VTPP 427 Lecture PDF

Excitable Cells (Chp. 3 & 4) 01/14 ​ Result of an action potential = NT release ​ When a neuron releases NT, does it always release the same amount? ○​ No ○​ More NT = stronger signal; less = weaker signal ○​ Depends on excite vs inhibit ​ Dependent on actio...

Excitable Cells (Chp. 3 & 4) 01/14 ​ Result of an action potential = NT release ​ When a neuron releases NT, does it always release the same amount? ○​ No ○​ More NT = stronger signal; less = weaker signal ○​ Depends on excite vs inhibit ​ Dependent on action potentials: muscle contraction, brain function (thoughts, memories, etc.), heart rhythm, etc. ​ Graded potentials- might cause an AP or might not; not every graded potential causes an AP ○​ Thermal-gated ○​ Light-gated ○​ Ligand-gates (chemical) ○​ Voltage-gate = AP! ​ RMP = dependent upon potassium; changes in potassium cause changes in resting ○​ High potassium = excitation; can cause muscle spasms/twitching ○​ Low potassium = fatigue ​ Calcium- determines threshold; changes in calcium change position of threshold ○​ Low calcium = threshold goes down ○​ High calcium = threshold goes up ​ Beta blockers = lowers blood pressure by slowing the heart down; affects calcium ​ Establishment of RMP: ○​ RMP is negative bc more potassium inside than out so when potassium leaves the cell, charge decreases and become negative ○​ If a positive ion is leaving, the cell is becoming more negative ○​ Theoretically, charge of cell becomes -90mV = equilibrium potential (no ion movement) ○​ Nernst equation for equilibrium potential: ​ E = 61 log ([outside]/[inside]); permeability is null in this equation ​ Potassium = -90mV ​ If the extracellular concentration of potassium goes up, what happens to the concentration gradient? ○​ Goes up because potassium is pulled back in sooner ○​ Cell becomes more excitable because it’s closer to threshold ○​ Potassium has most impact on RMP ○​ Cells are more permeable to potassium than sodium ​ Sodium membrane potential = 61mV ​ Diabetes cause of death = renal failure ​ Lethal injection = potassium chloride overdose to stop the heart ​ Seizure focus- regions of the brain are hyperexcitable (too close to threshold, too positive) ○​ What strategies could we use to decrease the excitability of these regions? ​ Increase calcium to increase threshold which decreases excitability ​ Increase permeability to potassium ​ Decrease sodium permeability (since positive, we want less sodium to enter which would decrease possibility of seizure)  ​ More excitable = more positive bc getting closer to threshold ​ Inhibitory = potassium leaving the cell OR chloride going into the cell (more negative) ​ Influences on RMP: ○​ Increase/decrease ECT K+ ○​ Increase/decrease K+ permeability ○​ Increase/decrease Na+ permeability 01/16 ​ If extracellular potassium is too low, RMP goes down and cell becomes less excitable ​ If extracellular potassium is too high, RMP goes up and cell becomes more excitable ​ Threshold- moves with/influenced by calcium ○​ EC calcium goes down = threshold goes down and cell becomes more excitable ○​ EC calcium goes up = threshold goes up and cell becomes less excitable ​ Lack of hydrogen = calcium goes down ​ RMP uses leak channels ​ Blood flow to which structure or organ is not innervated by the sympathetic nervous system? ○​ Skeletal muscle ○​ Brain ○​ Heart ○​ Kidneys ○​ Skin ​ Sympathetic response ○​ Sympathetic decreases blood flow to brain = pass out; sympathetic increases blood flow to brain = aneurysm ○​ Sympathetic increases skeletal muscle and heart blood flow when in fight or flight ○​ Sympathetic decreases kidney and skin blood flow when in fight or flight ○​ Redirects blood flow to where it needs to be in an emergency situation ​ Autonomic nervous system prevents us from going into shock (BP is 0 when blood is in capillaries) ​ Input ○​ CNS control center = hypothalamus ○​ Endocrine ​ Thyroid hormone- responsible for B1 receptors on the heart ​ Cortisol- responsible for a1 receptors on arterioles ​ Addison’s disease- “Addisonian crisis” = no cortisol resulting in shock ​ Estrogen- responsible for B2 receptors on coronary arteries and m2 receptors in certain vessels ​ Not in biological males ​ Giving estrogen to a biological male would NOT dilate coronary arteries ​ Androgens/estrogens- ANS receptors in the CNS ​ Parasympathetic has NO impact on kidney or renal function because there are no receptors ​ Output ○​ Most every organ system ​ Dual innervation is not always present  ​ Very few systems are not directly innervated by the ANS ○​ Tone- idea that the system is always running, always firing to organs; tone is when this activity increases or decreases ​ Often associated with dual innervation, but not always ​ Tone is not present in all cases of dual innervation ​ Most things are innervated by sympathetic ​ Skin is sympathetic ONLY ​ Heart rate low = parasympathetic is winning = has more tone ​ Heart rate high = sympathetic is winning = has more tone ​ Sympathetic INHIBITS digestion while parasympathetic excites/increases it ○​ Increased blood flow to the gut is an indirect effect caused by increase in digestion ​ Urination = parasympathetic ○​ Only time sympathetic causes bladder contraction is when under distress (scared) ​ Parasympathetic can kill you instantly, sympathetic can kill you over longer period of time (months) ​ Dogs have irregular heartbeat because they are controlled largely by parasympathetic tone ​ Sympathetic affects the eye to look long distances ​ NO parasympathetic hormones ​ Divisions: ○​ Sympathetic ​ Preganglionic fiber (cholinergic fibers) ​ Originates in thoracolumbar spinal cord ​ Very SHORT ​ Release ACh (cholinergic) ​ Postganglionic fiber- hit the target organ ​ Very LONG ​ Mainly release norepinephrine (adrenergic) ​ Some release ACh (cholinergic) - responsible for thermoregulatory sweat ○​ As temp rises, sympathetic causes sweat production to reduce it ​ Terminate in varicosities ○​ Parasympathetic ​ Preganglionic ​ Very LONG ​ Originate in cranial/sacral spinal cord ​ Release ACh (cholinergic) ​ Postganglionic ​ May be in the organ ​ Very SHORT ​ Release ACh (cholinergic) ​ Sympathetic response ○​ Heart- increased rate and increased force of contraction ○​ Blood vessels- skin and organs constricted while muscles and heart dilated ​ Different receptor on skin than arterial muscle; one excites while other inhibits ○​ Lungs- bronchodilation and inhibition of mucus secretion  ○​ Gallbladder, urinary bladder, and digestive system- relaxation and cessation of digestion ○​ Fat- lipolysis to increase energy availability ○​ Exocrine glands- increased sweat and increased salivary mucus ​ Nervous sweat = a1 sweat (adrenergic) Endocrinology - Hormones and Cell Signaling Across Endocrine Axes 01/23 ​ Different classes of hormones ○​ Membrane receptor binding ○​ Intracellular (and membrane) receptor binding ​ Polypeptide hormones ○​ Amino acid chains are synthesized at the rough ER ○​ Functional hormones cleaved from preprohormones ○​ Hormones are packaged into secretory vesicles in Golgi ​ Steroid hormones ○​ Cholesterol is able to move across membrane without special transporter because it’s hydrophobic ​ Cholesterol is stored within the cell ​ Shuttled to the mitochondria and converted into pregnenolone (starter steroid for everything) ​ Depending on the enzymes present in the cell, pregnenolone is converted to specific steroids ​ Steroid hormones are able to diffuse back across the plasma membrane into circulation ​ Cell communication via extracellular chemical messengers ○​ Paracrine ○​ Endocrine hormone ○​ Neurotransmitters (class of paracrine signals) ○​ Neurohormone (class of endocrine hormones) ​ Nervous system- speed of response = rapid; duration of action = brief ​ Endocrine system- speed of response = generally slow; duration of action = long ​ The same signaling molecule can induce different response in different target cells, depending upon which receptor is expressed ​ Hydrophilic hormones utilize membrane-bound receptors to cause cellular responses ○​ Ion-gated receptor channel ○​ Receptor-enzyme ○​ G-protein coupled receptor ​ Receptor-enzyme signaling via receptor tyrosine kinases ​ 7 transmembrane loop receptor signaling ○​ When ATP is converted into cAMP, it becomes the second messenger which activates protein kinase A ​ 2nd messenger systems allow for tremendous signal amplification ​ Classical signaling pathway: *not a fast mechanism ○​ Lipophilic hormones bind receptors inside the cell  ​ Bind to protein, come off to diffuse into capillaries in localized cells; in cytoplasm, they bind to the receptors ​ Hormones response element depends on what binds to the receptor ​ Estrogen signaling can occur via multiple types of receptors ○​ Steroid hormones can have quicker and amplified effects if bound to second messengers ​ Androgens can signal via multiple types of receptors Bioavailability ​ Hormone bioavailability ○​ Steroid hormones hate plasma so they are not free and readily available, most bind to some sort of transport protein ​ 54% weakly bound to albumin ​ 44% tightly bound to sex hormone-binding protein (SHBG) ​ Obese men have even more tightly bound causing less available testosterone ​ 2% circulating free of protein binding ​ Free and weakly-bound = bioavailable ○​ If bound, has to come off plasma protein of choice to go to target cells which cause physiologic response ​ 5 ways target cells become desensitized to a signal molecule (hormone) ○​ 1. Receptor sequestration- signal molecule is pulled into the cell endosome and hangs out there; does not get destroyed ○​ 2. Receptor down-regulation ○​ 3. Receptor inactivation ○​ 4. Inactivation of signaling protein ○​ 5. Production of inhibitory protein ​ *insulin is one of the only examples of feed forward signaling in the body ​ Hormone secretion patterns over time ○​ Pulsatile- a lot is reproductive ○​ Basal- most common ○​ Sustained- can be in response to stress; estradiol in women ​ Diurnal rhythms- when it’s dark, cortisol levels start to rise and then fall when morning hits The Hypothalamic-Pituitary Axis ​ Cells in the adenohypophysis produce hormones that stimulate other endocrine glands ​ Negative feedback loops: TSH, ACTH, prolactin, growth hormone, LH, and FSH ​ Hormones from the anterior pituitary: ○​ Glycoproteins- TSH, FSH, and LH; common a-subunit, unique B-subunit (confers biological specificity ○​ Pro-opiomelanocortin (POMC)- post-translational cleavage; ACTH, B-endorphin, a-, B-, and y (gamma) melanocyte stimulating hormones (MSH) ○​ Growth hormone and prolactin- structural and genetic (human placental lactogen) ​ Hierarchical chain of command and negative feedback in endocrine control ○​ Hypothalamus buffers against stress at the right amount ​ Chronic cortisol = maladaptive ​ Short term stress = good; long term stress = bad  ​ Neurons from the supraoptic and paraventricular nuclei terminate in the neurohypophysis ○​ Vasopressin and oxytocin released from posterior pituitary ​ Oxytocin- when released in respect to uterus, can only happen when estrogen is high; facilitates parturition through a positive feedback cycle ○​ Gap junctions increase communication between myometrial cells to coordinate contractions ○​ Upregulation in response to estrogen ○​ As oxytocin binds, it starts to slowly increase contractions ○​ Braxton-Hicks contractions- “false labor”; oxytocin is slowly increasing which causes contractions ○​ Oxytocin continues to increase until baby is born ○​ Released in response to suckling; contraction of myoepithelial cells surrounding alveoli ​ Prolactin- released from anterior pituitary ​ Vasopressin- aka