Download FUNCTION OF SIGNALING MOLECULES

FUNCTION OF SIGNALING
MOLECULES
Nela Pavlíková
[email protected]
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
Ø Transport in blood: OK
Ø Transport accross the
membrane: NO
Ø Transport in blood: carrier
(protein)
Ø Transport accross 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
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
HYPOTHALAMUS
Hypothalamic hormones
transported to the
neurohypophysis:
Ø Antidiuretic hormone (= ADH,
vasopressin)
Ø Oxytocin
Ø forms the ventral part of the
diencephalon
Ø represents the connection
between the nervous system
and the endocrine system
Hypothalamic hormones
controlling the hormone secretion
in adenohypophysis:
Ø Liberins (THRH, GHRH, GnRH,
CRH)
Ø Statins (dopamine, somatostatin)
ANTIDIURETIC HORMONE
(VASOPRESSIN)
Ø peptide hormone
Ø synthesized in hypothalamus →
transported along axons into
neurohypophysis, where it is
stored in vesicles → most are
released into blood, a part into the
brain
Ø Target: kidney (it influences the
reabsorption of molecules
from tubules)
cardiovascular system
(↑ peripheral vascular
resistance → increasing of
blood pressure)
brain (influence on social
behavior)
Ø receptor: on the cell surface
- G-protein coupled
3 subtypes (2xGq, 1xGs)
BLOOD-BRAIN BARRIER (BBB)
adenohypophysis + neurohypophysis + „median eminence“ of hypothalamus
is outside the barrier
OXYTOCIN
Ø peptide hormone
Ø synthesized in hypothalamus →
transported along axons into
neurohypophysis, where it is
stored in vesicles → most are
released into blood, a part into the
brain
Ø Target: breast (stimulation → milk
production)
uterus (it induces contractions)
brain („love hormone“)
Ø receptor: on the cell surface
- G-protein coupled
- Gaq type
LIBERINS
growth hormone-releasing
hormone (GHRH)
thyrotropin-releasing
hormone (TRH)
corticotropin-releasing
hormone (CRH)
Receptors:
Ø in adenohypophysis
Ø G-protein coupled
gonadotropin-releasing hormone (GnRH)
STATINS
dopamine (prolactin-inhibiting hormone, PIH)
Ø neurotransmitter
Ø Receptors:
- G-protein coupled
- 5 types: Gas (D1, D5)
Gai (D2, D3, D4)
somatostatin (growth hormone-inhibiting
Hormone, GHIH)
Ø besides in the brain it is produced
also in GIT
Ø Receptory: G-protein coupled
5 types
HORMONES OF ADENOHYPOPHYSIS
Ø adrenocorticotropic hormone
(ACTH)
Ø thyrotropin (TSH)
Ø follicle-stimulating hormone (FSH)
Ø luteinizing hormone (LH)
Ø growth hormone (somatotropin)
(GH, STH)
Ø prolactin (PRL)
ADRENOCORTICOTROPIC HORMONE
Hypothalamus:
CRH (corticotropin-releasing
hormone)
↓
Adenohypophysis:
ACTH (adrenocorticotropic
hormone)
ACTH
Ø Target: adrenal cortex (→ synthesis of glucocorticoids (cortisol) )
(glucose + cortex + steroid = glucocorticoid)
Ø Receptor:
- G-protein coupled
TSH, FSH, LH and hCG
Ø
Ø
Ø
Ø
thyrotropin (TSH)
follicle-stimulating hormone (FSH)
luteinizing hormone (LH)
human choriogonadotropin (hCG) – placenta („pregnancy hormone“)
- glycoproteins
- they have identical alpha-subunit (92 amino acids)
- they differs by their beta-subunit → recognition by receptors
………………..
