Download Receptor

FUNCTION OF SIGNALING
MOLECULES
Nela Pavlíková
[email protected]
1
HYPOTHALAMUS AND HYPOPHYSIS
2
NEUROHYPOPHYSIS
Vasopressin (ADH)
oxytocin
3
LIBERINS
„growth hormone-releasing
hormone“ (GHRH)
„thyrotropin-releasing
hormone“ (TRH)
„corticotropin-releasing
hormone“ (CRH)
„gonadotropin-releasing hormone“ (GnRH)
4
HYPOFYSEAL STATINS
dopamine (prolactin-inhibiting hormone,
PIH)
somatostatin (growth hormone-inhibiting
hormone, GHIH)
5
Charge in cell / organism
molecules
negatively charged
neutral
positively charged
Ca++, Mg++, H+
-NH3+
CH2=CH-Cl
↨
CH2=CH+ + Cl-
POLAR / NON-POLAR MOLECULES
adrenalin (epinephrine)
signaling molecule
cholesterol
precursor for steroid hormones
= POLAR MOLECULE
= NON-POLAR MOLECULE
 Transport in blood: OK
 Transport across the
membrane: NO
 Transport in blood: carrier
(protein)
 Transport across the
membrane: OK
CHOLESTEROL
•
•
•
•
High-density lipoprotein (HDL)
Intermediate-density lipoprotein (IDL)
Low-density lipoprotein (LDL)
Very low-density lipoprotein (VLDL)
ratio of protein part vs. lipid part
binding: non-polar interactions
9
Non-polar interactions
SIGNALING MOLECULES – EXAMPLES
Polar:
• neurotransmitters
(acetylcholine,
dopamine, serotonin, epinephrine,
norepinephrine, GABA,
histamine,…)
• hormones of hypothalamus
• hormones of adenohypophysis
and neurohypophysis
• hormones of pancreas (insulin)
•
•
•
•
Non-polar:
steroid hormones (estrogen,
testosterone, progesterone,
aldosterone, cortisol, . . .)
retinoids (ATRA)
vitamin D + derivatives
hormones of thyroid gland
BLOOD-BRAIN BARRIER (BBB)
adenohypophysis + neurohypophysis + „median eminence“ of hypothalamus
is outside the barrier
HORMONES OF ADENOHYPOPHYSIS
 adrenocorticotropic hormone
(ACTH)
 thyrotropin (TSH)
 follicle-stimulating hormone (FSH)
 luteinizing hormone (LH)
 growth hormone (somatotropin)
(GH, STH)
 prolactin (PRL)
FOLLICLE-STIMULATING HORMONE (FSH)
AND LUTEINIZING HORMONE (LH)
Hypothalamus:
GnRH (gonadotropin-releasing hormone)
↓
Adenohypophysis:
FSH
LH
)
 Receptor:
- G-protein coupled
- ovary, uterus, testicles
 Receptor:
- G-protein coupled
- activated also by hCG
- found also in skin, thyroid
gland, …
15
ESTROGENS
17b-estradiol
estriol
 Receptor: estrogen receptor
- nuclear receptor, 2 types (ERa, ERb)
- acting as homodimers
estron
ORGANOCHLORINE
PESTICIDES - DDT
DDT
•
•
Dichlorodiphenyltrichloroethane
Synthesized 1874, insecticide
effect discovered 1939 → fight
against typhus, malaria, dengue
•
1848 – Paul Hermann Miller –
Nobel Prize for Medicine
•
•
•
•
cca 40 000t per year
1962 – „Silent spring“
1970 – ban
present: fight against malaria
DDE
17
DDT
•
Toxicity:
genotoxicity
abortions
neurotoxicity (retardation)
„possible human carcinogen“
hypothyroidism→
cretinism
18
DDT – ENDOCRINE DISRUPTION
•
•
•
•
ER: o,p’-DDT , o,p’-DDE (agonists)
AR: DDE (antagonist)
AhR: o,p’-DDT (antagonist)
Th signalization: ↓ TSH, ↓ T3, T4,
binds to TBG (o,p’-DDD)
•
Diabetes – risk factor
–
–
Marine Food Pollutants as a Risk Factor for Hypoinsulinemia and Type 2 Diabetes
Epidemiology. 2011; 22(3): 410-417
Increased Serum Concentrations of Persistent Organic Pollutants among Prediabetic
Individuals: Potential Role of Altered Substrate Oxidation Patterns The Journal of Clinical
Endocrinology & Metabolism. 2012; 97: E1705-E1713
19
ANDROGENS
testosterone
 Receptor: androgen receptor
 disruption: DDE, HCHa
HCHa
Cl
Cl
Cl
Cl
Cl
Hexachlorocyclohexane – pesticide
- in use from the late 40’s of 20th century
Cl
- applicated as a technical mixture of six isomers:
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
alpha
beta
gamma
delta
epsilon
60-70%
5-12%
10-12%
6-10%
3-4%
Cl
eta
minor
