| Primary Channel Defect |
VGCC down, NMDA/AMPA dysregulation |
Cav1.3 (L-type) down, K+ channels down |
VGCC up, Nav1.6 up |
Nav1.1/1.2 down, Kv1.1 down |
L-type VGCC up, RyR up |
| Calcium Homeostasis |
ER Ca2+ leak, SOCE dysregulation |
Mitochondrial Ca2+ dysregulation |
ER stress, Store overload |
Moderate dysregulation |
Severe dysregulation (RyR) |
| Channel Genes Implicated |
CACNA1A, GRIN1, GRIN2A |
CACNA1D, KCNJ6, KCNJ11 |
CACNA1A, SCN10A, SCN11A |
SCN1A, SCN2A, KCNQ2 |
CACNA1C, GRIN2B, RYR2 |
| Excitability |
Reduced (hyperpolarized) |
Reduced (dopaminergic) |
Increased (hyperexcitability) |
Variable |
Reduced |
| Key Mechanism |
Abeta-tau interaction |
Mitochondrial stress |
SOD1-C9orf72 pathology |
TDP-43/GRN pathology |
mHtt direct interaction |
| Therapeutic Target |
VGCC modulators, RyR blockers |
L-type blockers, SK modulators |
VGCC/Na+ blockers |
Na+ modulators |
RyR modulators, L-type |