VTPP 427 TA Session Notes PDF

VTPP 427 TA Session Notes Session #1: Excitable Cells ​ Ligand-gated channel: ○​ Bind NTs and ions ○​ Ligand can be intracellular or extracellular ​ Voltage-gated channel: ○​ Respond to changes in potential by changing conformation ​ Ion distribution a...

VTPP 427 TA Session Notes Session #1: Excitable Cells ​ Ligand-gated channel: ○​ Bind NTs and ions ○​ Ligand can be intracellular or extracellular ​ Voltage-gated channel: ○​ Respond to changes in potential by changing conformation ​ Ion distribution and permeability ○​ Na+ is highly concentrated outside the cell ○​ K+ highly concentrated inside the cell ○​ Intracellular proteins have a negative charge ​ ICF is more negative than ECF ○​ Cell membrane is more permeable to K+ than to Na+ ○​ 2 forces act on ions: concentration gradient and electrical gradient ​ K+ concentration gradient goes outside; K+ electrical gradient goes inside ​ Na+ concentration gradient goes inside; Na+ electrical gradient goes inside ○​ Concentration values: ​ Na+: ECF = 150; ICF = 15; relative permeability = 1 ​ K+: ECF = 5; ICF = 150; relative permeability = 25-30 ​ A-: ECF = 0; ICF = 65; relative permeability = 0 ​ Membrane potential ○​ Separation of opposite charges across the membrane, the membrane itself is neutral ​ Only excitable tissues (muscle and nerve cells) can use membrane potentials to generate action potentials (electrical signals) ○​ Magnitude of membrane potential depends on the number of opposite charges separated ○​ RMP- membrane potential of non-excitable cells and excitable cells at rest (not producing electrical signals) = ~70mV ○​ Attractive force between opposite charges causes a thin layer to line up along membrane; the rest of the fluid is electrically neutral and does not contribute to membrane potential ​ Equilibrium potential- membrane potential at which the electrical gradient and concentration gradients are balanced ○​ No net movement ○​ Specific to each ion ○​ Calculated by Nernst and GHK equations ○​ Nernst- E = 61 log([outside]/[inside]) ​ Equilibrium potential for potassium ○​ 2 opposing forces act on K+: ​ 1. Concentration gradient moving outward ​ 2. Electrical gradient moving inward ○​ Dynamic equilibrium exists when gradients are exactly equally opposing, and no net movement occurs ○​ E(K) = 61 log (5nm/150nM) = -90mV ​ Sign indicates charge of ICF ​ Equilibrium potential for sodium  ○​ Concentration gradient moves inward, leaving other negatively charged ions unbalanced in ECF ○​ An opposing electrical gradient is established, an no net movement occurs at equilibrium ○​ E(Na) = 61 log (150nM/15nM) = +61mV ​ K+ and Na+ effects on the body ○​ Neither exist alone in the body, so equilibrium potentials are not present in any cells; they are strictly hypothetical ○​ The more permeable the membrane is to a certain ion, the more that ion contributes to membrane potential (potassium effects it most) ​ Membrane is more permeable to K+ than Na+ ○​ Calculated by GHK to = ~70mV ​ Polarization- any time the membrane potential is not 0mV ​ Hypopolarization (depolarization)- when the membrane potential is becoming less negative ​ Repolarization- the return to RMP after hypopolarization ​ Hyperpolarization- membrane potential becomes more negative than RMP ​ Triggering events- change the membrane potential by altering permeability to certain ions ​ Graded potentials- local changes in membrane potential do not change the potential of the entire membrane ○​ Stronger triggering events cause larger graded potentials; longer event = longer graded potentials ○​ Local current flow in an active area can change the potential in an adjacent inactive area ○​ Magnitude of local current progressively diminishes the further it gets from the initial active area ○​ Excitatory graded potentials bring the membrane potential closer to threshold (hypopolarization) ○​ Inhibitory graded potentials bring the membrane further away from threshold (hyperpolarization) ​ Action potentials- large changes in membrane potential that transiently cause the inside of the cell to become more positive than the outside ○​ Propagate non-decrementally throughout its entirety ○​ If a graded