-middle 60’s – the only isomer with pesticidal effect is
the gamma isomer (lindane)
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HCHa
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Alpha-(-)-HCH
alpha-(+)-HCH
- 1948-1997: 6 500 000 t alpha-HCH
- stable against light, higher
temperatures and acidic conditions
- half life - pH8, 5°C: 23years
- arctic conditions: alpha-(-)-HCH 23years
alpha-(+)-HCH 6years
22
ale
PROGESTERONE
hypothalamus:
GnRH
→ adenohypophysis:
FSH, LH
↓
ovary: ←
progesterone
progesterone
 Receptor: progesteron receptor
- nuclear receptor
- acting as homodimer
 disruption: bisphenol A
HORMONY AKTIVUJÍCÍ NUKLEÁRNÍ
RECEPTORY
24
HORMONES ACTIVATING NUCLEAR
RECEPTORS





Estrogens (estradiol)
Androgens (testosterone)
Progesterone
Glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
cholesterol = a source for steroid
hormones synthesis
 Retinoids (ATRA)
 Hormones of thyroid gland (thyroxin, triiodethyronine)
 Vitamin D (cholecalciferol)
Polychlorinated dibenzodioxins (PCDDs)
and dibenzofurans (PCDFs)
 PCDDs: 75 congeners
 PCDFs: 135 congeners
 from 210 are 17 highly toxic
 Trace contaminants of
industrial and thermal
processes
 Hepatotoxic, carcinogenic,
teratogenic, immunotoxic, skin
damage (chloracne), . . .
26
Agent Orange - TCDD
•
•
•
Mixture of two herbicides → defoliant used in Vietnamese
TCDD = side product (cca 150kg)
Endocrine disruption: ER (antiestrogen)
Th signalization (↑ thyroid hormones degradation)
RAR
AhR
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ADRENOCORTICOTROPIC HORMONE
Hypothalamus:
CRH (corticotropin-releasing
hormone)
↓
Adenohypophysis:
ACTH (adrenocorticotropic
hormone)
ACTH
 Target: adrenal cortex (→ synthesis of glucocorticoids (cortisol) )
(glucose + cortex + steroid = glucocorticoid)
 Receptor:
- G-protein coupled
GLUCOCORTICOIDS
hypothalamus:
CRH
→
cortisol
 Receptor: glucocorticoid receptor
- nuclear receptor
- acting as homodimer
adenohypophysis:
ACTH
↓
adrenal cortex: ←
cortisol
Polybrominated dibenzoethers
- 209 congeners
- bioaccumulation
- penta, octa – ended 2004
- deca – production continues
•
Toxicity: carcinogenic
neurotoxic
- learning, memory,
hepatotoxic
developmental disorders
(bones)
30
Polybrominated dibenzoethers
•
Endocrine disruption:
ThR (↓, brain development disorder)
GcR (↓, hydroxy-PBDEs)
AhR (agonism, antagonism)
bis(2-ethylhexyl) tetrabromophthalate
(TBPH)
31
MINERALOCORTICOIDS
 renin – angiotensin – aldosterone
 vasopressin (ADH), ACTH
 transport of ions and water
aldosterone
 Receptor: mineralocorticoid receptor
- nuclear receptor
- act as homodimer
- aldosterone, deoxycorticosteron,
glucocorticoids
HORMONES OF THYROID GLAND
THYROTROPIN
Hypothalamus:
TRH (thyrotropin-releasing
hormone)
↓
Adenohypophysis:
TSH (thyrotropin, thyroidstimulating hormone)
Target: thyroid gland
→ secretion of thyroxin (T4)
and triiodothyronin (T3)
TSH
Receptor:
- G-protein coupled (GaS)
HORMONES OF THYROID GLAND
Triiodethyronine (T3)
 In blood: very small concentrations of
free hormones → diagnostics
 transport into cell: transporters
 Target: the whole organism
Thyroxine (T4)
 They increase basal metabolism
- growth and development of organism
- synergism with growth hormone
- gigantism, nanism, goiter
 Receptor: „thyroid receptor“
 disruption: bisphenol A (antagonist)
- nuclear receptor
- acting as monomer, homodimer or
heterodimer with RXR
- 2 subtypes (TRa, TRb)
Perflorinated alkylated substances
(PFASs)
•
•
PFOS (perfluorooctane sulfonate)
PFOA (perfluorooctanoic acid)
PFCAs (perfluorinated carboxylic
acids)
PFOA (perfluorooctanoic acid)
•
surfactants, lubricants,
extinguishing foams, coatings,
food packaging materials. . .
