Membrane Receptor Intro Flashcards
What are Membrane Receptors
cell surface proteins that receive extracellular signalling molecules and induce a change in cell function through the concerted action of intracellular signalling and effector proteins.
What do we need to know to rationally design a new drug for a disease?
- Understand the disease
- Identify receptors that may be targeted
- Understand receptors
Expression-
Structure
Signaling - Protein Interactors and Function
- Consider potential off-target effects and toxicity
Properties of an ideal drug target :
- Target is disease-modifying and/or has a proven function in the pathophysiology of a disease.
- Target has a favorable ‘assayability’ enabling high throughput screening.
- Favorable prediction of potential side effects according to phenotype data (e.g. in k.o. mice or genetic mutation databases).
- Target has a favorable IP situation (no competitors on target, freedom to operate).
How does Xolair work
By blocking a protein called IgE so that it can’t react with allergens.
Sensitization to allergens in the airway leads to -
production of allergen-specific IGE and up-regulation of TH2 cells
IGE-Receptor crosslinking leads to -
Early phase of allergen-induced airway inflammation
Role of dendritic cells in allergic response
Allergen picked up by dendritic cells, chomp it up and migrate to lymph node, presents proteins to T-cells
Role of dendritic cells in allergic response
Allergen picked up by dendritic cells, chomp it up and migrate to lymph node, presents proteins to T-cells
role of IL-4 cytokine
if present , T cells become TH2 cells which then bind to B cell
Role of B cell
has class switch after TH2 binds and starts to produce antibodies specific to IgE that then pass into the blood and therefore all over body
Role of Mast cells
have specific IgE antibody receptor, respond quickly by secreting IL4 cytokines as a positive reinforcment. when exposed again, specific IgE binds and causes signalling cascade
signalling cascade caused by mast cell IgE activation by antigen
Secretions of inflammatory mediators e.g. histamine, lipid mediatorts, prostoglandins, leukakines, TNF
Vasodilation and increase in vascular permeability
Neutrophils and eosophils infiltrate area
Activate goblet cells - mucus, neuropeptides
mast cells also activate transcription factors that synthesise pro-inflammatory cytokines and chemokines (takes 3 hours)
role of Eosiniphils
secrete toxins that damage tissues
Role of Basophils
Also have IgE receptors- like moving mast cells
What happens 6-8 hr after allergen exposure
chemokines and cytokines recruit and activate other immune cells (e.g. eosinophils) inflammation & tissue damage
What happens in Chronic stage of allergen-induced airway inflammation
tissue damage
large amount of TH2 and B cells in lungs constantly so responses are quicker and longer
Mast cell count increase
Fibroblasts try to repair but cause scarring so less elastic lungs
Thickening of smooth muscle layer so longer constriction
Treatments
AVOIDANCE
DRUGS
- β2-adrenoceptor agonists (relax smooth muscle, inhibit mast cell degranulation, inhibit mucus secretion)
- Corticosteroids (repress transcription of newly synthesized mediators eg cytokines, chemokines, and prostanoids by inhibiting induction of COX2)
- Anti-histamines
- Anti-leukotrienes
- Anti-IGE Omalizumab/Zolair
