IPHY 4440: EXAM 2
119 Cards in this Set
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Dimer Formation
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occupied receptors often form dimers
homodimers
heterodimers
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How does Ro bring about a change in a target cell?
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open/close an ion channel
function as an enzyme
function as a transcription factor
if R is none of the above
= second messenger
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Second messenger concept
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bioregulator = 1st messenger
Ro activates effector protein
= signal generating protein
Ro --> actives signal generating protein--> 2nd messenger--> effect
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application of epinephrine (E) increases:
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blood glucose
lipid breakdown
contractile force of heart
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When E binds in liver
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E binds to beta-adrenergic receptor (GPCR) on membrane which then activates enzyme system
ex. glycogen--> glucose phosphate
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E-beta adrenergic receptor complex
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activates an enzyme
Adenylyl cyclase (AC) = signal generating protein*
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what takes ATP to cAMP?
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AC
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cAMP pathway
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ATP --(AC)--> cAMP-->PKA
phosphorylase b--(PKA)--> phosphorylase a
glycogen--(phosphorylase a)--> glucose phosphate--> metabolism/free glucose-->blood
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cAMP in liver can?
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activates enzymes
inactivates enzymes (through PKA)
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cAMP in adipose tissue can?
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activates PKA
PKA activates hormone dependent lipase & lipolysis
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cAMP in cardiac muscle can?
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open Ca++ channels
stronger, more sustained contractions
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Lipolysis
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Triacylglycerols (TAGs) break down into:
2 nonesterified fatty acids (NEFAs)
one MAG (monoacylglycerol)
TAGs have 3 carbons
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Metabolism of 2nd messenger
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Phosphodiesterase (PDE)
one PDE specific for cAMP
breaks down cAMP into AMP
PDE is inhibited by methyl xanthines
ex. caffeine & theophylline
lots of methyl xanthines will cause build up of cAMP
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2nd messengers of PIP2 pathway
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IP3 & DAG
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signal generating protein for PIP2 pathway
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phospholipase C (PLC)
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useful information for PIP2 pathway
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DAG activates protein kinase C (PKC)
PKC cannot be activated by cAMP only DAG**
these effects generated by PKC can be either fast or slow
transcription factors causes PKC to act slowly
Ca+ is the third 2nd messenger
IP3 can be broken down by phosphomonoesterase
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phosphomonoesterase
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inhibits IP3 which causes Ca++ build up
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shutting down the system (3 ways)
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inactivation of ligand
reuptake of ligand by secreting cell
internalization of Ro
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Inactivation of ligand
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degrading enzyme
in cell membrane
in ECF
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Reuptake of ligand by secreting cell
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works for:
neuromodulators
neurotransmitters
para/auto-crines
**NOT HORMONES**
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Internalization of Ro
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clathrin-coated pits
endocytosis --> endosomes fuse w/ lysosomes -->endolysosomes
Proteolysis
protein digestion
internalized occupied receptors either go for degradation or they are recycled
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Endocytosis of Ro
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receptor "down-regulation"
= reduction in membrane R
common in peptides, proteins, & biogenic amines
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Membrane Receptor Types
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G-protein couple receptors (use 2nd messengers)
receptors w/ inherent enzyme activity
receptors that are ion channels (mostly neurotransmitter receptors)
2 & 3 DO NOT need 2nd messengers
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G-Proteins
(first need to activate AC or cAMP to start cascade of g-proteins)
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bind GTP --(GTPase)--> GDP
G-proteins ediate the action of Ro
set activity of signal generating proteins
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G-proteins
A. are membrane bound proteins that contain 3 subunits and aid receptor function.
B. dissociate when a receptor is activated.
C. have subunits that activate other membrane proteins to relay a signal to the cell.
D. all of the above
E. none of those above …
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D. all of the above
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Gs = stimulatory G protein
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E + beta-aR --> Gs --> signal generating protein (AC)
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inactive state of G protein
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y-b-a-GDP
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active state of G protein
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a-GTP
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alpha sub unit on G protein does what?
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releases GDP
binds GTP
separates from B-Y unit
binds/activates AC
hydrolyzes GTP--> GDP
separates from AC
recombines w/ B & Y
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Gs directly activates what/ Gi directly inhibits what?
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AC
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cholera toxin
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increases
Gs activity
AC, cAMP
H2O & ion secretion in gut
opium was used to cure this back in the day
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Gq pathway?
