ACh, Alzheimers, and Myasthenia Gravis

what 4 areas are ACh neurons localized to?

1. neuromuscular junction (periphery)

2. basal nucleus of Meynert

3. medial septal nuclei innervate cortex

4. hippocampus

5. pontomesencephalotegmental complex

functions of ACh

• arousal

• responsiveness to sensory input

• emotional state

• attention

• innervate hippocampus (learning, memory)

• early to degrade in Alzheimer’s disease

______ neurons are early to degrade in Alzheimer’s disease

ACh

connectivity to __________ is much less in AD compared to control

right hippocampus

2 precursors to ACh

1. acetyl-CoA

2. choline

(by-products of metabolism)

what enzyme combines acetyl-CoA and choline to make ACh?

choline acetyltransferse

synthesis of ACh is dependent on _______ levels in cells

choline

where does synthesis of ACh occur?

1. cytoplasm of nerve terminals

2. mitochondria

activity of __________ controls levels of ACh

choline transporter

what controls the synthetic rate of ACh?

choline transporter

• regulates amount of choline available

what releases ACh at a cholinergic synapse?

VAT (vesicular acetylcholine transporter)

what enzyme anchored on membranes is critical in quickly breaking ACh back into choline and acetate?

acetylcholinesterase

acetylcholinesterase breaks ACh into what 2 things?

1. choline

2. acetate

what happens to choline and acetate after they are produced by acetylcholinesterase?

• acetate diffuses

• choline is recaptured by choline transporter

2 types of ACh receptors

1. muscarinic

2. nicotonic

are nicotinic receptors ionotropic or metabotropic?

ionotropic

how many proteins make up nicotinic receptors?

5 - pentameric

list 5 proteins of nicotnic receptor

• alpha

• alpha

• beta

• delta

• gamma/epsilon

what ions are nicotinic receptors permeable to?

primarily Na+, but also Ca2+

nicotinic ACh receptors rapidly …

desensitize

how many subtypes of muscarinic acetylcholine receptors?

5

are muscarinic ACh receptors ionotropic or metabotropic?

metabotropic

muscarinic ACh receptors are coupled to either of which 2 things?

1. Gq (excitatory)

2. Gi (inhibitory)

which muscarinic ACh receptor is found in the brain? is it excitatory or inhibitory?

M1 - excitatory (Gq)

ACh neurons gate neurons in the ____________ and impact _______ induction

hippocampus / LTP

how does ACh affect LTP in the hippocampus?

• ACh inhibits nAChR

• lessens GABA production

• lessens tonic inhibition of NMDAr and AMPAr, allowing LTP

what NT is important in the NMJ?

ACh

ACh acts on ________ to stimulate muscle contraction

nAChR (post-synaptic)

Myastehnia Gravis

• Autoimmune disorder which attacks the nAChR

• Leads to profound muscle weakness

• Especially prevalent in skeletal muscles which control the mouth, neck and limbs

• Affects men and women, but women often are affected before the age of 40 while men exhibit more symptoms after 60

• Symptoms can come and go

production of antibodies to the ACh receptor in myasthenia gravis leads to…

1. Activation of the complement cascade which leads to attack and loss of motor endpate

2. Block acetylcholine binding to receptors on the muscle endplate

3. Crosslinking of receptors leading to internalization of receptors