bipn 120 — midterm 1 ˚ ౨ৎ ⋆ ｡˚ ⋆

˚ ౨ৎ ⋆ ｡˚ ⋆ lectures 1-6!

what’s endocrinology?

what’s endocrinology?

how hormones control the body

how can hormones be released? (4 ways)

1. endocrine

2. paracrine

3. autocrine

4. intracrine

what’s endocrine signaling?

hormone gets into blood circulation

what’s paracrine signaling?

via local cells

what’s autocrine signaling?

hormone release stimulate cell itself (outside receptors)

what’s intracrine signaling?

hormone stimulates cell itself (inside receptor)

what are receptors?

receptors are proteins

what is the specificity of receptors?

receptors are highly specific

how do receptors interact with a hormone?

receptors form H:R complex with hormone

what influences H:R interactions? (5 types)

1. hydrogren bonds

2. van der waals forces

3. electrostatic interactions

4. hydrophobic interactions

5. non-covalent bonds

what is the law of mass action?

what is K₁?

rate of association; high K₁ = long lasting effect

what is K-₁?

rate of dissociation; high K-₁ = short effect

what is Kd?

dissociation constant; [H] needed to bind to 50% of receptors

what’s the relationship of Kd to affinity?

↓ Kd = ↑ affinity (interaction strength)

how do u find Kd on a graph?

what does higher and low affinities look like graphically (Kd)?

what affinities do the alpha and beta subunits have to norepinephrine and epinephrine?

1. alpha-1: ne > e

2. beta-1: ne = e

3. beta-2: ne << e

how does high affinity H:R relate to drug development?

high affinity compounds don’t need much hormone to be effective

what is an agonist? what’s one example?

• drug activates receptor

• agent that trigger effector mechanisms → biological effects

• drug mimicry

• ie. heroine

what is an antagonist? what’s one example?

• bind to receptor but prevent activation of effector mechanisms

• block receptor

• ie. naloxone

what are nuclear receptors?

• aka intracellular receptors; inside cell (cytoplasm/nucleus)

• use transcriptional regulation as effector

what are 3 different types of nuclear receptors?

1. steroid (ie. androgen, progesterone, estrogen*, glucocorticoid, mineralocorticoid)

2. thyroid (ie. T3, vitamin D)

3. organ receptors

*estrogen receptors function simialar to steroid receptors

what are steroid receptors? what dimers do they from? how do they enter the cell?

• type of nuclear receptor

• form homodimers

• H:R complex enter nucleus and bind HRE (hormone response element)

• transcribe genes

what happens if steroid receptors dont have hormone?

no hormone: heat shock proteins (HSP) prevent nuclear translocation

what happens if steroid receptors have a hormone?

heat shocked proteins (HSPs) have decreased affinity

what are thyroid receptors? what dimers do they form? do they have hsp? what are 3 examples?

• form heterodimers with retinoid X receptors (RxR)

• no heat shock proteins

• (ie. thyroid receptors (TR), vitamin D receptors (VDR), retinoid X receptors (RxR))

what happens if thyroid receptors dont have hormone bond?

• TR inhibits gene expression (assoc. w repressors)

what happends if thyroid receptors have a hormone bond?

• TR activated gene expression (assoc. w activators)

what are g-proteins? how are they activated/inactivated?

• inactive: β/𝛄 anchor ɑ to membrane + GDP bound

  • ɑ: high affinity for GDP + intrinsic GTPase acitivity

• active: hormone binds → conformational change/drop GDP → free ɑ binds to GTP

what are the 3 different types of alpha subunits? what do they do?

• ɑₛ

• ɑᵢ

• ɑq (starts PLCP pathway)

• all work w same β/𝛄

what is amplification?

one receptor can be coupled to many G-proteins

what are some GPCR cAMPs?

• Gₛ (activates AC)

• Gᵢ (inhibits AC)

what does adenylate cyclase (AC) do in CPCR cAMPs?

• AC catalyzes ATP → cAMP

• cAMP activates PKA

• PKA phosphorylates targets (CREB); allow gene transcription

how to stop GPCR cAMP?

• unbind hormone

• ɑ coverts GTP → GDP

• Phosphodiesterases convert cAMP → AMP

• phosphatases remove phosphates from targets

explain the process of IP₃ formation and effect?