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activate phospholipase c>lipids to PIP2>DAG and IP3
DAG>protein kinase c
IP3>increased intracellular calcium
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receptors w/ inherent enzyme activity
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do not need 2nd messengers to function
there is no signal generating protein
ex. Kinases
tyrosine kinase, serine kinase
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receptors may be ion channels
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can depolarize or hyperpolarize cell
can allow Ca++ influx (can be 2nd messenger)
does not necessarily need 2nd messenger
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other effects of 2nd messenger (cross talk)
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one messenger can effect another messenger via common intracellular pathways
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Transcription factors
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orphans
no known ligand
ex AhR, SF-1 receptor
ligand activated
ligand activated transcription factors (LATFs)
ex. steroid receptors, thyroid receptors, retinoid acid receptor, 1,25-dihydroxy (vit. d receptor)
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Steroid receptors
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Estrogen Receptors (ERs)
Androgen Receptors (ARs)
Corticoid receptors (CRs)
Progesterone receptors (PRs)
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estrogen receptors (ERs)
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ER-alpha, ER-beta
different affinities for various ligands
promiscuous
E1 E2 E3 (SERMS)
phthalates, BPA, nonylphenol, pesticides, etc.
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androgen receptors (ARs)
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two isoforms: A & B
DHT (highest affinity)
testosterone (2nd highest)
androstenedione (AND) (3/4 highest)
dehydroepiandrosterone (DHEA) (3/4 highest)
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corticoid receptors
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mineralocorticoid receptor (MR)
type I GR (GR-1)
B, F > Aldosterone
glucocorticoid receptor (GR)
type II GR (GR-2(
binds only corticosterone (B) or cortisol (F)
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progesterone receptors (PRs)
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two isoforms: PR-A, PR-B
progesterone is most common progestogen ligand
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Thyroid Receptors
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TRα (most tissues: cardiac & skeletal)
TRβ1 (brain, liver, kidney)
TRβ2 (hypothalamus, pituitary)
alpha and beta come from 2 different genes, made in different tissues
heterodimers
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Retinoic Acid Receptors
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RXR: retoid X receptor (orphan)
heterodimer
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Aryl hydrocarbon receptor (AhR)
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no endogenous ligand
binds PCBs, dioxins
increases liver detox enzymes
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SF-1 (steroidogenic factor-1)
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orphan
important transcription factor
numerous roles including sexual differentiation
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Nuclear receptors
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are found intracellularly (usually)
some are cytosolic (CR)
some occur in nucleus (ER, TR)
some are in cytosol in one cell & nucleic in others (AR, PR)
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structure of nuclear receptor (domains)
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ligand binding (LBD)
DNA binding (DBD)
dimerization (bind to coregulators)
ATF-1 (transactivating)
ATF-2 (transactivating)
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Hormone response element (HRE)
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in promoter region of gene
increases transcription
zinc fingers attach here
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Actual receptor complex
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receptor protein + chaparone proteins =
heatshock proteins
hsp70
hsp90
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structure of nuclear receptors (glucocorticoid receptor)
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L + GR (in cytosol)--> Loss of HSP70--(phosphorylation)--> Transportosome--> Translocaiton to nucleus--> Dimerization (homodimer)
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Progesterone Receptor (in depth)
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multi step process, usually cytosolic
PR usually tethered to chaperone proteins
glucocorticoid binds to receptor which allows for the extension of the zinc fingers
2 receptors come together & form dimer, then they bind themselves to DNA w/ the help of nuclear receptor coregulators
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what do coregulators bind to dimer formation?
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in order to recruit transcription apparatus
RNA polymerase does this
coregulators bind to ATF domains
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ATF 1 & 2 domains
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coregulators bind to ATF’s
coregulators very specific for receptors and ATF’s
coregulators very important for steroid activation
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cytoplasmic conversion
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lots of ligands go under transformation once they pass thru cytoplasmic wall
ex. T --(P450aro)--> E2
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steroid binding proteins
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not very soluble in plasma
majority use binding/carrier proteins
binding proteins <-->steroid <--> target cell
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which domain of AR, PR, and GR likely shares the greatest similarity?
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DNA binding domain (zinc fingers)
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Activation of nuclear receptors usually produces a ____ response than membrane receptors
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slower
exceptions:
peptides can have genomic effects
steroids can have non-genomic effects
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cell membrane rapid responses
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corticosterone
progesterone
estradiol
androgens
vit. d
steroids can infrequently bind to cell membrane receptors
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nature of the membrane steroid receptors
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may be "nuclear unclear"
may be unique steroid receptor
may be allosteric sites on other receptors
some steroid hormones have been known to bind to allosteric sites, which alter the cells response & also have rapid effect
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releasing hormones (RHs)
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RH = increase tropic hormone secretion
RIH = decrease tropic hormone secretion
produced in the hypothalamus
transported to & stored in median eminence ME
released from ME--> portal system--> adenohypophysis
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all RIHs come from?