potential is large enough, it can initiate an action potential ○​ Hypopolarization from RMP to threshold (-50mV) causes peak to +30mV and then repolarization and after hyperpolarization back to RMP ○​ Duration and amplitude of action potentials do NOT vary ​ Propagate in only one direction ​ Strength of stimulus depends on frequency of action potentials ​ Voltage-gated sodium channels- both activation and inactivation gates must be open to allow passage of Na+ through ○​ Activation gate (voltage-gated) opens above -50mV ○​ Inactivation gate (chronotropic) is initiated to close at threshold and takes ~0.5ms to close ​ Reopens once membrane is repolarized below threshold ​ Voltage-gated potassium channels- activation gate triggered to open at threshold ○​ Slow to open, so K+ doesn’t start efflux until ~+30mV ​ All-or-none law- either threshold is reached and fires an action potential, or its not; no in between ​ Absolute refractory period- period in which a cell cannot undergo another action potential ○​ Starts at threshold and ends when Na+ channels have reset ○​ Defines maximum frequency of action potentials ​ Relative refractory period- period in which a cell can undergo another action potential, but it is more difficult to initiate because membrane potential is below RMP ​ Refractory periods- ensure one-way propagation of action potentials ​ Propagation along neurons- axon conducts action potentials away from the cell body and eventually terminates at other cells ○​ Action potentials are triggered at the axon hillock (first portion of axon) ​ More Na+ voltage-gated channels present in this region ​ Contiguous conduction- conduction in UNmyelinated fibers; action potential spreads along every section of the membrane down the entire axon ○​ Rapid influx of Na+ down the axon ○​ Na/K pump cleans up afterwards ​ Saltatory conduction- conduction in myelinated fibers; action potential “jumps” from one node to the next, skipping over the myelinated regions ○​ Schwann cells (PNS) and oligodendrocytes (CNS) ○​ Between myelinated regions are nodes of ranvier, bare patches of membrane ○​ Much faster than contiguous conduction ​ Conduction velocity- directly influenced by myelination and nerve fiber diameter ○​ Small unmyelinated fibers are the slowest ​ C-type pain (dull, lingering aches), digestive tract, etc ○​ Large myelinated fibers are the fastest ​ A-type pain (sharp), reflexes, skeletal muscle, etc. ​ Regeneration of fibers- if nerve fibers become damaged, the portion of the axon furthest from the cell body degenerates ○​ In PNS, Schwann cells phagocytize debris and form regeneration tube to guide growing axon in proper direction ○​ In CNS, oligodendrocytes synthesize proteins to inhibit axonal growth ○​ Multiple sclerosis and Guillain-Barre syndrome involve the loss of myelin sheaths ​ Synapses- the junction between 2 neurons; a neuron can terminate on a muscle, gland, or another neuron and releases chemical messengers to alter activity of those cells ○​ Electrical synapses- allow charge-carrying ions to flow directly between the 2 cells in either direction ○​ Chemical synapses- involve a chemical messenger that transmits information once way across the space between the neurons ​ Involves axon terminal of presynaptic neuron and dendrites/cell body of postsynaptic neuron ​ Excitatory postsynaptic potential (EPSP)- glutamate NT; nonspecific cation channels allow movement of Na+ and K+ simultaneously ○​ Large Na+ movement inward and small K+ movement outward = hypopolarization ​ Inhibitory postsynaptic potential (IPSP)- GABA NT; ion-specific channels allow movement of K+ out and Cl- in = hyperpolarization ​ Summation- EPSPs and IPSPs are graded potentials, so they can be added on top of each other  ○​ EPSPs + IPSPs occurring around the same time = grand postsynaptic potential (GPSP) ○​ Temporal summation- action potentials from the same presynaptic neuron occur in close succession and graded potentials in the postsynaptic neuron add together ○​ Spatial summation- action potentials from several presynaptic neurons occur simultaneously ○​ EPSP and IPSP will cancel each other out ​ Neuromodulators- do not cause formation of graded potentials or