ADH; increase water reabsorption and causes vasoconstriction ○​ High concentration and low volume = increase in thirst response and increased vasopressin ○​ Also causes changes in the permeability of nephrons in the kidneys to increase plasma volume Circadian Rhythms ​ Circadian rhythms are controlled by the pineal gland and the suprachiasmatic nucleus ​ Melanopsin-containing retinal ganglion cells sense the light change ​ Melanopsin stimulates the SCN “master biological clock” to: ○​ Synthesize clock proteins ○​ Stimulate pineal gland release of melatonin and help to synchronize the SCN rhythm with the light-dark cycle ​ Suprachiasmatic stimulation by light = negative input/feedback on pineal gland ○​ Positive input/feedback = synthesis of clock proteins ○​ Then cyclic changes in clock proteins occur to synchronize circadian rhythms in effector organs throughout the body ​ Melatonin production goes up in the dark and down in the light ○​ Negative input on the melanopsin-containing retinal ganglion cells ​ Bright light late at night advances the rhythm 01/28 ​NE and E come from the medulla ​ZG = mineralocorticoids: aldosterone ​ZF = glucocorticoids: cortisol ​ZR = sex steroids ​Medulla = catecholamines (E = 80%; NE = 20%) ​Cholesterol is the backbone of steroid hormones ○​ Then turns into pregnenolone which can then become anything (“catch-all”) ​ Glucocorticoids are precursors to aldosterone (a mineralocorticoid) ​ Aldosterone directly causes: ○​ Increase Na+ absorption ​ RAAS ○​ Main goal is to maintain blood pressure ○​ Liver = angiotensinogen ○​ Kidney = renin → angiotensin I ○​ Lungs = angiotensin-converting enzyme → angiotensin II ​ Converts angiotensin I into angiotensin II ○​ Angiotensin causes vasoconstriction ○​ Angiotensin II stimulates the adrenal cortex to make aldosterone ○​ When potassium increases, the adrenal cortex senses that and stimulates the release of aldosterone ​ Cortisol release and feedback loops ○​ ACTH- released from anterior pituitary ​ Triggered by CRH from the hypothalamus ○​ Zona fasciculata ○​ Bound to plasma proteins ​ Cortisol control of metabolism ○​ Hepatic gluconeogenesis ○​ Inhibits glucose uptake, but NOT in the brain ○​ Protein degradation - mainly muscle ○​ Facilitates lipolysis ○​ Released as an adaptive response to stress because…? ​ Hypothalamus → posterior pituitary → increased vasopressin release = conserve salt and H2O to expand the plasma volume; help sustain blood pressure when acute loss of plasma volume occurs ○​ Vasopressin and angiotensin II cause arteriolar vasoconstriction to increase blood pressure ○​ Both pituitary glands are firing at the same time ​ Pancreas does have sympathetic innervation ​ Pharmacology of cortisol ○​ Anti-inflammatory ○​ Immunosuppressive ○​ Side effects: ​ Prone to infections ​ Gastric ulcers ​ High blood pressure ​ Atherosclerosis - causing mobilization of fatty acids ​ Suppression of HPA (hypothalamic pituitary adrenal) axis ​ Shuts down normal ACTH secretion ​ May cause atrophy of cells in adrenal gland that secrete cortisol ​ Adrenocortical insufficiencies interrupt cortisol and aldosterone secretion and downstream actions ○​ Primary adrenocortical insufficiency = adrenal gland issue → Addison’s disease → all products of adrenal cortex low) ○​ Secondary adrenocortical insufficiency = hypothalamic/pituitary issue → low ACTH → low cortisol  ○​ If the lesion/damage is in the adrenal gland, ACTH is high ○​ If the lesion/damage is in the hypothalamus, ACTH and cortisol is low ​ Primary adrenocortical insufficiency = Addison’s disease ○​ Potassium retention and sodium depletion → low BP ○​ Poor response to stress ○​ Hypoglycemia ○​ Changes to body hair distribution ○​ Aldosterone and cortisol are deficient ○​ Typical signalment is 30-50 year old female (or dog, no cats) ○​ Symptoms: ​ Adrenal gland DOES NOT make: mineralocorticoids, glucocorticoids, or androgens ​ Hyperpigmentation - increased melanin in epidermal layer of skin cells ​ Happens because of ACTH, POMC, and MSH relationship ​ Seizures ​ Low blood pressure ○​ *can’t have both primary and secondary ​ Secondary adrenocortical insufficiency = pituitary defect/disease ○​ ACTH secretion is decreased ○​ Cortisol (and sex steroids) is (are) deficient ○​ Causes: ​ Pituitary tumor ​ Infection (TB) ​ Autoimmune destruction of pituitary ​ Pituitary trauma (car accident, etc.) ○​ Chronic exogenous glucocorticoid use OR stopping glucocorticoid trial abruptly ​ Ex. prednisone pack prescribed but patient stops taking the full dose 4 days into the 2 week prescription ○​ Symptoms: ​ NO hyperpigmentation ​ Due to low cortisol levels: ​ Hypotension ​ Shock ​ Hypoglycemia ​ Fatigue ​ Vomiting ​ Decreased appetite ​ Abdominal pain ​ Due to DHEA levels: ​ Females are mostly affected ​ Irregular menstrual periods ​ Decreased pubic hair and axillary hair ​ Decreased libido ​ Adrenal gland hypersecretion of aldosterone  ○​ Zona glomerulosa ○​ Primary hyperaldosteronism ​ Conn’s syndrome ​ Hypersecreting adrenal tumor ○​ Secondary hyperaldosteronism ​ High activity of the RAAS ​ Many causes ○​ Symptoms of this disease are related to exaggerated effects of aldosterone (excess Na+ retention, K+ depletion (peed out), high fluid retention, and increased blood pressure) ​ Primary hyperaldosteronism ○​ Causes: ​ Idiopathic (most common cause) ​ Adenoma ​ Adrenal gland hypersecretion of cortisol ○​ Cushing’s syndrome- adrenal tumors or ACTH-secreting pituitary tumors ​ Main symptom = excessive gluconeogenesis ○​ Similar to diabetes mellitus ○​ Clinical signs: ​ Fat deposited in face, above the shoulder blades (buffalo hump), and in abdomen ​ Muscle wasting ​ Potbelly appearance Adrenal androgens ​ DHEA and ? ​ Adrenogenital syndrome- produces androgens, but not cortisol; hypothalamus continues to secrete CRH to turn into ACTH in an attempt to make more cortisol but ultimately just left with excess androgen secretion ○​ Infertility issues because gametes are not produced; sex hormones has to be produced locally ​ Polycystic ovary syndrome ○​ 30% of PCOS patients have excessive adrenal androgen production ○​ Hirsutism ○​ Male pattern baldness ○​ Infertility ○​ Metabolic disturbances- prone to insulin resistance and diabetes ○​ Still have androgens produced from adrenal gland even after entering menopause Adrenal medulla ​ Adrenal medulla- an endocrine component of the sympathetic nervous system ​ B2- dilates bronchioles ​ B1- heart contraction (Starling’s law) ​ Catecholamines are derived from tyrosine in the adrenal chromaffin cells ​ Dopamine is a precursor to NE and E; helps us focus ​ Epinephrine- fight or flight hormone ○​ Promotes release of glucose from stored muscle glycogen ○​ Contributes to glucagon stimulation of hepatic glycogenolysis and gluconeogenesis  ○​ Made in chromaffin cells ​ Catecholamines ​ NE to E ○​ Cortisol sensitive ○​ Inhibit insulin release ○​ Activates lipases to increase the release of fatty acids into the bloodstream ​ Catecholamine hypersecretion ○​ Adrenal medullary tumors ​ Phaeochromocytoma → hypertensive crisis ​ Ganglioneuroma- tumor from ANS neurons ​ Neuroblastoma ​ Paraganglioma → tumors from chromaffin cells 01/30 Endocrine: Thyroid and Growth Axes and Integration Across Axes ​ Thyroid- a lobed gland below the larynx that regulates metabolism ○​ Secretes thyroid hormone (T3 and T4) ​ Increases metabolic rate and heat production ​ Enhances growth and CNS development ​ Enhances sympathetic activity ​ TRH (thyroid-releasing hormone)- binds to GPCR 7-transmembrane receptor on the pituitary to stimulate release of TSH (thyroid stimulating hormone) ○​ TSH binds to 7-transmembrane receptor on thyroid to stimulate release of T3 and T4 ​ Thyroid-follicular cells surround a colloid-filled lumen ○​ Follicular cells produce T3 (triiodothyronine) and T4 (thyroxine) from precursor tyrosine (also makes E, NE, and dopamine) ​ The active form of thyroid hormone is T3 and is predominantly converted from T4 in the liver ​ How do T3 and T4 get made? ○​ Iodine gets added to Tg and changes name ○​ Colloid- space 1.