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hypophysiolotropic nuclei
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all RHs are contained in?
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portal system
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Tropic hormones (TRs)
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GH
PRL
TSH
ACTH
LH / FSH
MSH
all produced/released in adenohypophysis
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Nonapeptides
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Oxytocin (OXY)
Arginine vasopressin (AVP)
antidiuretic hormone (ADH) in humans
produced in hypothalamus
stored in & released from neurohypophysis to general circulation
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Hypothalamus
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releasing hormones (RH & RIH)
produced in neurosecretory nuclei
axons project to ME
hypothalamo-hypophysial portal system
a circ. that begins/ends in cap. beds
nonapeptides
produced in neurosecretory nuclei
axons project to neurohypophysis then gen. circ.
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advantages of portal system
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speed
prevents
degradation
dilustion
RHs cannot be found in general circ.
can't measure RHs in humans
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adenohypophysis
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adeno = gland
glandular portion of pituitary
secretes tropic hormones
3 parts:
PD / PI / PT
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pars distalis (PD)
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FSH, LH --> gonads
TSH --> thyrotropin
GH --> somatotropin/growth
PRL --> mammary, testes
ACTH --> adrenal cortex
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gonadotrope
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produce gonadotropins
FSH, LH
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thyrotropes
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produce thyrotropins
TSH
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somatotropes
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produce somatotropins
GH
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lactotropes
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produce lactotropins
PRL
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corticotropes
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produce corticotropins
ACTH
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pars intermedia
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produces melanocyte-stimulatin hormone (MSH)
melanotropin
MSH--> pigment cells
produced by melanotropes
lose PI as we age
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pars tuberalis
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some tropic hormones made here
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what is the major hormone in the ME?
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releasing hormone
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what are the major hormones in portal vessels?
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releasing hormones
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major hormones found in pars distalis?
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releasing hormones and tropic hormones
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major hormones found after pars distais?
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tropic hormones
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major hormones found after pars nervosa?
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nonapeptides
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Neurohypophysis (extension of hypothalamus)
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pars nervosa (PN)
stores & releases nonapeptide hormones
Median Eminence (ME)
stores & releases RHs & RIHs
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neurosecretory nuclei that make nonapeptides
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SON (supraoptic nucleus)
PVN (paraventricular nucleus)
both have small axons that start in the hypothalamus and travel to the Pars Nervosa
both make OXY & AVP
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Major Releasing Hormones (RH) in ME
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TRH (thyrotropin)
CRH (corticotropin)
GnRH (gonadotropin)
GHRH (growth hormone)
GH-RIH (somatostatin SST)
PRIH (prolactin release-inhibiting hormone)
aka DOPAMINE
ALL ARE PEPTIDES EXCEPT DOPAMINE
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other hypothalamic hormone stored in ME
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PRL
GAP (gonadotropin releasing hormone associated peptide
part of GnRH prohormone
VIP (vasoactive intestinal peptide)
GTH
NPY (neuropeptide Y)
Galanin
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Hypothalamic hormone stored in pars nervosa
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oxytocin (OXY)
arginine vasopressin (AVP)
lysine vasopressin (LVP-only in pigs)
phenypressin (found in kangaroos)
arginine vasotocin (AVT- only in babies not adults, helps w/ h2o content in amniotic fluid)
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Hypothalamic control (evidence in-vitro)
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Pars distalis culture
secrete only PRL
add hypothalamus extract (ME)
secrete TSH, GTHs, ACTH, sometimes GH
except PRL**
most hormones are stimulatory but PRL & GH are inhibitory
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Who discovered the first RHs and what are they?