THYROTROPIN
Hypothalamus:
TRH (thyrotropin-releasing
hormone)
↓
Adenohypophysis:
TSH (thyrotropin, thyroidstimulating hormone)
ØTarget: thyroid gland
→ secretion of thyroxine (T4)
and triiodothyronine (T3)
TSH
ØReceptor:
- G-protein coupled (GaS)
FOLLICLE-STIMULATING HORMONE
(FSH) AND LUTEINIZING HORMONE (LH)
Hypothalamus:
GnRH (gonadotropin-releasing hormone)
↓
Adenohypophysis:
FSH
Ø essential for growth, development
of secondary sex characteristics and
reproduction
Ø Target: sexual organs
(→ maturing of gem cells)
Ø Receptor:
- G-protein coupled
- ovary, uterus, testicles
LH
Ø essential for reproduction
ØTarget: ovary (→ it starts ovulation
and the development of
corpus luteum)
testicle (→ stimulates
testosterone production)
Ø Receptor:
- G-protein coupled
- activated also by hCG
- found also in skin, thyroid
gland, …
GROWTH HORMONE (SOMATOTROPIN)
Hypothalamus:
GHRH
(growth hormone-releasing hormone)
↓
Adenohypophysis:
GH
Ø protein (191 amino acids)
Ø Target: organism (anabolic effect →
increased lipolysis,
increase of muscle muss,
Ø 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
Ø Hormone: heterogenic
Ø Receptor: coupled with tyrosine
kinase
Ø Production: adenohypophysis
uterus, prostate,
lymphocytes,
leukocytes
Ø Target: various tissues
HORMONES ACTIVATING NUCLEAR
RECEPTORS
HORMONES ACTIVATING NUCLEAR
RECEPTORS
HORMONES ACTIVATING NUCLEAR
RECEPTORS
Ø
Ø
Ø
Ø
Ø
Estrogens (estradiol)
Androgens (testosterone)
Progesterone
Glucocorticoids (cortisol)
Mineralcorticoids (aldosterone)
cholesterol = a source for steroid
hormones synthesis
Ø Retinoids (ATRA)
Ø Hormones of thyroid gland (thyroxine, triiodethyronine)
Ø Vitamin D (cholecalciferol)
ESTROGENS
17b-estradiol
estriol
estron
Ø Receptor: estrogen receptor
- nuclear receptor, 2 types (ERa, ERb)
- acting as homodimers
Ø Target: sexual organs (ovary, mammary gland, uterus,
prostate, testis → growth and proper
function)
others (liver, adipose tissue, bones, central and peripheral
nervous system, …)
Ø disruption: DDT, bisphenol A
ANDROGENS
Ø Target: bone marrow
muscles (→ masculinization)
prostate, testis, foreskin
mammary gland
testosterone
Ø Receptor: androgen receptor
- nuclear receptor
- acting homodimer
- testosterone
- dihydrotestosterone
- androstendion
Ø disruption: DDE, HCHa
ale
PROGESTERONE
hypothalamus:
GnRH
→ adenohypophysis:
FSH, LH
↓
ovary: ←
progesterone
progesterone
Ø Receptor: progesteron receptor
- nuclear receptor
- acting as homodimer
Ø disruption: bisphenol A
Ø Target: mammary gland, uterus
ovary
testis
muscles, brain
women – level fluctuation during
menstrual cycle
- maintenance of pregnancy
GLUCOCORTICOIDS
hypothalamus:
CRH
→
cortisol
Ø Receptor: glucocorticoid receptor
- nuclear receptor
- acting as homodimer
adenohypophysis:
ACTH
↓
adrenal cortex: ←
cortisol
Ø Target: the whole organism
→ antiinflammatory effect
metabolism of glucose
→ during starving it tries to
keep normal glucose level
in blood
MINERALCORTICOIDS
Ø renin – angiotensin – aldosterone
Ø vasopressin (ADH), ACTH
Ø transport of ions and water
aldosterone
Ø Receptor: mineralcorticoid receptor
- nuclear receptor
- acting as homodimer
- aldosterone, deoxycorticosteron,
glucocorticoids
Target: kidneys
liver, heart, CNS, adipose
tissue, sweat glands, …
RETINOIDS
