FUNCTION OF SIGNALING

MOLECULES

Nela Pavlíková

nela.pavlikova@lf3.cuni.cz

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HYPOTHALAMUS AND PITUITARY GLAND

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LIBERINS

„thyrotropin-releasing

hormone“ (TRH) „growth hormone-releasing

hormone“ (GHRH)

„gonadotropin-releasing hormone“ (GnRH)

„corticotropin-releasing

hormone“ (CRH)

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HYPOFYSEAL STATINS

dopamine (prolactin-inhibiting hormone,

PIH)

somatostatin (growth hormone-inhibiting

hormone, GHIH)

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POSTERIOR PITUITARY GLAND

Vasopressin (ADH) oxytocin

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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

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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, …

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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

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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

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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

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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), . . .

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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)

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

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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

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• Toxicity: chloracne

carcinogenic

• Endocrine disruption: AhR (dioxin-like PCBs)

ER (polychlorinated hydroxybiphenyls)

AR (antagonist)

GcR (brain)

Th signalization (transport proteins)

Vitamin D

Polychlorinated biphenyls

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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.

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