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Andrew Schalley & Roger Guillemin (shared nobel prize)
TRH (tripeptide)
GnRH (decapeptide)
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what is the only hormone that is not made in the Pars distalis and is made in the pars intermedias
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MSH
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AVP
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secreted by PVN & SON
can sometimes end up in ME and be secured as regulatory hormone --> becomes stimulatory for ACTH
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Pars tuberalis
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little tropic hormone synthesis
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Pars intermedia
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secretes MSH
melanocyte-stimulating hormone
Melanotropin
cell type= melanotropes
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Pars distalis (tropes)
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gonadotropes (FSH, LH)
lactotropes (prolactin)
somatotropes (growth hormone)
corticotropes (ACTH)
thyrotropes (TSH)
Acidophils (stain w/ acidic dyes)
Basophils (stain w/ basic dyes)
non granulated cells (don't stain)
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Basophils (strong)
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Gonadotrope
gonadotropins (GTHs) = LH & FSH
Thyrotrope (TSH)
secretory granules secrete GTHs
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Basophils (weak)
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corticotrope --> ACTH
melanotrope --> MSH
same size granules just in less abundance
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Acidophils
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somatotrope (GH)
GH good for storing amino acids which further up regulate glucose
lacotrope (PRL)
mammosomatotrope
only in women that are pregnant
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Melantropes
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made in pars intermedia when we are babies
PI disappears as we age so melanotropes migrate to the pars distalis
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nongranulatedcell types
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chromophobes
undifferentiated / exhausted (no more secretory granules)
Null Cell
follicostellate cells (most important type)
glial cells in origin (we think)
connect thru gap junctions
possible role in Ca2+ signals
secrete paracrine
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Tropic Hormones (chemical classification)
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glycoproteins
simple "proteins"
POMC complex of peptides
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Glycoproteins
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TSH - thyroid gland
LH
androgen synthesis
gamete release
corpus luteum
FSH
androgens
gamete formation
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glycoprotein stucture
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2 units
α (common to all)
excess of subunits
β (unique to each)
confers special identity to each hormone
subunits are limited
regulation on subunit gene
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simple "proteins" (GH)
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in muscle:
increase AA uptake & protein synthesis
in liver:
IGF-1 synthesis + cartilage growth (lengthens)
acts as endocrine cell
in bone:
IGF-1 synthesis + bone growth (grows wider)
acts as paracrine cell
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somatomedin
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IGF-1 that mediates effects of somatotropin
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GH needs to go thru ___ in order to stimulate IGF-1 to stimulate growth
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liver
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Simple "protiens" (PRL)
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structurally similar to GH
bionic hormone b/c a lot of tissues in our body react to it
PRL in mammary glands:
stimulates the production of milk
increases protein synthesis & many other targets
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chemistry of simple proteins (GH & PRL)
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both have single polypeptide chain
both have about 200 AA's
both have S-S bonds (sistine)
GH has 2
PRL has 3
considerable overlap in AA sequence
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GH & PRL may occur in oligomeric forms
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GH monomer
GH dimer (big GH)
GH trimer (bigger GH)
when GH travels throughout the blood, it usually does not travel as a monomer
Exact same story for PRL
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how does GH travel throughout the blood?
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GH binding protein
GHR located on cell membrane sometimes falls off into the circulation and bind to GH which allows it to travel thru the blood
GH is water soluble and should be able to travel thru the blood w/o a binding receipt
this is an exception because it needs the binding prote…
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POMC peptides
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ACTH + adrenal cortex
Pars distalis
increases glucocorticoid (GC)
MSH + melanocytes
pars intermedias
EOPs (endogenous Opioid Peptides)
POMC is a large enzyme and depending where you cleave it, will determine whether or not it will be ACTH or MSH or EOPs
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Endorphins comes from what?
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Endogenous morphine
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EOPs examples
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Enkepalins
dynorphins
both only in the CNS
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different EOPs have different prohormones
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POMC --> Endorphins
Proenkephalin --> Enkephalins
Prodynorphins --> Dynorphins
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chemistry of POMC
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all peptides derived from same pro hormone
Pro-Opio-Melano-Cortin = POMC
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what peptide derivatives are in the Pars distalis?
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ACTH (39AA)
beta-LPH (91 AA)
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what peptide derivatives are in the pars intermedia
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ACHT-gamma-LPH
made up of alpha-MSH & CLiP
gamma-LPH is not important
beta-END (31AA)
alpha-MSH (1-13 AA of ACHT**)
CLiP (Corticotropin-like peptide)
biologically inactive
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which peptides are the most biologically active?
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ACTH
B-END
A-MSH
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if you treat B-LPH w/ an enzyme from a melanocyte, what would you make?
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B-END
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if you inject high doses of ACTH into an animal, what would happen?
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glucocorticoid levels would go up
the animal would turn darker
ACTH is binding to MSH receptor which makes the animal darker
the first 13 AAs of ACTH is MSH)
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affinity of opioids for major opioid receptor types
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micro receptor
morphine / naloxone (antagonist) / B-END
delt receptor
Enkephalins
kappa receptor
Dynorphin
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feedback loop in gonadal track
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gonadal steroids have negative feedback on both the hypothalamus and the pituitary gland
long-loop feedback includes the lowest/last substance made and relating back to the beginning of the pathway
short loop feedback rarely observed
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IPHY 4440: EXAM 2