alter membrane permeability and potential ○​ Act as presynaptic and postsynaptic sites to alter action of the synapse ​ Ex. neuromodulator influences level of enzyme responsible for production of NT ​ Ex. neuromodulator influences number of NT receptors of postsynaptic neuron ○​ Presynaptic neurons can also be innervated by another axon terminal to alter the amount of NT released from it (presynaptic inhibition and presynaptic facilitation) Session #2: Autonomic Nervous System I ​ Peripheral nervous system (PNS)- lies outside the brain and spinal cord ○​ Afferent division- signals from body receptors to CNS ○​ Efferent division- signals from CNS to muscles and glands; 2 divisions: ​ Somatic nervous system- motor neurons ​ Autonomic nervous system (ANS)- everything else ​ Autonomic nerve pathway ○​ 1. Cell body of the first neuron is located in the CNS ​ Preganglionic fiber synapses with a second neuron in a ganglion ○​ 2. Postganglionic fiber innervates the effector organ ○​ 3 functional classes of neurons: afferent, efferent, interneurons ○​ 2 divisions of the ANS: sympathetic and parasympathetic ​ Sympathetic nervous system ○​ Fight or flight ○​ Nerve fibers originate in thoracic and lumbar regions of the spinal cord ○​ Preganglionic fibers are short - cholinergic (release ACh) ○​ Postganglionic fibers are long - adrenergic (release norepinephrine) ​ Have nicotinic receptors that bind ACh from preganglionic fibers ​ Parasympathetic nervous system ○​ Rest or digest ○​ Nerve fibers originate in cranial and sacral regions of the spinal cord ○​ Preganglionic fibers are long - cholinergic (release ACh) ○​ Post ganglionic fibers are short - cholinergic (release ACh) ​ Often originate near or in the effector organ ​ Have nicotinic receptors that bind ACh from preganglionic fibers ​ Cholinergic- release acetylcholine (ACh) which binds to: ○​ Nicotinic receptors on postganglionic cell bodies and on adrenal medulla ○​ Muscarinic receptors on effector organs ​ Adrenergic- release norepinephrine (NE) which binds to: ○​ a1, a2, B1, and B2 adrenergic receptors (1 = excitatory, 2 = inhibitory)  ○​ Can also bind epinephrine from adrenal medulla ​ ***Notable exception: ○​ Adrenergic receptors bind NE and cause nervous sweat ○​ Muscarinic receptors bind ACh and cause thermoregulatory sweat ​ All sympathetic postganglionic fibers are adrenergic except this one ​ Dual innervation- effector organs that are innervated by both sympathetic and parasympathetic nerve fibers; generally have opposite effects ○​ Sympathetic or parasympathetic tone- both systems are partially active, but activity of one can dominate the other ​ Balance between them can be shifted separately for individual organs to meet specific demands or a more general favoring of one system for body-wise functions ○​ Not all organs are dually innervated ​ Sympathetic ONLY: sweat glands, adrenal medulla, kidneys, skin, and uterus ​ Parasympathetic ONLY: lacrimal glands ​ Salivary glands are dually innervated, but sympathetic and parasympathetic activities are not antagonistic ​ Bladder is dually innervated, but has no tone Session #3: Autonomic Nervous System II ​ Cholinergic receptors ○​ Nicotinic: ​ Found on postganglionic cell bodies in all autonomic ganglia ​ Respond to ACh from sympathetic and parasympathetic preganglionic fibers ○​ Muscarinic: ​ Found on effector cell membranes to stimulate or inhibit that organ ​ Respond to ACh from parasympathetic postganglionic fibers ​ EXCEPT for thermoregulatory sweat ​ M1: stimulates brain and stomach ​ M2: lowers HR ​ M3: stimulates glands (salivary, lacrimal, sweat, and digestive) ​ SLUDD ○​ Parasympathetic overload ○​ Salivation, lacrimation, urination, defecation, and death ○​ Can be prevented with atropine, a muscarinic antagonist ​ Adrenergic receptors: A1 ○​ Present on most sympathetic tissue ○​ Has greater affinity for NE than E, but will bind both ○​ Activates Gq (IP3-Ca2+) pathway ○​ Produces excitatory effect: ​ Peripheral vascular smooth muscle: constriction of blood vessels ​ Digestive tract: constriction of sphincters ​ Eye: contraction of radial muscle  ​ Sweat and salivary glands: nervous sweat, thick saliva/mucus, ejaculation/orgasmic