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FUNCTION OF SIGNALING
MOLECULES
Nela Pavlíková
nela.pavlikova@lf3.cuni.cz
1
HYPOTHALAMUS AND PITUITARY GLAND
2
LIBERINS
„thyrotropin-releasing
hormone“ (TRH) „growth hormone-releasing
hormone“ (GHRH)
„gonadotropin-releasing hormone“ (GnRH)
„corticotropin-releasing
hormone“ (CRH)
3
HYPOFYSEAL STATINS
dopamine (prolactin-inhibiting hormone,
PIH)
somatostatin (growth hormone-inhibiting
hormone, GHIH)
4
POSTERIOR PITUITARY GLAND
Vasopressin (ADH) oxytocin
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
= POLAR MOLECULE
Transport in blood: OK
Transport across the membrane: NO
cholesterol
precursor for steroid hormones
= NON-POLAR MOLECULE
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: Non-polar:
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
Receptor:
- G-protein coupled
- ovary, uterus, testicles
LH
Receptor:
- G-protein coupled
- activated also by hCG
- found also in skin, thyroid
gland, …
15
ESTROGENS
17b-estradiol estriol estron
Receptor: estrogen receptor
- nuclear receptor, 2 types (ERa, ERb)
- acting as homodimers
ORGANOCHLORINE
PESTICIDES - 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
DDT DDE
17
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
18
ANDROGENS
testosterone
Receptor: androgen receptor
disruption: DDE, 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
HCHa
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PROGESTERONE
hypothalamus:
GnRH → adenohypophysis:
FSH, LH
↓
ovary: ←
progesterone
progesterone
Receptor: progesteron receptor
- nuclear receptor
- acting as homodimer
disruption: bisphenol A
ale
HORMONY AKTIVUJÍCÍ NUKLEÁRNÍ
RECEPTORY
22
HORMONES ACTIVATING NUCLEAR
RECEPTORS
Estrogens (estradiol)
Androgens (testosterone)
Progesterone
Glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
Retinoids (ATRA)
Hormones of thyroid gland (thyroxin, triiodothyronine)
Vitamin D (cholecalciferol)
cholesterol = a source for steroid
hormones synthesis
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), . . .
24
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
25
ADRENOCORTICOTROPIC HORMONE
Hypothalamus:
CRH (corticotropin-releasing
hormone)
↓
Adenohypophysis:
ACTH (adrenocorticotropic
hormone)
Target: adrenal cortex (→ synthesis of glucocorticoids (cortisol) )
(glucose + cortex + steroid = glucocorticoid)
Receptor:
- G-protein coupled
ACTH
GLUCOCORTICOIDS
hypothalamus:
CRH → adenohypophysis:
ACTH
↓
adrenal cortex: ←
cortisol
cortisol
Receptor: glucocorticoid receptor
- nuclear receptor
- acting as homodimer
Polybrominated dibenzoethers
- 209 congeners
- bioaccumulation
- penta, octa – ended 2004
- deca – production continues
• Toxicity: carcinogenic
neurotoxic
- learning, memory,
hepatotoxic
developmental disorders
(bones)
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• Endocrine disruption: ThR (↓, brain development disorder)
GcR (↓, hydroxy-PBDEs)
AhR (agonism, antagonism)
Polybrominated dibenzoethers
bis(2-ethylhexyl) tetrabromophthalate
(TBPH)
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MINERALOCORTICOIDS
renin – angiotensin – aldosterone
vasopressin (ADH), ACTH
transport of ions and water
aldosterone
Receptor: mineralocorticoid receptor
- nuclear receptor
- act as homodimer
- aldosterone, deoxycorticosteron,
glucocorticoids
THYROTROPIN
Hypothalamus:
TRH (thyrotropin-releasing
hormone)
↓
Adenohypophysis:
TSH (thyrotropin, thyroid-
stimulating hormone)
Target: thyroid gland
→ secretion of thyroxin (T4)
and triiodothyronin (T3)
Receptor:
- G-protein coupled (GaS)
TSH
HORMONES OF THYROID GLAND
HORMONES OF THYROID GLAND
Triiodothyronine (T3)
Thyroxine (T4)
In blood: very small concentrations of
free hormones → diagnostics
transport into cell: transporters
Target: the whole organism
They increase basal metabolism
- growth and development of organism
- synergism with growth hormone
- gigantism, nanism, goiter
disruption: bisphenol A (antagonist) Receptor: „thyroid receptor“
- nuclear receptor
- acting as monomer, homodimer or
heterodimer with RXR
- 2 subtypes (TRa, TRb)
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)
PFOS (perfluorooctane sulfonate)
PFOA (perfluorooctanoic acid)
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,
support of bone
mineralization,
growth of internal organs)
Receptor: coupled with enzyme
tyrosine kinase:
„JAK-STAT“ signaling pathway
+ indirect effect (IGF-1)
PROLACTIN
Hypothalamus:
dopamine
↑dopamine in hypothalamus
= ↓ prolactin in adenohypophysis
Production: adenohypophysis
uterus, prostate,
lymphocytes,
leukocytes
Target: various tissues
Hormone: heterogenic
Receptor: coupled with tyrosine
kinase
RETINOIDS
37
RETINOIDS
retinol (vitamin A)
all-trans retinoic acid
(ATRA)
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, …)
Diseases: acne
leukemia (APL)
lung cancer
esophagus cancer
disruption → teratogenity,
embryotoxicity
- HCH (pesticides)
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
40
• Toxicity: chloracne
carcinogenic
• Endocrine disruption: AhR (dioxin-like PCBs)
ER (polychlorinated hydroxybiphenyls)
AR (antagonist)
GcR (brain)
Th signalization (transport proteins)
Vitamin D
Polychlorinated biphenyls
41
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
dopamine
- attention and
concentration
- Parkinson d.
- schizophrenia
histamine
- sleep regulation
GABA
-mental relaxation
-antiepileptics
epinephrine
(adrenalin) norepinephrine
(noradrenalin)
- peripheral NS – part of sympathetic
-CNS: attention, concentration
↓ = depression
acetylcholine
- peripheral NS – parasympatethic, part of
sympathetic
- CNS: Alzheimer
Answers on questions
• Can ethanol pass through blood-brain barrier? Yes, even though it looks like polar molekule, it is solubile in both water and fat, so it can pass through the membrane on its own.
• Can amonium (NH3) pass through blood-brain barrier? Yes, and it can cause quite a lot harm in brain.
• Can you overdose yourself with beta-karoten? Yes, if you try hard. In normal doses no, it is even in vitamin pills for pregnant women.
• Does increased extracelular level of Ca++ cause spasm? No, it causes muscular fatigue.
• Does growth hormone influence the involution of thymus? Involution of thymus is caused by increasing levels of sexual hormones.
• Mechanism of skin atrophy caused by glucocorticoid therapy: it decreases proliferation and number of keratocytes, that leads to thinning of epidermis and stratum corneum. The skin is more permeable and loses water.
47
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