodotyrosine (MIT) ▪ Attachment of two I- yields di-iodotyrosine (DIT) o MIT + DIT = T3 o DIT + DIT = T4 o Products remain attached to Tg and are stored in the colloid until stimulated for secretion Secretion of Thyroid Hormone o On stimulation for release of TH, follicular cells phagocytize a piece of colloid o Vesicles of colloid fuse with lysosomes in the follicular cell and enzymes split active T3/T4 and inactive MIT/DIT from Tg o TH is lipophilic, so it diffuses out of the follicular cell into the bloodstream ▪ Most binds to thyroxine-binding globulin o Deiodinase inside the follicular cells removes I- from MIT/DIT ▪ Free I- is recycled o 90% of secreted TH is in T4 form, but T3 (active form) is ~10x more biologically potent ▪ Liver and kidneys can convert T4 to T3 Thyroid Axis o Thyrotropin Releasing Hormone (TRH) ▪ Stimulates anterior pituitary ▪ Signal transduction via Gq (IP3+-Ca2+) ▪ TRH secretion stimulated by cold (infants) and diurnal rhythm ▪ TRH secretion inhibited by stress o Thyrotropin Stimulating Hormone (TSH) ▪ Stimulates thyroids gland to produce T3/T4  ▪ Tropic actions on thyroid gland (*This is important for causes of goiter, which is an enlarged thyroid gland*) ▪ Signal transduction via Gs (cAMP) o Regulation – TH does not have massive changes in secretion levels ▪ Diurnal rhythm (highest in the morning and lowest in the evening) ▪ Negative feedback of TH to AP is more immediate lil changes; TH to hypothalamus is more long- term changes Thyroid Hormone Actions o Metabolic Rate and Heat Production ▪ Increases BMR ▪ Regulation of the body’s rate of O2 consumption and energy expenditure under resting conditions ▪ Calorigenic effect – increased BMR causes increased heat production o Sympathomimetic Effect ▪ Any action similar to one produced by the sympathetic nervous system ▪ TH increases target-cell responsiveness to catecholamines by increasing the number of catecholamine receptors on target cells o Cardiovascular Effects ▪ Increases heart rate and force of contraction ▪ Increases cardiac output o Growth ▪ Stimulates growth hormone (GH) secretion ▪ Increases production of IGF-1 ▪ Promotes effects of GH and IGF-1 on the synthesis of protein and bone growth ▪ Promotes development and normal activity of CNS Diseases o Hypothyroidism ▪ Primary failure of the thyroid gland Hashimoto’s disease – autoimmune destruction of the thyroid gland ▪ Deficiency of TRH, TSH, or both ▪ Inadequate dietary iodine ▪ Reduced BMR, poor tolerance of cold, excessive weight gain, fatigue, slow pulse, slow mental responsiveness  ▪ Myxedema – puffy appearance of face, hands, and feet ▪ Cretenism – hypothyroidism from birth Dwarfism and mental retardation ▪ Eurythroid sick syndrome Not actually hypothyroidism If T4 is cleaved wrong, we can get rT3 instead of T3 and that blocks the effects of T3 o Hyperthyroidism ▪ Graves’ Disease Thyroid-stimulating immunoglobulin (TSI) binds TSH receptors on follicular cells TSI activates TSH receptors and has trophic effects on glands, but is not subject to negative feedback Exophthalmos – bulging eyes caused by inflammation and swelling of eye muscles and fat stores behind the eyes ▪ Primary hyperthyroidism – hypersecreting tumor on thyroid gland ▪ Secondary hyperthyroidism – hypersecreting tumor in hypothalamus or AP ▪ Elevated BMR, excessive sweating, poor heat tolerance, excessive weight loss, palpitations Causes of Goiter Formation o Iodine deficiency o Autoimmune disease that stimulates the thyroid gland (Graves Disease) o Eating large amounts of soy, brassica vegetables, or peanuts which have antithyroidal compounds in them o Smoking causes goiter because compounds in cigarettes decrease iodine uptake Growth o Net synthesis of proteins, lengthening of bones, hypertrophy and hyperplasia in soft tissue ▪ Not just simply weight gain o Affected by genetics, adequate diet, chronic disease and stress (cortisol promotes protein breakdown, inhibits the growth of long bones, and blocks secretion of GH), normal hormone levels (GH, insulin, TH, sex hormones) o Fetal growth is influenced by placental hormones, not GH o Postnatal and pubertal growth spurts ▪ Postnatal during the first two years of life ▪ Pubertal growth spurt during adolescence Prepubertal Growth Spurt o Age 2 until puberty, rate of linear growth starts to decline ▪ Little sexual difference in height or weight ▪ Still growth happening, just not as fast o Puberty begins ~11 y/o in girls and ~13 y/o in boys  ▪ Lasts for several years in both ▪ Elevated GH contributes to growth ▪ Increase in sex hormones contributes to growth and stimulates more release of GH ▪ Estrogen and testosterone will eventually stop bone growth Functions of GH o GH uses JAK/STAT signaling pathway o GH is the most abundant hormone produced by the AP, even after longitudinal growth has ceased → metabolic effects! ▪ Primarily acts on adipose tissue, skeletal muscle, and the liver ▪ Promotes the breakdown of fat stores to increase FA levels in the blood; decreases glucose uptake by muscle and promotes glucose output by the liver to increase glucose levels in the blood ▪ Muscles will use mobilized fat for energy instead of glucose so that glucose can be saved for glucose- dependent organs (ie. the brain) ▪ Stimulates amino acid uptake and protein synthesis; inhibits protein degradation o Most of GH’s growth-promoting effects are indirect via insulin-like growth factors ▪ IGFs act directly on target cells to cause the growth of soft tissues and bone ▪ Signals via TK pathway ▪ IGF-1 and IGF-2 Functions of IGF o IGF-1 synthesis is stimulated by GH primarily in the liver ▪ Most tissues produce IGF-1, but only the liver secretes it into circulation ▪ Production depends on adequate nutrition, age-related factors, and tissue-specific factors ▪ GH and IGF-1 directly stimulate protein synthesis and inhibit protein degradation ▪ IGF-1 stimulates cell division and prevents apoptosis ▪ IGF-1 causes lengthening and thickening of bone, stimulates proliferation of epiphyseal cartilage, and promotes osteoblast activity  o IGF-2 is not influenced by GH ▪ Mostly involved with fetal development ▪ Role in adults is less well understood GH Regulation o Growth hormone-releasing hormone (GHRH) from the hypothalamus stimulates GH release o Growth hormone-inhibiting hormone (GHIH)/Somatostatin from the hypothalamus inhibits GH release o GHRH and GHIH act on AP somatotropes o GH promotes secretion of IGF-1 from the liver; IGF-1 inhibits GH at AP, inhibits GHRH secretion at hypothalamus, and stimulates GHIH secretion at hypothalamus o GH also inhibits GHRH at hypothalamus and stimulates GHIG at hypothalamus o GH factors for secretion… ▪ Diurnal rhythm – highest at night, lowest during the day ▪ Stimulated by exercise, stress, low blood glucose, elevated blood amino acids, low blood fatty acids, and ghrelin (appetite stimulant) ▪ No known growth-related signals Bone Growth o Long bones made up of a diaphysis and epiphysis ▪ Diaphysis is separated from epiphysis in growing bone by epiphyseal plate (layer of cartilage) o Thickening of bones happens by osteoblasts in the periosteum depositing new bone on the outer surface and osteoclasts on the inner surface dissolve bone tissue to enlarge the marrow cavity o Lengthening of bones happens by division of chondrocytes in the epiphyseal plate on the epiphysis border ▪ Older chondrocytes near the diaphyseal border grow ▪ Epiphysis is pushed away from diaphysis ▪ Oldest chondrocytes calcify and die; osteoclasts clear them away ▪ Osteoblasts from diaphysis deposit bone Diseases o GH Deficiency ▪ Primary pituitary defect ▪ Secondary hypothalamic defect ▪ Dwarfism – hyposecretion in children Retarded skeletal growth, poorly developed muscles, excess subcutaneous fat ▪ Laron dwarfism – inability of tissues to respond normally to GH ▪ African pygmies – deficiency of IGF-1 ▪ GH deficiency in adulthood has less pronounced symptoms  Reduced skeletal muscle mass and strength, decreased bone density, heart failure o GH Excess ▪ Primary hypersecreting AP tumor ▪ Gigantism – overproduction in childhood Rapid growth in height without distortion of body proportions ▪ Acromegaly – overproduction in adulthood Thicker bones, proliferation of soft tissue Coarsenss of features (skull does not stop growth)