​ Tyrosine-containing Tg produced within the thyroid follicular cells by the endoplasmic reticulum-Golgi complex is transported by exocytosis into the colloid ○​ Iodide is carried by secondary active transport from the blood into the colloid by symporters in the basolateral membrane of the follicular cells ○​ In the follicular cell, the iodide is oxidized to active form by TPO at the luminal membrane ○​ The active iodide exits the cell through a luminal channel to enter the colloid ○​ Catalyzed by TPO, attachment of one iodide to tyrosine within the Tg molecule yields MIT ○​ Attachment of 2 iodides to tyrosine ○​ Etc… ​ Extrathyroidal conversion of T4 to T3 is critical to affect target tissues ○​ 93% is in the form of T4, the inactive form, and must be converted to T3 before it can be used in the body  ○​ 60% of T4 is converted to T3 in the liver ○​ 20% of T4 is converted to an inactive form of T3 called reverse T3 (rT3) which is excreted from the body ○​ 20% of T4 is converted to T3S and T3AC (inactive forms) ○​ A small amount of T4 is converted to T3 in the peripheral tissues ​ T3 and T4 are important regulators of basal metabolic rate ○​ Increase the basal metabolic rate ​ Regulates the body’s use of oxygen ​ Energy expenditure ​ Calorigenic (heat-producing) ○​ Modulate the rates of many specific reactions ○​ Synthesis and degradation of carbohydrate, fat, and protein ​ Sympathomimetic effects of thyroid hormone ○​ Similar to the effects produced by the SNS ○​ Increases target cell responsiveness to E and NE (catecholamines) ​ Causes proliferation of catecholamine receptors in target cells ​ Permissive effect ​ Cardiovascular effects of thyroid hormone ○​ Unhealthy heart = mobilizes lipids from our tissues causes predisposition to heart disease ○​ Increases heart rate and the force of heart contractions ○​ Increases blood pressure ○​ Increases body heat ​ Peripheral vasodilation (blood flow increases; keeps limbs warm) ​ Carry heat to the surface for elimination ​ Effects of thyroid hormone on growth ○​ Promotes effect of GH on skeletal growth and protein synthesis ​ Synergistic effect ○​ Thyroid-deficient children have stunted growth ​ Excess thyroid hormone does not lead to excess growth ○​ Thyroid hormone triggers differentiation of tissues ​ Cretinism: congenital hypothyroidism ○​ Congenital defect in thyroid function ○​ In utero, baby does not get appropriate iodine intake and therefore can’t make thyroxine ​ Causes of goiter formation ○​ Iodine deficiency ○​ Autoimmune disease that stimulates the thyroid gland (Graves disease) ○​ Eating large amounts of soy, brassica vegetables, or peanuts which have anti-thyroidal compounds in them ○​ Smoking causes goiter because compounds in cigarettes decrease iodine uptake ○​ ***any disorder that causes constantly high TSH without the release of T3/T4*** ​ HPT axis dysfunction can occur in various ways ○​ Abnormal presence of TSI = increased T3 and decreased TSH; goiter is present ○​ Secondary to excess hypothalamic or anterior pituitary secretion = increased T3 and T4, increased TRH and/or increased TSH; goiter present  ○​ Hypersecreting thyroid tumor = increased T3 and T4, decreased TSH; no goiter present ​ Graves disease: hyperthyroidism ○​ Symptoms due to increased BMR: ​ Exophthalmos ​ Goiter ​ Sweating and poor heat tolerance ​ Tachycardia ​ Nausea/diarrhea ​ Weight loss ​ Anxiety/nervousness ​ Tremor ​ Muscle fatigue ​ Thyroid storm: massive release of T4 ○​ Thyroxine increases catecholamine receptors in tissues ​ Increases cardiac muscle sensitivity to E ○​ Increases tissue metabolic activity ​ Increases cardiac