- výroba teflonu a Gore-Texu
•
cumulating in blood, liver and
kidney
long-range transport
•
Perflorinated alkylated substances
(PFASs)
•
Toxicity: abortions, reduced birth weight
changes in lipid homeostasis
effect on immune system
effect on brain development
•
Endocrine disruption: ThR (disrupted signalization on the whole axis)
ER (agonist, effect on aromatase)
PPARs (partial agonist)
GROWTH HORMONE (SOMATOTROPIN)
Hypothalamus:
GHRH
(growth hormone-releasing hormone)
↓
Adenohypophysis:
GH
 protein (191 amino acids)
 Target: organism (anabolic effect →
increased lipolysis,
increase of muscle muss,
 Receptor: coupled with enzyme
support of bone
tyrosine kinase:
mineralization,
„JAK-STAT“ signaling pathway
growth of internal organs)
+ indirect effect (IGF-1)
PROLACTIN
Hypothalamus:
dopamine
↑dopamine in hypothalamus
= ↓ prolactin in adenohypophysis
 Hormone: heterogenic
 Receptor: coupled with tyrosine
kinase
 Production: adenohypophysis
uterus, prostate,
lymphocytes,
leukocytes
 Target: various tissues
RETINOIDS
40
RETINOIDS
retinol (vitamin A)
all-trans retinoic acid
(ATRA)
Diseases: acne
leukemia (APL)
lung cancer
esophagus cancer
disruption → teratogenity,
embryotoxicity
- HCH (pesticides)
 Retinoid acid receptor (RAR)
- nuclear receptor
- acting as homodimer / heterodimer
with RXR
- three subtypes (RARa, RARb, RARg)
 Retinoid X receptor (RXR)
- nuclear receptor
- acting as homodimer / heterodimer
with various receptors
- three subtypes (RXRa, RXRb, RXRg)
 growth and development of organism
 Target: many tissues (brain, liver, kidney,
heart, ovary, testis, …)
VITAMIN D
cholecalciferol
(vitamin D3)
liver: ↓
cholecalcidiol
kidney: ↓
calcitriol
 Receptor: vitamin D receptor
- nuclear receptor
- heterodimer with RXR
 Target: most of tissues
 Regulation of Ca2+ a Pi metabolism
- ↑resorption of Ca2+ a Pi from intestine
 deficiency:
rachitis
 disruption: PCB
Polychlorinated biphenyls
•
•
209 congeners
„dioxin-like“ PCBs - 12
- 4-7 chlorines
- planar structure
•
additives in varnishes, paints,
hydraulic equipment, filling in
transformers, capacitors, inhibitors
of combustion, …
•
70th years: banned
43
Polychlorinated biphenyls
• Toxicity: chloracne
carcinogenic
• Endocrine disruption: AhR (dioxin-like PCBs)
ER (polychlorinated hydroxybiphenyls)
AR (antagonist)
GcR (brain)
Th signalization (transport proteins)
Vitamin D
44
HORMONES OF PANCREAS: INSULIN
 synthesis:
- b cells of islets of Langerhans
in pancreas
- stimulus: ↑ glucose in blood
- stored in vesicles
 glucose → by transporter to the
cell → closing of K+ channel
→ activation of phospholipase C
→ increased concentration of Ca2+
→ releasing of insulin from the cell
HORMONES OF PANCREAS: INSULIN
 Receptor: coupled with tyrosine
kinase enzyme
→ transporters GLUT4 →
from intracellular vesicles into
plasmatic membrane →
increased intake of glucose to
the cell
 Target: muscles, adipose tissue,
heart
 disruption: arsenic, pesticides
HORMONES OF PANKREAS: GLUCAGON
 synthesis:
- a cells of islets of Langerhans
in pancreas
- stimulus: hypoglycemia
adrenalin (epinephrine)
 Receptor:
- G-protein coupled
(Gas) → PKA
 Target: liver, kidney, intestine,
adipose tissue, …
 Increase of glucose blood level
HORMONES OF ADRENAL MEDULLA
epinephrine (adrenalin)
norepinephrine (noradrenalin)
 synthesis: adrenal medulla (hormones)
axon (neurotransmitters)
 Receptors: G-protein coupled
„adrenergic receptors“
a1 (Gq), a2(Gi)
b1, b2, b3 (Gs)
NEUROTRANSMITTERS
serotonin
- psyche
- ↓ = depression
epinephrine
(adrenalin)
dopamine
- attention and
concentration
- Parkinson d.
- schizophrenia
histamine
- sleep regulation
GABA
-mental relaxation
-antiepileptics
norepinephrine
acetylcholine
(noradrenalin)
- peripheral NS – parasympatethic, part of
- peripheral NS – part of sympathetic
sympathetic
-CNS: attention, concentration
- CNS: Alzheimer
↓ = depression