文档介绍：Aberrant Cell Signaling and the Related Disorders
Disorders of signal transduction systems
Causes
Gene mutation-- Function loss or gain
Change of quantity of signal proteins
Change of activity of signal proteins
Autoimmune diseases
Secondary changes
Abnormality:
Ligands, Receptors, Post-receptor pathways, Effectors
Down-regulation / interruption of signaling
Signal Insufficiency
Receptors down-regulation/desensitization: decreased quantity, binding affinity, inhibitory Ab, cofactor disorders, function loss, etc.
Defects in Adaptors, Signal transducers, Effectors (Enzymes, Transcription factors, etc)
Up-regulation / over-activation of signaling
Signal Excess
Receptor up-regulation, hypersensitivity, stimulatory Ab, etc
Signal transducers, TFs: over-expression, persistent activation
Others
Pathogenesis and diseases
1. Aberrant Signal
Viral infections or other damages to pancreatic -cell
insulin production
hyperglycemia
Diabetes (Type I)
(1) Aberrant Signal (Signal Insufficiency)
Insulin receptor (IR): heterotetramer (2, 2)
Insulin binding leads to change in conformation
Activates IR -subunit PTK activity
-subunit phosphorylates Tyr residues on cytoplasmic domains
as well as downstream substrates (IRS)
ischemia, epilepsy, neurodegenerative diseases
extracellular glutamate/aspartic acid
NMDAR activation
(N-methyl-D-aspartate receptor, Ion Channel Linked Receptor)
Ca2+ influx
[Ca2+]i , activation of enzymes
excitatory intoxication
(2) Aberrant Signal (Signal Excess)
2. Aberrant Receptor in Cell Signaling
Disturbance of receptors can occur in:
gene level,
processes of protein synthesis, post-translational modification, conformation, oligomerization, translocation, endocytosis, and etc.
Receptor alterations in number, structure, function, and regulation:
down-regulation: decrease in number of receptors
desensitization: decreased response to ligand stimulation
up regulation: increase in number of receptors
hypersensitivity: increas