contractions ​ Adrenergic receptors: A2 ○​ Present on digestive organs and CNS ○​ Has greater affinity for NE than E, but will bind both ○​ Activates Gi (inhibit cAMP) pathway ○​ Produces inhibitory effect: ​ CNS: inhibits sympathetic output ​ Digestive tract: inhibits smooth muscle contractions and digestive secretions ​ Pancreas: inhibits insulin production, promotes glycogenolysis ​ Other: inhibits mucus secretion in lungs ​ Adrenergic receptors: B1 ○​ Present on heart ○​ Has equal affinity for NE and E ○​ Activates Gs (activate cAMP) pathway ○​ Produces excitatory effect ​ Increase heart rate ​ Increase force of contraction ​ Adrenergic receptors: B2 ○​ Present on vascular and lung tissues ○​ Has affinity for E ONLY ○​ Activates Gs (activate cAMP) pathway ○​ Produces inhibitory effect: ​ Blood vessels: dilation of coronary, hepatic, and skeletal muscle arteries ​ Lungs: dilates bronchioles ​ Digestive tract: relaxes GI motility ​ Eye: inhibits constriction of circular muscle ​ Fat tissue: promotes lipolysis ​ Liver: promotes glycogenolysis ​ 1 = excitatory ​ 2 = inhibitory Session #4: Intro to Endocrinology ​ Intercellular communication ○​ Most common way cells communicate with each other is indirectly by extracellular chemical messengers ​ Paracrines/autocrines, NTs, hormones, and neurohormones ​ Messengers are released into ECF by specialized controlling cells to act on target cells ○​ Senders: endocrine pancreas, parathyroid glands, pituitary gland, thyroid gland, adrenal glands, and gonads ○​ Feedback/receivers: mechanism to signal that the hormones were received, and further response is not needed ​ Types of signaling  ○​ Intracrine- cell produces hormone for intracellular use ○​ Autocrine: cell secretes hormones that binds to cell-receptor ○​ Paracrine- cell secretes hormones that binds to a local target cell ○​ Endocrine- cell secretes hormones that travels through the blood and binds to distant target cell ○​ Neurohormone- neuron secretes hormones that travels through the blood and binds to distant target cell ○​ Neurotransmitter- neuron secretes hormone that binds to local target cell ​ Peptide hormones ○​ Amino acid chains are synthesized in rough ER and functional hormones are cleaved from preprohormones ○​ Hormones are packaged in secretory vesicles in the Golgi complex ○​ Vesicles fuse with plasma membrane upon stimulation to release hormones into ECF ○​ *Water soluble* ​ Lipid hormones ○​ Derived from cholesterol that is stored inside the cell ○​ Cholesterol moves to mitochondria and is converted into pregnenolone ○​ Pregnenolone is converted into difference steroids, depending on the enzymes present in that cell ○​ Steroid hormones diffuse through plasma membrane into ECF ○​ Most circulate is bound to plasma proteins ​ Free or weakly-bound steroids are bioavailable ​ Signal transduction- process by which incoming signals are conveyed into the target cell and how they dictate the cellular response ​ Lipid-soluble extracellular chemical messengers ○​ Steroids ○​ Dissolve and pass through the cell membrane; bind to receptors inside the cell ○​ Typically change gene activity ​ Water-soluble extracellular chemical messengers ○​ Peptide hormones ○​ Bind to receptors on outer surface of the cell membrane ○​ Triggers sequence of intracellular activity (second-messenger systems) ​ Combination signaling- integration of all signaling input ​ The same signaling molecule can induce different effects in different target cells Membrane-bound receptors- mostly for hydrophilic hormones ​ Ion-gated receptor-channel- chemical messenger binds to receptor, causing it to open or close ○​ Regulate movement of particular ions across the membrane ​ Receptor enzymes- chemical messenger activates intracellular protein kinase ○​ Usually act in a chain reaction (cascade) ○​ Tyrosine kinase, JAK/STAT, G-protein coupled ​ Tyrosine kinase pathway ​ Two extracellular messengers are required for TK activation ​ Activation of receptor causes phosphorylation of tyrosines on receptor  ​ The designated intracellular protein is phosphorylated by active tyrosine kinase and carries out cellular response ​ JAK/STAT pathway ​ Receptor and attached enzymes function