INTRACELLULAR SIGNALLING
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1 INTRACELLULAR SIGNALLING R. Benacka,, MD, PhD Department of Pathophysiology Medical faculty, Safarik University 1. Long distance chemo A. Receptors without enzymatic activity c-amp IP3- dependent c-gmp/no PLA2 dependent Ca dependent
2 c AMP- dependent Trigger: many hormons, transmitters, cytokines Membrane G.protein coupled receptors Stimulatory & inhibitory transfer (Gs( or Gi) Effectors: Adenyl cyclase camp - PKA Effects cts: widespread Immediate: phosphorylation of proteins Late: gene expression IP3 / DAG Trigger: many hormons, transmitters, cytokines Membrane G.protein coupled receptors (Go) Both stimulatory & inhibitory influence Effectors: Phospholipase C (PLC) DAG, IP3 - PKC Effects cts: widespread Immediate: phosphorylation of proteins Late: gene expression
3 cgmp MP/NO Triggers: A. Ca2+ - B. ANP,BNP C. NO - donors Membrane G-protein G coupled receptors + Membrane receptors with GC activity Effectors: NO, cgmp - PKG Effects cts: phosphorylation of proteins Use: - vascular smooth muscle dilation - vision, etc. PLA2 dependent G-protein coupled receptors Use: supplementar to IP3- dependent Phospholipase A2 (PLA2) Arachidonic acid (AA) 2nd messeng.: AA derivatives Leucotriens (LT) Prostaglandins (PG) Tromboxans (TX) Epoxides (EPX) HETE Interactions with other s: : camp, cgmp, JAK/STAT, MEK
4 Ca 2+ - dependent Ubiquitous,, of particular importance in skeletal & smooth muscles, nervous sy. Trigger: any rise e of cytosolic [Ca 2+ ]i Effectors: calmodulin (CaM) Ser/Thr kinase Effects: Immediate: phosphorylation/ dephos-phorylation phorylation Late: gene transcription Use: trasmission of excitatory processes 1. Long distance chemo B. Receptors with enzymatic activity c-amp IP3- dependent c-gmp/no PLA2 dependent Ca dependent
5 Classical growth Trigger: growth factor familes Receptors with enzymatic activity Effectors: Ras switch MAPK cascade Effect: Gene transcription Use: proliferative & growth process mitosis Stress Trigger: growth factor familes physical : UV, X-rays, temp. chemicals Receptors with enzymatic activity Effectors: Ras switch MAPK cascade Effect: Gene transcription Usage: proliferative & growth process (mitosis) adaptations
6 Signalling via PI-3K Trigger: growth factor familes Receptors with enzymatic activity Effectors: PI3K PKB, PDK Effect: Gene transcription Vesicular transportation Apoptotic machinery Fosforylation of proteins Use: proliferative & growth process control Signalling through JAK/STAT Membrane receptors with associated enzymatic activity Trigger: : IL-2, IL.4, IL-6 family, GH, PRL EPO Effectors: : SMAD family Effect: early responses gene expression Use: growth & differentiation processes
7 Signalling via SMAD Mutiunite membrane receptors with enzymatic activity Trigger: TGF & BMP factors Effectors: SMAD family Effect: delayed - gene expression Use: growth & differentiation processes Signalling via nuclear receptors Trigger: gonadosteroids, retinoids adrenocorticosteroids, T4/T3, vitd3, deoxycholesterol, PGJ2, LTB4, fatty acids?, bile acids Effect: gene transription
8
9 Signalling via Toll receptors Trigger: components of bacterial body, chemicals Effectors: IRAK, TRIF, TIRAP Effect: modifing other pathways Use: Component of innate immune response Inflammation specific response to antigen Signalling via NFkB Trigger: TNF.alpha family Effectors: TRAF, TRADD, RIP Effects: Gene expression Use: wide spead immune reactions
10 a 2. Close contact chemo BCR TCR Wnt +β-catenin DSL-Notch Hedgehog
11 BCR Trigger: antigen Receptors multicomponent Ig-family Effectors: Growth pathway (Ras- Raf-MEK-ERK) Stress pathway (Rac- MEKK-Jnk,P38) Ca 2+ -CaM pathway Effect: Gene transcription Use: proliferation (mitosis) synthesis of new proteins TCR
12 BCR is formed by membrane-bound IgM (migm) TCR is formed by special alpha and beta Ig chains Wnt + b - catenin
13 DSL-Notch
14 Hedgehog Trigger: Hh family Receptors: Ptc patched Smo smoothed Effect: Gene expression Other s Use: Control over prolifertion & differentiation
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