muscle’s metabolic demands which can result in myocardial ischemia ​ HPT axis dysfunction can occur in various ways ○​ Primary failure of the thyroid gland = decreased T3 and T4, increased TSH; goiter present ○​ Secondary to hypothalamic or anterior pituitary failure = decreased T3 and T4, decreased TRH and/or decreased TSH; no goiter present ○​ Lack of dietary iodine = decreased T3 and T4, increased TSH; goiter present ​ Hashimotos disease: hypothyroidism ○​ Symptoms due to decreased BMR (basal metabolic rate) ​ Weight gain ​ Poor tolerance to cold (low blood flow to hands and feet) ​ Fatigues easily ​ Slow, weak pulse ​ Slow reflexes ​ Depression ​ Memory difficulties ○​ Euthyroid sick- patient appears to be hypothyroid but instead has some other underlying illness that is driving the thyroid hormones down ​ Concomitant disease alters T4 → T3 conversion ​ rT3 formed, will not be as low as T3 ​ The ratio of T3 to rT3 must be determined to diagnose this condition accurately Growth Axis - the hypothalamic pituitary growth (HPG) axis has many inputs and regulators ​ Main driver is stress (cortisol), blood glucose levels, and diurnal rhythm (changes throughout the day) ​ Somatostatin (GHIH) and GHRH feed into anterior pituitary to either say “release GH” or “don’t release GH” ​ GPCR 7-transmembrane receptor  ○​ GHRH binds to this receptor to stimulate the release of GH from the somatotropes ​ GHRH and somatostatin regulate GH production by stimulating and inhibiting adenylyl cyclase via Gs or Gi to alter cAMP levels (don’t bind each other but both use adenylyl cyclase) ​ Growth hormone signals via the JAK-STAT pathway in end tissues ○​ One ligand molecule per dimeric receptor ○​ This dimer drives transcription ​ IGF = made in the liver and then goes to tissues to cause effects ​ IGF-1 signals via receptor tyrosine kinases ​ Cross-phosphorylation of non-receptor tyrosine kinases by GH ​ Receptor tyrosine kinase dimerization and cross-phosphorylation stimulated by IGF-1 ​ JAK takes phosphates and attaches them to the enzyme (GH) ​ IGFs stimulate hypertrophy AND hyperplasia in several tissues ○​ GH in the liver directly produce IGF-1 ○​ GH in the muscle increases lean body mass ○​ GH in the chondrocytes increases linear growth ○​ GH and IGF-1 grow organs and increase organ function ○​ GH directly in adipose tissue decrease adiposity (decreases adipose tissue) ​ Postnatal growth spurt is not gender dependent ○​ Pubertal growth spurt relies on sex hormone production ​ Girls start around age 11: adrenal androgen-dependent and ovarian estrogen-dependent ​ Boys start around age 13: testicular androgen-dependent ​ Factors regulating growth ○​ Genetics ○​ Fetal: maternal/fetal/placental factors, not including GH ○​ Postnatally: normal levels of growth-influencing hormones (GHRH, GH) ○​ Adequate diet (protein, essential amino acids in food intake) ​ Malnourished diets decrease maximum growth potential ​ Excess food intake → obesity, not growth ○​ Freedom from chronic disease and environmental stress ​ What happens when the HPG axis is dysfunctional? ○​ Lack of growth hormone from somatotrophs in adolescence: ​ Hypopituitary dwarfism ○​ Making GH but not converting in the liver: ​ Laron dwarfism ○​ Making GH, converting in the liver, but lesion in growth tissue because receptors aren’t functioning properly ​ End-organ resistance dwarfism ○​ Lesion in pituitary that drives GH in adulthood; typically from pituitary tumor ​ Acromegaly - epiphyseal growth plates already closed, GH builds in face ​ Bones in the face can still be sensitive to GH so head becomes enlarged ​ A juvenile patent has a pituitary tumor which causes an increased amount of somatostatin secretion. What is the effect on this patient’s body? ○​ A. decrease long-bone growth ○​ B. decreased muscle mass ○​ C. Decreased adiposity ○​ D. A and B are correct, C incorrect ○​ E. A, B, and C correct