retinol (vitamin A)
all-trans retinoic acid
(ATRA)
Diseases: acne
leukemia (APL)
lung cancer
esophagus cancer
disruption → teratogenity,
embryotoxicity
- HCH (pesticides)
Ø Retinoid acid receptor (RAR)
- nuclear receptor
- acting as homodimer / heterodimer
with RXR
- three subtypes (RARa, RARb, RARg)
Ø Retinoid X receptor (RXR)
- nuklear receptor
- acting as homodimer / heterodimer
with various receptors
- three subtypes (RXRa, RXRb, RXRg)
Ø growth and developement of organism
Ø Target: many tissues (brain, liver, kidney,
heart, ovary, testis, …)
HORMONES OF THYROID GLAND
HORMONES OF THYROID GLAND
Triiodethyronine (T3)
Ø In blood: very small concentrations of
free hormones → diagnostics
Ø transport into cell: transporters
Ø Target: the whole organism
Thyroxine (T4)
Ø They increase basal metabolism
- growth and developement of organism
- synergism with growth hormone
- gigantism, nanism, struma
Ø Receptor: „thyroid receptor“
Ø disruption: bisphenol A (antagonist)
- nuclear receptor
- acting as monomer, homodimer or
heterodimer with RXR
- 2 subtypes (TRa, TRb)
VITAMIN D
cholecalciferol
(vitamin D3)
liver: ↓
cholecalcidiol
kidney: ↓
calcitriol
Ø Receptor: vitamin D receptor
- nuclear receptor
- heterodimer with RXR
Ø Target: most of tissues
Ø Regulation of Ca2+ a Pi metabolism
- ↑resorption of Ca2+ a Pi from intestine
Ø deficiency:
rachitis
Ø disruption: PCB
HORMONES OF PANCREAS: INSULIN
Ø synthesis:
- b cells of islets of Langerhans
in pancreas
- stimulus: ↑ glucose in blood
- stored in vesicles
Ø 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
Ø Receptor: coupled with tyrosine
kinase enzyme
→ transporters GLUT4 →
from intracellular vesicles into
plasmatic membrane →
increased intake of glucose to
the cell
Ø Target: muscles, adipose tissue,
heart
Ø disruption: arsen, pesticides
HORMONES OF PANKREAS:
GLUCAGON
Ø synthesis:
- a cells of islets of Langerhans
in pancreas
- stimulus: hypoglycaemia
adrenalin (epinephrine)
Ø Receptor:
- G-protein coupled
(Gas) → PKA
Ø Target: liver, kidney, intestine,
adipose tissue, …
Ø Increase of glucose blood level
HORMONES OF ADRENAL MEDULLA
epinephrine (adrenalin)
norepinephrine (noradrenalin)
Ø synthesis: adrenal medulla (hormones)
axon (neurotransmitters)
Ø Receptors: G-protein coupled
„adrenergic receptors“
a1 (Gq), a2(Gi)
b 1, b 2, b 3 (Gs)
CYTOKINES
Ø
Ø
Ø
Ø
Ø
peptides, proteins, glycoproteins
produced by cells with nucleus: macrophages, epithelial cells, …
autocrine, paracrine but even endocrine (pyrogen) signalization
activation of cell surface receptors
effect on just short distance
Ø Receptors: mostly enzyme coupled (kinases)
chemokines → G-protein coupled receptors
JAK-STAT
INTERLEUKINS
Ø group of cytokines
Ø formerly defined as compounds produced by leucocytes (not all of
them!)
Ø significantly participate on the activity of the immune system
- maturation and development of leucocytes (e.g. IL-2, IL-4)
- direct share in the defense reactions
Ø pro-inflammatory interleukins: e.g. IL-1, IL-6, IL-17
Ø anti-inflammatory interleukins: e.g. IL-10, IL-13
GROWTH FACTORS
Ø mostly proteins
Ø stimulate cell growth, their proliferation and differentiation
Ø examples: epidermal growth factor (EGF)
nerve growth factor (NGF)
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