6/15- Neurochem and Pharm of Brain Disorders Flashcards
Mechanism of transmitter release?
- Voltage-gated Ca ion channels are abundant in nerve terminals
- AP depolarizes nerve terminals and opens Ca channels
- Influx of Ca results in vesicles containing NT to fuse with synaptic membrane and release their contents by exocytosis
- There is interaction between SNARE proteins that promotes exocytosis (in a Ca-dependent process)
- More Ca = more exocytosis
What is SNARE protein?
SNap REceptor
(SNAP = soluble NSF Attachment Protein; NSF = N-ethylamide Sensative Fusion Protein) that mediates/promotes exocytosis
What is the mechanism of Butlnum toxin (BoNT) and Tetanus Toxin (TeNT)?
Capable of cleaving at different places on different SNARE proteins/synaptic proteins
Process of recycling the synaptic vesicle membrane?
- During exocytosis, SNARE proteins stay bound to cell membrane
The fused vesicle is recycled:
- Vesicle gets coated with clathrin
- Dynamin helps release it to cytoplasm
- Clathrin is removed
- Few more steps, the vesicle is ready to get loaded with NT, pick up SNARE proteins, and ready to dock and deliver its cargo
What steps are involved in the synthesis and transport and release of NTs (small molecule and peptide)?
Small molecule transmitters:
- Synthetic enzymes are transported from cell body
Peptide transmitters:
- Precursors and cleavage enzymes are transported from cell body
What disorders are associated with the neuromuscular junction (involving what NT)?
Acetylcholine
- Myasthenia gravis
- Lambert-Eaton syndrome
What is myasthenia gravis?
Treatment?
Autoimmune disorder where Abs against acetylcholine Rs are produced.
Treatment: Neostigmine (inhibitor of AChE)
What is Lambert-Eaton syndrome?
Treatment?
Autoimmune disorder where Abs against pre-synaptic Ca channels are produced
Treatment: no good; plasma exchange, inhibit Ab production, increase pre-synaptic Ca release
What major disease is associated with acetylcholine in the CNS?
Levels high or low?
Symptoms?
Alzheimer’s (memory processes)
- There is a severe loss of cholinergic neurons with people who have Alzheimer’s
- Personality change, dementia, loss of memory
What nuclei in the CNS ar associated with ACh?
Functions?
Nucleus of Meynert
- Involved in learning and memory (consolidation and recall of memory)
Pontine nucleus
- Involved in regulation of forebrain activities
What is the nicotinic ACh receptor (structure, location…)
- 5 subunits, each with 4 trans-membrane domains (TM1-TM4)
- 2 ACh molecules bind to open channel
- Subunit cmposition in: fetal neuromuscular junction, adult neuromuscular junction, ganglia, and cerebral cortex ACh Rs are different
What is the structure/mechanism of muscarinic ACh Rs?
Muscarinic ACh receptors are G-protein coupled (M1-M5)
Steps involved in the synthesis and release of glutamate?
- Glutamate made from glutamine
- Removed by pre-synaptic reuptake
- Also taken up by glial cells and inactivated/converted to glutamine
- Glutamate works on ionotropic and also metabotropic receptors; all EPSP, Na and/or Ca enters cells
What diseases are associated with glutamate?
Excitotoxicity (neuronal cell death) implicated in:
- ALS (Amyotrophic Lateral Sclerosis)
- Alzheimer’s disease
- Epilepsy (inappropriate excitation)
What Glutamate receptor is important in memory? Structure?
NMDA
- Glutamate (NMDA) ionotrophic receptors consist of 5 subunits (each with 4 TMs)
- 2 glutamates bind and Na/Ca enters cell (K leaves); EPSP
How many types of ionotrophic glutamate receptors are there? What are they?
Three:
- NMDA
- AMPA
- Kainate
(In addition, many metabotropic GPCRs)
It is thought that perhaps supplements of __ may result in __?
It is thought that perhaps supplements of glutamate may result in increased memory and more intelligence…
- Oral gluatmine (or glutamic acid) is sold, but no improvement in memory seen and is toxic in large doses
- However, genetic experiments with mice where Glutamate/NMDA transmission was increased resulted in “smarter” mice; downside was that mice also feel more pain (mediated by Substance P)
What NT is associated with increased levels of glutamate?
Substance P (resulting in more pain)