as a unit, but they are separate pieces ​ Binding of extracellular messenger activates JAK x2 ​ JAK phosphorylates STAT, which influences gene expression ​ Gs-protein pathway (cAMP) ​ First messenger activates G protein and a portion of it dissociates to activate 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 ​ Gq-protein pathway (IP3-Ca2+) ​ Activation of g-protein activates phospholipase C ​ PLC converts PIP2 into IP3 and DAG ​ IP3 mobilizes intracellular Ca2+ 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 ​ Amplification- multiple steps of the cascade pathways will amplify the original signal Classical signaling- mostly for lipophilic hormones ​ Intracellular receptors ○​ All lipophilic hormones bind with intracellular receptors and primarily produce effects by modulating gene expression ○​ Hormones diffuses through the membrane and binds to portion of receptor specific to that molecule ​ Other portion binds to DNA ​ Hormone response element (HRE) ​ Estrogen and testosterone ○​ Lipophilic steroid hormones use classical signaling ○​ Estrogen and testosterone also have extracellular membrane receptors (cascade responses) ​ Estrogen- GPER ​ Testosterone- SHBG-R ​ Reception regulation ○​ Receptor sequestration: “hiding” receptors intracellularly ○​ Receptor down-regulation: intracellular destruction of receptors ○​ Receptor inactivation- usually by dephosphorylation ○​ Inactivation of signaling protein- compromise of protein kinase  ○​ Production of inhibitory protein- blocks second messenger signaling ​ Hormone secretion patterns ○​ Pulsatile- secretion peaks and drops ​ Diurnal rhythm ○​ Basal- normal, relatively constant secretion ​ Insulin (in fasted state) ○​ Sustained- increase that stays elevated for long periods of time ​ Chronic stress, hormone-secreting tumors ○​ *hormones don’t fit perfectly into just one category; secretion patterns can change based on certain conditions Hypothalamic-pituitary axes ​ Anatomy review ○​ Neurohypophysis- hypothalamus and posterior pituitary ​ Hormones are synthesized in neuronal cell bodies within the hypothalamus ​ Hormones are released at the axon terminals into the posterior pituitary ​ *Hormones are not synthesized in the posterior pituitary* ○​ Adenohypophysis- anterior pituitary ​ Posterior pituitary ○​ Supraoptic and paraventricular nuclei extend through the hypothalamus posterior pituitary stalk ○​ Each nucleus produces either vasopressin or oxytocin, but not both simultaneously ○​ Travels down the axon with kinesin ​ Anterior pituitary ○​ Composed of glandular epithelial tissue ○​ Connected to hypothalamus via portal system ​ Fancy vascular link between the two ○​ Most AP hormones are tropic (hormones that regulates secretion of a different hormone from a different endocrine gland) ​ Contrast with trophic hormones, which promotes growth of the target organ ○​ 5 cell types in APs and what they secrete: ​ Somatotropes = growth hormones (GH) ​ Thyrotropes = thyroid-stimulating hormone (TSH) ​ Corticotropes = ACTH cleaved from POMC ​ Gonadotropes = follicle-stimulating hormone (FSH) and luteinizing hormone (LH) ​ Lactotropes = prolactin (PRL) ​ Hypothalamic-hypophyseal portal system ○​ Portal system- vascular arrangement where venous blood flows directly from one capillary bed into another by a connecting vessel ○​ Almost all blood supplied to AP must pass through the hypothalamus, allowing exclusive movement of hormones between the two and bypassing systemic circulation ○​ As a general rule, hormone secreted by target gland has negative feedback on both AP and hypothalamus ​ Oxytocin has positive feedback loop during parturition  ​ Pineal gland ○​ Suprachiasmatic nucleus is responsible for setting circadian rhythm ○​ Transcription factors CLOCK and BMAL-1 in SCN activate transcription for clock proteins PER and CRY ○​ During the day, clock proteins accumulate and are transported into the nucleus at their critical level ○​ In the nucleus, PER and CRY inhibit CLOCK and BMAL-1 ○​ No more production of clock proteins and existing clock protein start to degrade ○​ As they degrade, less inhibition on transcription factors and the cycle starts over; cycle takes ~1 day ​ In reality