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Pharmacology 1-8 (G protein coupled receptors (Heterotrimeric G protein…

- - - - Gq binds PLC - catalyses breakdown of PIP2 into DAG (activates PKC) and IP3 (controls release of Ca2+ from intracellular stores)
    - - Gi inhibits adenylate cylase, activate K+ channels, inhibit Ca
      - Eg. autonomic stimultion of heart - sympathetic excitatory action by b1 (Gs) but parasymp inhibitory by M2 (Gi)
      - Regulation of adenylate cyclase by toxins (modulate G proteins
        
        Cholera toxin - prevents GTP hyrdolysis by Gs- get locked GTP, continuously acting
        
        Pertussis toxin (whooping cough) - stops exchange of GTP for GTP, cant inactivate adenylyl cyclase or open K channels
    - - Gs binds adenylate cyclase, get cAMP from ATP, activates PKA
        
        in heart muscle, PKA phosphorylates Ca transporters/channels so intracellular Ca is increased - get contraction of muscle (beta adrenergic receptors
        
        PKA binds to cardiac Ca channels, some GPCRs (eg. CREB), adipocyte enzymes etc
        
        PDE (phosphodiesterases) break down cAMP into AMP
  - - - Down regulation - (long term)- decrease in total number of receptors
      - Phosphorylation & internalisation (short term)
        
        Homologous desensitisation -loss of cellular response to agonist following stimulation by agonist alone -GPCRs are phosphorylated by GPCR kinases (GRKs) to stop further activation of receptor
        
        Heterologous - loss of response following stimulation by ifferent agonist - GPCRs phosphorylated by second messenger dependent kinases
- - - - cytokine receptor activated, links to enzyme IkB kinase which phosphorylates inhibitory protein IkB and enables it to move to cytoplasm - NFkB binds to kB response element - get cytokines, pro inflammatory gene products
      - Transrepression - GR monomer interacts with NFkB instead of DNa to inhibit activation of kB response element (suppress pro inflammatory gene transcription) -GR recruits HDAC
    - - Cell type specificity: SERMs (selective estrogen receptor modulators)- selective expoitation of some beneficial actions of ER to treat post menopausal symptoms (eg, raloxifene- ER agonist in bone - less fractures but antagonist in breast -less cancer)
      - Tissue specificity: in bone cells, X and Y proteins are expressed , -gene 1 requires X, gene 2 requires Y, gene 3 requires both to get gene expression
        -SERM only able to recruit cofactor X and turns on gene 1 only but gene 1 dictates bone mineralisation (partial agonist)
- - - - (FGFR)2  Grb2SosRasRafMEKERK1/2 targets
      - further signalling recruited from PLC (increases DAG and Ca which activate PKC) - PKC activates Ras which increases ERK
      - FGFr activates PI-3K which activates Akt (has its own targets)
      - need this integrated signalling to get proliferation
    - - Erk phosphorylates Elk1 (transcription factor), binds cyclin D1 promoter, binds cdk4, phosphorylates Rb
      - Akt increases activity of p70s6k (makes ribosome more efficient - more cyclin D1 promoter made)
      - Rb sits in complex with E2F and stops trans activating activity of E2F - stops E2F dependent gene expression (stops cell division genes)
  - - - Trastuzuma b - effective in breast cancers that overexpress HER2, targets Mab vs HER2
      - tumours are unstable and can have many mutations, when finding treatments, test for mutations in Ras because if its mutated then regulating upstream kinase wont work
      - use combination therapy to treat tumour - anti proliferative, kinase inhbitior,, target blood vessels
    - - outgrowth of new blood vessels from pre existing -essential for tumour ggrowth
      - regulated by multiple growth factors -implicated in many normal processes so targeting them has side effects
      - can starve tumour of blood supply: avastin (monoclonal antibody)
  - - - receptors dimerise, ALK5 phosphorylates Smad 2/3, binds with Smad4 to get into nucleus, switch on genes associated with production of ECM and contractile proteins
    - - complete inhibition causes autoimmune disease -TGFb is a drug target in many diseases but blocking it will produce intolerable adverse effects
      - selective intervention with parts of signalling pathway yeilds therapeutic effect- cant block whole thing
- - - - fatigue, sleep, weight changes can measured in mouse but thoughts/mood cannot -forced swim test
- - - - aspirin blocks COX1 /2 (important in platelets and endothelial cells) -platelet has no nucleus so once its targeted doesnt have ability to make more COX, endothelial cells can regain capacity to make prostaglandins
      - COX - vasodilator and inhibits platelet formation, thromboxin activates PLC, activates Ca and PLA2 -causes platelets to be crosslinked into network of fibrinogen - further platelet aggregation
    - - thrombin activated from prothrombin, use flurogenic substrates which can detect small molecule inhibitors of thrombin - requires high degree of selectivity, oral activity, low bleeding risk
      - thrombin prevents formation of fibrin (prevents formation of clot, reduce risk of second myocardial infarction/stroke)
      - Heparin: binds antithrombin 3 (ATIII) - ATIII binds thrombin and cleaves it into inactive form - heparin binds both and increases catalytic efficiecy of inactivation of thrombin
      - Hirudin: eg. bivalirudiin -bind thrombin active site, slowly metabolised substrate
      - Dabigotran - active site /competitive inhibitor indicated for prophylaxis in those at risk of atrial fibrilation -associated thrombo/embolus