1. Gq activates PLCβ: PIP₂ → IP₃ + DAG

2. IP₃ makes IP₃R on ER release Ca2+

3. DAG + Ca2+ = ↑ PKC activity

(GPCR ex.) cholera ↓ GTPase of ɑ subunit in GI mucosa. how does this effect the following:

1. level of active Gɑₛ

2. AC activity and cAMP levels

3. Cl- movement to the lumen

4. water movement

5. what symptoms?

• GTPase: GTP → GDP

1. ↑ Gɑₛ (bc activates cyclic amp cascade)

2. ↑ AC activity/cAMP levels

3. ↑ Cl- movement to lumen

4. ↑ water movement (bc ↑ osmotic movement; water loss from blood cells → lumen)

5. diaherrea; excessive dehydration

what are enzyme-linked receptors? examples?

• have enzymatic activity; most dimerize for max activity

• ie. receptor tyrosine kinases, cytokine receptors

explain the process of receptor tyrosine kinases. examples?

• enzyme-linked receptors

• activations → autophosphorylation of tyrosie groups on R

  • start enzymes → gene transcription (growth + mitosis)

• ie. insulin; igf-1

explain cytokine receptors. examples?

• enzyme linked receptors

• no enzyme activity; have hormone → recruit tyrosine kinase

  • lead to STAT phosphorylation → go to nucleus + transcribe genes

• ie. GH, prolactin

what 3 types of hormones are there?

1. steroid

2. peptides

3. amines

what are steroid hormones?

• from cholesterol

• all lipid-soluble; use nuclear receptors

  • exc. androgen receptors: membrane bound receptor

how are steroid hormones made? how does its starting molecule enter the cell? what transporter brings the starter to where? what enzyme does steroid synthesis use? what pathway does it take?

1. cholesterol enters cell as low-density lipoproteins (apolipoprotein B/cholesterol esters) via LDLR

2. STAR (steroidogenic acute regulator) transporter brings cholesterol to mitochondria

3. P450ₛcc enzyme on inner mitochondrial membrane

4. synthesis continues w delta 5/4 pathway; location depends on enzyme location

(steroid synthesis ex.)

if P450c21 is inactive what happens to the following:

1. aldosterone

2. cortisol

3. androstenedione

1. ↓

2. ↓

3. no effect; or ↑ bc of shift in pathway (more substrate)

what are the sex hormones in steroid synthesis pathway?

what are the mineralcorticoid hormones in steroid synthesis pathway?

what are the glucocorticoid hormones in steroid synthesis?

what are the 3 different classes of sex steroids?

1. progestins (progesterone)

2. androgens (DHEA, androstenedione, testosterone, DHT)

3. estrogens (estradiol)

how can steroids reach:

1. adjacent cells?

2. far locations?

steroids lipid soluble; move thru membrane easily

1. diffusion one cell plasma membrane → near tissue

2. transport proteins

   • (general: albumin)

     • has ↓ binding affinity but ↑[albumin] in blood

   • (specific: SHBP; sex hormone binding proteins)

     • “sex hormone binding globulin”

     • transcortin: transport cortisol

how often are steroid hormones released?

• once made → secreted (bc lipid soluble)

what is the relationship of bound and free steroid hormones?

• free [H] = active

  • ↑ unbinding in capillaries near target tissue

    • allow steroid come off transport protein

  • ↑ free: ↑ enzymatically degraded

• bound [H] takes long to clear fr body

  • ↑ bound: ↑ steroid in circulation

how are steroid hormones excreted? what does this do to its activation? is this reversible?

• degrading enzymes; active → inactive forms

• Irreverisble changes

• excreted in urine + poop

  • urine: 80% via organic anion symporter

what is the half-life of steroid hormones?

• slow bc is bound

• hours - days

  • exc. aldosterone: limited binding → faster removal

what is the solubility of peptides?

• not lipid soluble

• needs membrane bound receptors

  • ie. GPCR, enzyme-linked receptors

what are the 3 characteristics of peptide synthesis?

• genes are transcribed/translated

• usually made as inactive prohormones

• post-translational modifications in golgi/vesicles

how are peptides released?

1. ↑ Ca2+ (via IP₃ + voltage gated Ca2_ channels)

2. protein binding

3. exocytosis (vesicles)

• similar to neurotransmitter release

(peptide release ex.)

botulin cleaves SNARE protiens (does vesicle fusion) in synpases that use ACh. what is the effect on the following:

1. vesicle fusion

2. muscle contration in limbs

3. breathing

4. testosterone release

1. ↓

2. ↓; ACh involved in musc contr. toxin → flacid paralysis

   • flacid paralysis: no vesicular release of Ach → no sig

3. ↓; all voluntary movement = skeletal muscle → paralyzed

4. ↓; ↓ vesicle fusion and release

how are peptides transported?