is a little slower than 24 hours, so SCN resets every day with environmental cues ○​ Melanopsin is a protein found in the retina and transmits signals to SCN to keep body’s time in sync with external time ​ Once SCN has this input, it regulates pineal gland for melatonin secretion ​ Melatonin is “darkness hormone”, also helps to match circadian rhythm to light-dark cycle Session #5: Adrenal-RAAS Axis Regulation ​ Functional zones of the adrenal gland ○​ Adrenal cortex- outer layer; secretes steroids: ​ Zona glomerulosa = mineralocorticoids (aldosterone) ​ Zona fasciculata = glucocorticoids (cortisol) ​ Zona reticularis = sex hormones (DHEA) ​ Also secretes a little bit of cortisol ​ Major source of sex hormones is gonads ○​ Adrenal medulla- inner layer; secretes catecholamines (NE and E) ​ Steroidogenesis ○​ Steroids are lipophilic!!! ○​ Needs plasma proteins to travel in ECF ​ Cortisol binds to transcortin ​ Aldosterone binds to albumin ​ DHEA binds to albumin ○​ Each has specific HRE ​ i.e. mineralocorticoid HRE is MRE ​ Aldosterone ○​ Mineralocorticoid ○​ Intracellular receptor and response element: MR and MRE ○​ Plasma protein: albumin ○​ Target cells: principal cells of distal and collecting tubules of kidney ○​ Trigger for release: low [Na+] = indirect via RAAs, high [K+] = direct ○​ Actions: increase Na+ retention, increase H2O retention, increase ECF volume and BP, increase K+ elimination ​ Save sodium, pee potassium ​ Renin-angiotensin-aldosterone system (RAAS) ○​ System is activated by low pressure (from low sodium and/or low ECF volume) ○​ Kidneys release renin into bloodstream, which converts angiotensinogen in the liver to angiotensin I ○​ Angiotensin I is converted to angiotensin II in the lungs by ACE ○​ Angiotensin II causes: ​ Increased ADH release to increase H2O reabsorption ​ Increased thirst to increase fluid intake ​ Vasoconstriction of arterioles to increase BP ​ Stimulates adrenal cortex to release aldosterone to increase Na+ reabsorption ○​ Purpose is to correct low BP ​ How does aldosterone save sodium? ○​ Inserts Na+ leak channels on luminal membrane of tubular cells ○​ Inserts Na+/K+ pumps on basolateral membrane of tubular cells ○​ Also indirectly promotes water retention because water follows salt ​ Abnormal secretion of aldosterone ○​ Hypersecretion: ​ Primary hyperaldosteronism (Conn’s syndrome): hypersecreting adrenal tumor ​ Secondary hyperaldosteronism: inappropriate high activity of RAAS ​ Causes exaggerated effects of aldosterone ○​ Hyposecretion: ​ Primary adrenocortical insufficiency (Addison’s disease): autoimmune destruction of adrenal cortex ​ Deficiency in ALL corticosteroids ​ Cortisol ○​ Glucocorticoid ○​ Intracellular receptor and response element: GR and GRE (also has low affinity for MR/MRE) ○​ Plasma protein: transcortin ○​ Trigger for release: ACTH (ACTH stimulated by CRH) ​ Negative feedback to anterior pituitary and hypothalamus ○​ Actions: ​ Metabolic actions- increases blood glucose by increasing gluconeogenesis and decreasing glucose uptake; increases blood amino acids by increasing protein degradation; increases blood fatty acids by increasing lipolysis ​ Cardiovascular actions- assists catecholamines in inducing widespread vasoconstriction ​ Adaptation to stress- increases blood glucose/amino acids/fats for use in stressful situations (not well understood) ​ Anti-inflammatory- interferes with phagocytic activity, suppresses production of inflammatory cytokines, inhibits production of antibodies, etc. ○​ Short term= good; long term = bad ​ Abnormal secretion of cortisol ○​ Hypersecretion (Cushing’s syndrome):  ​ Primary- adrenal tumors ​ Secondary- increased CRH/ACTH from hypothalamus/anterior pituitary ​ Tertiary- ACTH-secreting tumor outside 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 with this condition ○​ Hyposecretion ​ Primary adrenocortical insufficiency (Addison’s disease- autoimmune destruction of adrenal cortex) ​ Hyperpigmentation from excessive secretion of ACTH ​ a-MSH is cleaved from same preprohormone as ACTH and promotes dispersion of melanin ​ Secondary adrenocortical insufficiency- insufficient ACTH secretion due to hypothalamic or pituitary abnormality ​ Poor stress response, hypoglycemia ​ Adrenal androgens (DHEA) ○​ Sex hormone ○​ Intracellular receptor and response element: AR and ARE ○​ Plasma protein: albumin ○​ Trigger for release: ACTH ​ Has negative feedback on GnRH, not CRH/ACTH ○​ Actions ​ Female- growth of pubic and axillary hair, enhancement of pubertal growth spurt, sex drive ​ Male- minimal effects since testosterone is stronger than DHEA ​ Abnormal secretion of DHEA ○​ Hypersecretion ​ Adrenogenital syndrome- caused by inherited enzymatic defect that prevents synthesis of cortisol ​ No cortisol = increased CRH/ACTH ​ Female symptoms- hirsutism (male pattern body hair), virilization (male secondary sex characteristics like deeper voice, greater muscle mass, etc.), smaller breasts, cessation of menstruation, pseudohermaphroditism (female gonads with male external genitalia) ​ Male symptoms- precocious pseudopuberty (premature development of secondary sex characteristics not associated with gonadal activity) ​ No effect in adult males ​ Adrenal medulla ○​ Modified portion of sympathetic nervous system made up of chromaffin cells (modified postganglionic neurons) ○​ Epinephrine and norepinephrine are catecholamines produced by chromaffin cells and secreted by exocytosis of chromaffin granules ○​ Associated more with short-term stress  ​ Stress response- integration of cortisol, aldosterone, and catecholamines Session #6: Thyroid and Growth Axes ​ Thyroid gland ○​ Follicular cells are the major thyroid secretory cells and are arranged into functional units called follicles ○​ Follicles are filled with inner lumen called colloid ​ Extracellular storage for TH ​ Mostly made up of thyroglobulin (Tg) ○​ Follicular cells produce tetraiodothyronine (T4, thyroxine) and triiodothyronine (T3) ​ T3 and T4 collectively are thyroid hormones (TH) ○​ C cells in interstitial spaces between follicles ​ Secrete calcitonin ​ Synthesis of thyroid hormone ○​ Follicular cells must take up tyrosine and iodine from the blood ​ Iodine must be obtained from the diet; comes in the cell through sodium symporter ○​ Tg is produced by ER-Golgi complex in thyroid follicular cells with incorporated tyrosine ○​ Tg transported to colloid by exocytosis ○​ Iodide is transferred from the blood into follicular cell via iodide trap ​ Na/I symporter (secondary active transport) ○​ Iodide is oxidized to its “active” form by thyroperoxidase (TPO) inside the follicular cell (on the luminal membrane) ​ Active I- enters colloid ○​ TPO attaches I- to a tyrosine in a Tg molecule​ ​ Attachment of 1 I- yields monoiodotyrosine (MIT) ​ Attachment of 2 I- yields di-iodotyrosine (DIT) ○​ MIT + DIT = T3 ○​ DIT + DIT = T4 ○​ Products remain attached to Tg and are stored in the colloid until stimulated for secretion ​ Secretion of thyroid hormone ○​ On stimulation for release of TH, follicular cells phagocytize a piece of colloid ○​ Vesicles of colloid fuse with lysosomes in the follicular cell and enzymes split active T3/T4 and inactive MIT/DIT from Tg ○​ TH is lipophilic, so it diffuses out of follicular cell into bloodstream ​ Most binds to thyroxine-binding globulin ○​ Deiodinase inside the follicular cells removes I- from MIT/DIT ​ Free I- is recycled ○​ 90% of secreted TH is in T4 form, but T3 is ~10x more biologically potent ​ Liver and kidneys can convert T4 to T3 ​ Thyroid axis ○​ Thyrotropin releasing hormone (TRH) ​ Stimulates anterior pituitary  ​ Signal transduction via Gq (IP3+ - Ca2+) ​ TRH secretion stimulated by cold (infants) and diurnal rhythm and inhibited by stress ○​ Thyrotropin stimulating hormone (TSH) ​ Stimulates thyroid gland to produce T3/T4 ​ **trophic actions on thyroid gland** (this is important for causes of goiter, which is an enlarged thyroid gland) ​ Signal transduction via Gs (cAMP) ○​ 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 anterior pituitary is more immediate/little changes; TH to hypothalamus is more long-term changes ​ Thyroid hormone actions ○​ Metabolic rate and heat production ​ Increases BMR ​ Regulation of body’s rate of O2 consumption and energy expenditure under resting conditions ​ Calorigenic effect- increased BMR causes increased heat production (want this to happen