Neurological Disorders Flashcards
(10 cards)
The pore and hydration
- ions going through never lose their hydration shell
- opposite to voltage-gated ion channels!
- tight (near 6’) and loose (2’) pentagon of H2O above and below the ion
- mutagenesis to put valine at 6’ = lack of H2O going through
- suggests the Ser at 6’ is essential for allowing hydrated ions through
Neurological disorders
nAChR disorders
- myasthenia gravis
- Alzheimer’s disease
- slow channel syndrome
- COVID-19
GABA-A R disorders
- epilepsy
GlycineR disorders
- hyperplexia
- inherited congenital myoclonus
Alzheimer’s disease
- neurodegenerative disease - amyloid-beta plaques and neurofibrillary tangles
- low [Abeta] = activates alpha7 nAChRs
- high concentrations inhibit
- form of Abeta is important = fibrillar Abeta inhibits, oligometric activates
COVID-19
- COVID-19 infects lung cells
- immune cells produce cytokines
- cytokines attract more immune cells which produce more cytokines
- cycle of inflammation damages the lung - damage can occur through fibrin formation - scar tissue prevents oxygen entering the bloodstream
- weakened blood vessels allow fluid to seep in and fill the lung cavities = respiratory failure
macrophages
- activating alpha7 nAChR downregulates this response
- so could target alpha7 nAChRs
Genetic nAChR diseases
- often autosomal dominant
- prolonged nAChR activation
e.g. slow channel myasthenic syndrome
- range of mutants
- most located in pore region, M2 or M2-M3 loop
- some mutations increase channel mean open time
Myasthenia gravis
- autoimmune channelopathy
- Abs block nAChRs at NMJ
- inhibits excitatory effect of ACh
- muscle weakness and fatigue
- treated with AChE inhibitors
GABA-ARs
- GABA = opening of chloride channel
- may allosteric sites e.g. for benzodiazepines
Benzodiazepines
- anxiolytic
- hypnotic
- myorelaxant
- anticonvulsant
- amnesia
Epilepsy
- childhood absence epilepsy (CAE) = predominantly genetic
- SMEI = severe myoclonic epilepsy in infancy
- GEFS = generalised epilepsy with fibrile seizures
R82Q mutation
- associated with CAE and fibrile seizures
- at B2delta2 interface
- impairs B2delta2 oligomerisation
- decreased receptor currents due to ER retention of unassembled subunits
K328M
- associated with GEFS
- in M2-M3 loop
- receptors have accelerated deactivation and single channel currents show reduced mean open times
- decreased receptor currents due to reduced stability of the open state
GlyR disorders
hyperplexia (startle disease)
- loss of postural control upon startle
- stiffness in infancy
- fatal apnea
inherited congenital myoclonus
- in cattle is due to low expression of GlyRs
- looks like strychnine poisoning (glycine receptor inhibitor)
