Lecture 3

Question 1

Histamine

Answer 1

historical importance
Dale’s discovery
richly rewarding for investigators
paracrine mediator
later also identified as a neurotransmitter
significant in physiology and pathophysiology

Question 2

General facts of histamine

Answer 2

one molecule, many effects
contraction
relaxation
neurotransmitter
where was the locus of specificity
recognition site = different receptors?
beyond recognition site?

Question 3

Histamine synthesis

Answer 3

enzymatic conversion of histidine (non-toxic) to histamine (toxic)
via histidine decarboxylase

Question 4

Types of histamine storage

Answer 4

mast cells (connective tissue or mucosal) =  paracrine
basophils
enterochromaffin-like (ECL) cells = paracrine-major role in stimulating gastric secretion
neurons = neurotransmitters

Question 5

Histamine storage in mast cells

Answer 5

ATPase pumps protons into the granules

VMAT2 exchanges protons within the granules with the histamine molecules in the cytoplasm

Question 6

Mast-cell degranulation

Answer 6

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

Question 7

Effects of released histamine

Answer 7

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

Question 8

How the effects are brought about

Answer 8

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)

Question 9

Histmaine receptors

Answer 9

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

Question 10

H1

Answer 10

smooth muscle, endothelium, brain

Question 11

H2

Answer 11

gastric mucosa, cardiac muscle, mast cells, brain

Question 12

H3

Answer 12

brain, neurons

Question 13

H4

Answer 13

immune cells (eosinophils, neutrophils, T cells)

Question 14

Termination of histamine

Answer 14

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)

Question 15

Enzymatic degradation pathways

Answer 15

histamine -> (N-methyltransferase) -> N-methylhistamine -> (MAO-B) -> N-methylimidazole-acetic acid
histamine -> (diamine oxidase) -> imidazoleacetic acid -> (ribose) -> imidazoleacetic acid riboside

Question 16

Pathophysiological roles

Answer 16

allergy and anaphylaxis
food intolerance (histamine containing food items)
asthma
duodenal ulcers, gastroesophageal reflux disease (GERD)
pain and itch
narcolepsy
scombrotoxic fish poisoning

Question 17

Antigen stimulated release of histamine (Part 1)

Answer 17

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

Question 18

Antigen stimulated release of histamine (Part 2)

Answer 18

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

Question 19

Scombrotoxic fish poisoning

Answer 19

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

Question 20

Summary

Answer 20

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

Question 21

Overview of histamine process

Answer 21

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)