• packaged into vesicles

• released fr proteins made in

• hydrophilic + dissolve in plasma

  • few binding proteins (ADH, oxytocin, GH, IGF)

how are peptides broken down? (2 ways)

1. broken down enzymatically (proteases in blood/tissue)

2. peptide binds to receptor → internalized → lysosome degredation

what is the half-life of proteins?

• minutes - hours

• faster bc most peptides x bound to carrier proteins

(ie. half life)

12 hrs after their production is suddenly stopped, what is the cirulcating levels of the following:

1. steroid hormones (androgens)

2. peptide hormones (FSH)

1. ↑; longer half life: ↑ abundant

2. ↓; shorter half life: ↓ abundant

what are amine hormones?

all derived from tyrosine aa

what are the 2 types of amines? where do they bind?

1. catecholamines: all released fr adrenal glands

   • bind to membrane bound receptors

   • ie. epinephrine, norepinephrine, dopamine

2. thyroid hormones

   • bind to intracellular receptors

   • ie. T3/T4

what is a negative feedback loop?

• maintain hormones in normal range; holds set point

• most common

• odd number of inversions

what is a positive feedback loop?

• amplification; disrupts steady state

• stopped by endpoint/external stimulus

• even number of inversions

what does the hypothalamus do in regards to the pituitary axis?

• lots blood flow to pituitary

• neurons in hypothalamus

  1. dump hormones → blood → anterior pituitary

  2. dump hormones → blood @ level of posterior pit

what is the pituitary stalk?

• “infundibulum”

• stalk connects pituitary to brain

what is the posterior pituitary?

• “neurohypophysis”

• collections of axons/axon terminals

• release contents → blood vessels

what is the anterior pituitary?

• “adenohypophysis”

• not neurons

• hypothalamus: hormone → blood vessel → apR + stimulate ap cells release contents → another blood vessel

  • blood vessels of ap = fenestrated (porous)

what are the 3 components of the anterior pituitary?

1. neurons (make hormones → capillaries₁)

2. portal veins: carry blood from hypothalamus → ant pit

3. endocrine cells: release peptide hormones → capillaries₂/circulatory system → distribute to target organs

what are the arteries that are connected to the anterior and posterior pituitaries?

1. Anterior: Superior hypophyseal artery

   • hypothalamus hormone → superior —portal vein→ ant pit → another hormone → blood → body

2. Posterior: Inferior hypophyseal artery

   • hypothalamus hormone → blood → inferior → posterior → body

(pituitary ex.)

sharp blow to head restricts blood flow thru infundibulum.

what happens to circulating levels of hormones?

↓ anterior pituitary hormones

• ant: vascular, pos: neural

*”theres ants in my blood”

what 2 hormones does the posterior pituitary synthesize?

1. oxytocin (peptide)

2. anti-diuretic hormone (peptide)

   • “ ADH, vasopressin, arginine vasopressing/AVP”

• neurons release hormone into blood in posterior

what is the role of oxytocin? how is it controlled?

• smooth muscle contraction (MLCP/MLCK pathways)

• controlled via mechanical stimulation

  • stim contractions for labor

    • (uterus) myometrium contract: ↑ oxy: labor

  • eject milk fr alveoli in breast

    • nipple stim: ↑ oxy: myoepithelial cells contract: squeeze milk into ducts

  • EtOH: ↓ oxy

• love hormone/pair-bonding

what is oxytocin coupled to? how does it work?

• oxy is couples to Gq receptors → IP3 cascade: ↑ MLCK/ ↓ MLCP

(oxytocin ex.)

in transgenic mice wo oxytocin synthesis, what happens to lactation?

• ↑ prolactin: milk still amde

• wo oxy: milk not secreted

what is the relationship of contraction and oxytocin in parturition?

• ↑ contraction: ↑ oxy (+ feedback)

• progesterone inhibits contraction before w35

what does anti-diuretic hormone do? what are the 3 effects?

