Lecture 3 Flashcards
(21 cards)
Histamine
historical importance
Dale’s discovery
richly rewarding for investigators
paracrine mediator
later also identified as a neurotransmitter
significant in physiology and pathophysiology
General facts of histamine
one molecule, many effects contraction relaxation neurotransmitter where was the locus of specificity recognition site = different receptors? beyond recognition site?
Histamine synthesis
enzymatic conversion of histidine (non-toxic) to histamine (toxic)
via histidine decarboxylase
Types of histamine storage
mast cells (connective tissue or mucosal) = paracrine basophils enterochromaffin-like (ECL) cells = paracrine-major role in stimulating gastric secretion neurons = neurotransmitters
Histamine storage in mast cells
ATPase pumps protons into the granules
VMAT2 exchanges protons within the granules with the histamine molecules in the cytoplasm
Mast-cell degranulation
various stimuli physical = injury, heat, X-rays, UV chemical agents = snake venoms, bee venoms, drugs, detergents antigens = clinically most important release of mediators immediate = histamine, serotonin delayed = leukotrienes
Effects of released histamine
smooth muscle = contraction of intestine, bronchioles
cardiac muscle = increases heart rate
glands = increases secretion of gastric acid
vasculature = promotes vasodilation, causes edema
nervous system = stimulates sensory nerve endings (pain, itch), multiple central nervous system effects
How the effects are brought about
receptors protein molecules, either on plasma membranes or intracellular respond to exogenous or endogenous chemicals ligands bind to receptors recognition transduction response ligand (primary messenger) receptor-ligand binding signal transduction via second messengers (in cytosol) cellular responses (in cytosol) changes in gene expression (in nucleus)
Histmaine receptors
4 major subtypes = H1, H2, H3, H4 each respond to histamine different signal transduction mechanisms selective antagonists allow for specific effects to be either reduced or eliminated clinically important
H1
smooth muscle, endothelium, brain
H2
gastric mucosa, cardiac muscle, mast cells, brain
H3
brain, neurons
H4
immune cells (eosinophils, neutrophils, T cells)
Termination of histamine
enzymatic degradation (major) diamine oxidase = located in intestines, kidney, placenta scavenges extracellular histamine histamine methyltransferase = located in kidney, liver, colon, pancreas, bronchi, central nervous system deals with intracellular histamine uptake into cells (minor)
Enzymatic degradation pathways
histamine -> (N-methyltransferase) -> N-methylhistamine -> (MAO-B) -> N-methylimidazole-acetic acid
histamine -> (diamine oxidase) -> imidazoleacetic acid -> (ribose) -> imidazoleacetic acid riboside
Pathophysiological roles
allergy and anaphylaxis
food intolerance (histamine containing food items)
asthma
duodenal ulcers, gastroesophageal reflux disease (GERD)
pain and itch
narcolepsy
scombrotoxic fish poisoning
Antigen stimulated release of histamine (Part 1)
first exposure to antigen (sensitization)
stimulates/induce plasma cells to produce IgE antibodies
IgE molecules fix onto specific IgE receptors
binds onto cell membranes of mast cells and basophils
Antigen stimulated release of histamine (Part 2)
subsequent exposure-antigens (reaction)
antigens bind to the IgE antibodies on the mast cells and basophils
perturbation of the mast cells and basophils leads to the release of granules (degranulation) and other mediators of inflammation
though cross-linking
Scombrotoxic fish poisoning
scombroid fish (tuna, mackerel, herring, marling, bonito) have high levels of histidine
converted by bacterial HDC to histamine
eating contaminated fish can lead to effects of histamine poisoning
rash, flushing, sweating, nausea, vomiting, diarrhea, abdominal cramps, headache, dizziness, palpitations, oral burning sensation, metallic taste, hypotension
symptoms resolve within 24 hours
easily treated with antihistamines
Summary
general approach to messenger molecules: synthesis, storage, release, effects, termination
histamine as an exemplar
pathophysiological implications
H1 antagonists (urticaria, allergic rhinitis, motion sickness, insomnia)
H2 antagonists (inhibit gastric secretion)
Nobel prizes given to Bovet for H1 antagonists, Black for H2 antagonists
Overview of histamine process
synthesis = histidine decarboxylase (enzymatic machinery exists) storage = granules, via VMAT antiporter (presence of granules, packaging process) release = exocytosis (histamine in extracellular spaces) response = receptor subtypes, 2nd messengers (responses, signal transduction, functional responses) termination = diamine oxidase and N-methylhistamine transferase (enzymatic machinery)
