Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

INTRODUCTION PART 2

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

Plasma membrane

Nucleus Receptor

Cytoplasm

Signal

Chaperone protein Outside of cell

Inside of cell

Intracellular receptor signaling

Ligands binding to intracellular receptors

Cortisol O

HO OH

C O

CH₂OH

Retinoic acid CH₃

CH₃ CH₃ CH₃

H₃C O

OH C

O OH HO C

I I

I I

O CH₂ CH

NH₂

Thyroxine

Steroid receptor superfamily

DNA binding domain (≈68 aa)

Ligand binding domain (≈225-285 aa)

553 Estrogen receptor

946 Progesterone receptor

777 Glucocorticoid receptor

408 Thyroid hormone receptor

432 Retinoid acid receptor

COOH

NH2 General primary structure

Variable region (≈100-500 aa) Amino acid

identity 0% 42-94% 15-57%

1

1

1

1

1

Glucocorticoid receptor phosphorylation

GR phosphorylation sites:

• Thr171 – Glycogen synthase kinase-3 (GSK-3)

• Ser 224 and 232 – Cyclin-dependent kinases (CDK)

• Ser246 – JNK

• Thr547 – p38 - MAPK → GCR inhibition

1 2 3 4

5

Thr 171

Thr 547 Ser

224 Ser 232

Ser 246

Slow Medium slow Rapid

Transmembrane currents Phosphorylation events

Calcium levels

Plasma membrane

Cytoplasm

Glucocorticoid

mGR

cGR Specific cGR dependent effects

Specific mGR

dependent effects Nonspecific GC effects

GRE TF

nGRE pGRE

Transrepression Transactivation

Genomic GC effects Nongenomic GC effects

IL-2 IkB

STAT

NFkB TCR

MAPK

GC hormone mechanisms

Hormones are classified into three categories based on their structure

• Peptides: Comprises most hormones, including those secreted by the hypothalamus, anterior and posterior pituitary, pancreas and parathyroid.

• Amines: Derived from the amino acid, tyrosine, and include the hormones secreted by the thyroid gland, and adrenal medulla. Adrenomedullary hormones are called

catecholamines.

• Steroids: Neutral lipids derived from cholesterol; include hormones secreted by the adrenal cortex, ovaries and testes. Steroid and thyroid hormones are lipid soluble (lipophilic).

Primary hormone-secreting glands

• Pituitary gland (anterior pituitary) secretes GH which is a

protein stimulating protein synthesis and growth (depression at bottom of skull just over back of roof of mouth)

• Hypothalamus

• Pineal gland secretes melatonin, a modified amino acid to hypothalamus for sleep

The other hormone-secreting glands are:

• Sex organs (gonads)

– Ovaries: androgens and progesterones – Testes: androgens

• Adrenal glands

– Adrenal medulla secretes epinephrine, norepinephrine, modified amino acids stimulate fight-or-flight response (increase heart, redistribute blood to

muscles, raise blood sugar)

– Adrenal cortex secretes glucocorticoids (cortisol), steroids targeting muscles, immune system, and other tissues to mediate response to stress, reduce metabolism of glucose, increase metabolism of proeins and fats, reduce inflammation and immune responses

• Thyroid gland secretes calcitonin, which is a peptide acting on bones to stimulate bone formation and lower blood calcium, parathyroid raises blood calcium

• Pancreas secrets insulin and glucagon

Other Chemical messengers

• Cytokines

• Interferons are proteins released when a cell has been attacked by a virus. They cause neighboring cells to produce antiviral

proteins. Once activated, these proteins destroy the virus

• Prostaglandins are fatty acids that behave in many ways like hormones. They are produced by most cells in the body and act on neighboring cells

• Pheromones are chemical signals that travel between organisms, rather than between cells within an organism. In the animal world, pheromones are heavily used to mark territory, signal prospective mates and to communicate. The presence of a pheromone as a human sex attractant has not been established

Basic characteristics of cytokines

• Low molecular weight (10-40 kDa) glycoproteins

• Isolated cells secrete them, due to gene activation

• They mediate cell-cell interaction:

– Sending information

– Regulation of immune response

• Mechanism of action:

– Produced after transient gene activation

– Act through receptors triggering signal transduction – High affinity

– Picomolar concentration

• They act mostly locally

initiators

• Microbial products: viral nucleotides, bacterial

lipopolysaccharides stimulate TLR, and protein antigens B cell and T cell receptors

• Physical stimuli: light striking cells in the retina of the eye, odorants binding to odorant receptors in the nasal

epithelium, bitter and sweet tastes stimulating taste receptors in the taste buds

Toll-like receptors (TLRs)

• They are single, membrane-spanning, non-catalytic

receptors that recognize structurally conserved molecules derived from microbes.

• They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'.

The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as

"That´s wild„.

MyD88 TRIF TLR3 TLR7

TLR2

PKA TAK1 PKR

p38 JNK

MKKs lkB

p50 p65 MyD88

LPS

TLR4

MyD88 MD2 LBP

dsRNA

TBK1 IKKe

MDA-5 RIG-1

IPS1 TLR9

JAK2

mTOR PI3K CD14

TLR types