• ADH: water retention: ↓ peeing

  • ↑ hypothalamus action potential: ↑ ADH

1. ↑ osmolarity*

2. ↓ blood volume

3. ↓ blood pressure

* shrink neuron = ↑ action potential

* swell neuron = ↓ action potential

what is the mechanism of ADH?

• ADH binds to receptors in nephron → cAMP pathway (G5 protein)

• ↑ protein kinaseL cell inserts aquaporin₂ inro collecting duct lumen

  • water follow on osmotic gradient

(ADH ex.)

what happens if ADH production stops?

1. lose a lot of water

2. ↓ water absorption when needed

3. ↑ urine production

what is diabetes insipidus (DI)?

• high water vol in urine → dilute urine

• ↓↓/no ADH (central)

• broken vasopressin2R (nephrogenic)

how can DI be treated?

with desmopressin (synthetic ADH)

• if fails to work, then defective V2R is the issue

what is diabetes malitus?

sweet pee; lots of glucose in urine

how to graphically find the cause of ones diabetes?

• test for DI by depriving ppl of water and give demsopressin (synthetic ADH)

what are the 4 classifications of diabetes insipidus?

1. central: ↓ ADH production

2. nephrogenic: kidneys not responding to ADH

   • broken V2 receptors

3. dipsogenic: excessive fluid intake

   1. hypothamalus damage (tell self vv thirsty)

4. gestational: placenta has enzymes that clears ADH

(syndrome of inappropriate ADH ex.)

how does majorly increased levels of ADH affect the following:

1. osmolarity of urine?

2. osmolarity of blood?

1. ↑

2. ↓

• this is bc ADH reabsorbs water ( filtrate → interstitial fluid → blood); ↑ ADH: ↑ water leave filtrate: ↑ urine osmolarity

what are the 5 effects of SIADH (syndrome of inappropriate ADH)? how does it effect blood osmolarity? ADH levels? urine concentration? water retention? osmolarity?

1. low blood osmolarity

2. high [ADH]

3. concentrated urine

4. excess water retention

5. hypO-osmolarity

(SIADH ex.)

what are low [Na+] levels bad in extracellular fluid?

• all cells need Na+ to function (neurons, cardiac, nephron)

• low [Na+] in blood = bad

  • cerebral edema = convulsions, coma, death

what is the cause of SIADH?

• SIADH: ↑↑ ADH

• ectopic ADH release

  • often from lung; tumor (secrete peptides/ADH)

how can SIADH be treated?

• fluid restriction

• diuretics (↑ urine formation)

  • destroy osmotic gradient in renal medulla by blocking NKCC transporters so water reabsorption to blood is difficult

• remove tumor

what is the general pathways for the hypothalamus to the anterior pituitary?

what does the hypothalamus release to stimulate the anterior pituitary to release thyroid stimulating hormone (TSH)?

hypothalamus — TRH → binds to TRH receptor coupled to Gq proteins on thyrotroph cells on anterior pituitary → TSH

• TSH = “thyrotropin”

how commom are thyrotroph cells?

• least common cell in anterior pituitary

• thyrotroph cells: have TRHR → TSH

does somatostain (SS) inhibit GH or TSH release more?

GH more

what does the hypothalamus release to inhibit the anterior pituitary to release thyroid stimulating hormone (TSH)?

hypothalamus — SS → binds to SS receptor coupled to Gi protein on thyrotroph cells on anterior pituitary —| TSH

• SS = “somatostain”; has small effect of inhibiting TSH

what does the hypothalamus release to stimulate the anterior pituitary to release Adrenocorticotropin (ACTH)?

hypothamalus — CRH → binds to CRH receptor coupled to Gs protein on corticotroph cells on anterior pituitary → ACTH

what does the hypothalamus release to stimulate the anterior pituitary to release GH?

hypothalamus — GHRH → binds to GHRH receptor coupled to Gs protein on somatotroph cells on anterior pituitary → GH

what does the hypothalamus release to inhibit the anterior pituitary to release GH?

— hypothalamus → SS → binds to SS receptor coupled to Gi protein on somatotroph cells on anterior pituitary —| GH

how common are somatotroph cells in the anterior pituitary?

• 50% of cells = somatotroph

what does the hypothalamus release to stimulate the anterior pituitary to release follicle stimulating hormone (FSH)/luteinizing hormone (LH)?

hypothalamus — GnRH → binds to GnRH receptors couples to Gq protein on gonadotroph cells on anterior pituitary → FSH/LH

• GnRH = gondatropin releasing hormone