in infants to keep them warm) ○​ Sympathomimetic effect ​ Any action similar to one produced by SNS ​ TH increases target-cell responsiveness to catecholamines by increasing number of catecholamine receptors on target cells ○​ Cardiovascular effects ​ Increases heart rate and force of contraction ​ Increases cardiac output ○​ Growth ​ Stimulates growth hormone (GH) secretion ​ Increases production of IGF-1 ​ Promotes effects of GH and IGF-1 on synthesis of protein and bone growth ​ Promotes development and normal activity of CNS ​ Hypothyroidism ○​ Primary failure of the thyroid gland ​ Hashimoto’s disease- autoimmune destruction of 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 ○​ Cretinism- hypothyroidism from birth ​ Dwarfism and mental retardation ○​ Euthyroid sick syndrome- not actually hypothyroidism ​ If T4 is cleaved wrong, we can get rT3 instead of T3 and that blocks effects of T3 ​ 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 ​ Goiter- anytime TSH is increased = GOITER ○​ In hypothyroidism: ​ Failure of thyroid gland = decreased T3 and T4, increased TSH; yes goiter ​ Failure of hypothalamus or AP = decreased T3 and T4, decreased TSH; no goiter ​ Inadequate iodine = decreased T3 and T4, increased TSH; yes goiter ○​ In hyperthyroidism: ​ Grave’s disease = increased T3 and T4, decrease TSH, increased TSI; yes goiter ​ Thyroid tumor = increased T3 and T4, decreased TSH; no goiter ​ Hypothalamic or AP tumor = increased T3 and T4, increased TSH; yes goiter ​ **Shellfish are high iodine ​ Growth ○​ Net synthesis of proteins, lengthening of bones, hypertrophy and hyperplasia in soft tissue ​ Not just simply weight gain ○​ Affected by genetics, adequate diet, chronic disease and stress (cortisol promotes protein breakdown, inhibits growth of long bones, and blocks secretion of GH), normal hormone levels (GH, insulin, TH, sex hormones) ○​ Fetal growth influenced by placental hormones, not GH ○​ Postnatal and pubertal growth spurts ​ Postnatal during first 2 years of life ​ Pubertal growth spurt during adolescence ​ Pubertal growth spurt ○​ 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 ○​ Puberty begins age ~11 in girls and ~13 in boys ​ Lasts for several years in both ​ Elevated GH contributes to growth ​ Increase in sex hormones contribute to growth and stimulate more release of GH ​ Estrogen and testosterone will eventually stop bone growth ​ Functions of GH ○​ GH uses JAK/STAT signaling pathway  ○​ GH is most abundant hormone produced by AP, een after longitudinal growth has ceased → metabolic effects ​ Primarily acts on adipose tissue, skeletal muscle, and the liver ​ Promotes breakdown of fat stores to increase FA levels in the blood; decrease glucose uptake by muscles and promote glucose output by 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 ​ Stimulates amino acid uptake and protein synthesis; inhibits protein degradation ○​ Most of GH’s growth-promoting effects are indirect via insulin-like growth factors ​ IGFs act directly on target cells to cause growth of soft tissues and bone ​ Signals via TK pathway ​ IGF-1 and IGF-2 ​ Functions of IGF ○​ 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 ○​ IGF-2 is not influenced by GH ​ Mostly involved with fetal development ​ Role in adults is not well known ​ GH regulation ○​ Growth hormone-releasing hormone (GHRH) from the hypothalamus stimulates GH release ○​ Growth hormone-inhibiting hormone (GHIH) from the hypothalamus inhibits GH release ○​ GHRH and GHIH act on AP somatotropes ○​ 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 ○​ GH also inhibits GHRH at hypothalamus and stimulates GHIH at hypothalamus ○​ 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 FA, and ghrelin (appetite stimulant) ​ No known growth-related signals ​ Bone growth ○​ Long bones made up of diaphysis and epiphysis ​ Diaphysis separated from epiphysis in growing bone by epiphyseal plate (layer of cartilage)  ○​ 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 ○​ 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 ​ 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 ​ 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 tissues ​ Coarseness of features