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 Identification number: TÁMOP /1/A

INTRODUCTION PART 2 Tímea Berki and Ferenc Boldizsár Signal transduction 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 Identification number: TÁMOP /1/A

TÁMOP /1/A Plasma membrane Nucleus Receptor Cytoplasm Signal Chaperone protein Outside of cell Inside of cell Intracellular receptor signaling

TÁMOP /1/A Ligands binding to intracellular receptorsCortisol O HO OH O C CH 2 OH Retinoic acid CH 3 H3CH3C O OH C O C HO I I I I O CH 2 CH NH 2 Thyroxine

TÁMOP /1/A Steroid receptor superfamily DNA binding domain (≈68 aa) Ligand binding domain (≈ aa) 553 Estrogen receptor 946 Progesterone receptor 777 Glucocorticoid receptor 408 Thyroid hormone receptor 432 Retinoid acid receptor COOHNH2 General primary structure Variable region (≈ aa) Amino acid identity 0%42-94%15-57%

TÁMOP /1/A 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 Thr171 Thr547 Ser224 Ser232 Ser246

TÁMOP /1/A Slow Medium slow Rapid Transmembrane currents Phosphorylation events Calcium levels 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 nGREpGRE Transrepression Transactivation Genomic GC effects Nongenomic GC effects IL-2 IBIB STAT NF  B TCR MAPK GC hormone mechanisms

TÁMOP /1/A 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).

TÁMOP /1/A 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

TÁMOP /1/A 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

TÁMOP /1/A 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

TÁMOP /1/A 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

TÁMOP /1/A Environmental stimuli as signal 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

TÁMOP /1/A 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„.

TÁMOP /1/A MyD88 TRIF TLR3TLR7 TLR2 PKA TAK1 PKR MKKs lBlB lBlB p50 p65 MyD88 LPS TLR4 MyD88 MD2 LBP dsRNA TBK1 IKK  MDA-5 RIG-1 IPS1 TLR9 JAK2 mTOR PI3K CD14 TLR types