E2 autocoids Flashcards
Examples specific autacoids
kinins
Histamine
Serotonin (5-HT)
Describe autacoids
produced on demand and act locally to the site of synthesis.
- autocrine & paracrine
Very short half-lives
Give examples of major classes of autacoid
- Polypeptides: e.g. angiotensin and kinins (bradykinin & kallikidin)
- Biogenic amines: e.g. histamine, serotonin (5-HT)
- Phospholipid-derived: e.g. Eicosanoids
kinins describe role how are they formed what are the main kinins (remember alternative names) what separates KD from BK?
proteins in the blood that cause inflammation & affect blood pressure
- following cleavage of kininogens via kallikrein (enzyme)
- Bradykinin BK (9a.a) & Kallidin KD (10 a.a.) (often called Lys-Bradykinin)
- KD has additional Lys a.a. that BK does not.
- kallidin can be converted to BK via aminopeptidase enzymes
what type of reaction is BK produced in
name site of degradation
what are the BK receptors
inflammatory reaction: sites of degradation by ACE & other kinases
- GPCRs, Bradykinin receptors B1 & B2, Bradykinin receptors B3-B5 less known
binding of BK or LysBK to B2 receptors results in what (through what signaling)
Gaq
- constitutive vasodilation/ neuroprotector
eNOS –> NO (transient upreg)
Binding of Des-Arg9-BK or Des-Arg10-BK results in what (through what signaling)
Gai proinflammation cytokines prostaglandins ROS glutamate neuronal death iCa2+ iNOS --> NO long lasting upreg
Typical kinin signaling cascades produce
- Releases intracellular Ca2+
- Activates PLA2
- Release PGI2 and or NO (vasodilatation)
- Link with eicosanoid pathways
!! how do the actions of autacoid and eicosanoid converge
through the actions of kinins via B2 receptor coupling to the Gq pathway and triggers a rise in intracellular calcium levels that promote PLA2 dependent release of arachidonic acid and prostacyclin synthesis.
(integral to the vasodilatation observed in response to bradykinin (BK))
inflammation leads to the activation & release of what
during inflammation what is upregulated
- activation of kallikreins –> produces more bradykinin
- release of inflammatory PG mediators
- Upregulation of the B1 receptor
- Release of B1 receptor agonists
- Vasodilation
- Oedema
- Increased vascular leakage
Histamine roles
blood clots gastric acid secretion Blood vessel dilation Adr release swelling & inflammation frequent heartbeat Bronchonconstriction Increases permeability of capillaries
Major histamine-producing cells & their activation signals
Minor histamine-producing cells
other histamine triggers
IgE crosslinking, complement, allergy inducing drugs –> mast cells
also –> Basophils
Somatostatin Gastrin –> ECL cells
Activation of N-methyl-D-aspartate, U opioid, dopamine D2 & serotonin receptors
minor:
DC, Tc, Macrophages, Neutrophils, Epithelial cells
Release from mast cells (e.g. sensory pain receptors)
Anaphylatoxins
(peptides of the complement system - C3a, C4a and C5a)
Tissue damage
Heat mechanical injury
where is histamine generated
In granules: Mast cells & WBC
when allergens bind mast-cell bound IgE antibodies = degranulation
What are the histamine receptors coupled to?
GPCRs – Histamine H1-H4R
- H1 couple to Gαq: Increases Ca2+
- H2 couple to Gαs: increases cAMP
- H3 and H4 couple to Gαi: decreases cAMP
Give examples of histamine H1 antagonists
H2 antagonists
H1: Mepyramine, Promethazine > both antihistamines
H2: Ranitidine, cimetidine > treatment of peptic ulcers/ stomach acid production
