Tell me about the ANS and what it regulates?
- Regulates activity of:
Exocrine glands (some endocrine glands)
- Regulates by brain stem centres
Tell me about the somatic NS
- Activates skeletal muscle contraction
- Voluntary body movements
- Regulated by corticospinal tracts + spinal reflfexes
Tell me about exocrine and endocrine secretion i.e. what it goes through and to where?
exocrine- section into external environment through ducts, e.g. (sweat, oil, wax, enzymes, etc)
endocrine- secretion into internal environment with no ducts and hormones secreted
Receptors/ agonists present in the sympathetic, parasympathetic and somatic nervous system
What does the somatic NS not have a relay neuron between?
The cell body and muscle receptor
Acetylcholine synthesis and degradation
Tell me the types of nicotinic receptors?
Where are they located?
N1 or NM and N2 or NN
type 1 sits in muscle and type 2 in neuron
Ligand-gated ion channels
How many acetylcholine molecules do nicotinic receptors require to bind?
What is the structure of the nicotinic receptors?
- Required binding of two acetylcholine molecules
- Composed of five subunits (pentamer)
- Five different types of subunits
- Alpha, beta, gamma, delta and epsilon
- 10 different alpha and 4 different beta subunits
-NM receptors contain only alpha1 and beta1 subtypes plus delta and gamma/epsilon
- NN receptors contain alpha2-10 and beta2-4 subtypes
When was the AA sequence for the nicotinic receptor determined?
The amino acid sequence for the nicotinic receptor was determined after solubilization of the receptor from the electric organ of Torpedo californica using anionic detergents such as sodium dodecyl sulfate, passing the receptor through an affinity column containing a bungarotoxin (from snake venom) and washing the receptor from the column. Subsequently, molecular biological techniques were used to clone additional receptor subunits. The nicotinic receptor consists of five polypeptide subunits. The amino acid sequence for the a subunits consists of a glycolipid region (which contains the ACh binding site and a sulfhydryl groups) with four hydrophobic regions that span the membrane. Nine a subunits have been cloned, along with four b subunits. In the neuromuscular junction, d and g subunits also have been identified. The g subunit is replaced by an e subunit in the adult muscle.
ACh and receptor
What is the neuromuscular junction?
a specialised form of synaptic transmission: communication between neurons and skeletal muscle
Tell me the steps to the major events that occur in NMJ transmission?
Major events in NMJ transmission
- Motor neuron depolarization causes action potential to travel down the nerve fiber to the neuromuscular junction
- Depolarization of the axon terminal causes an influx of Ca2+
- which triggers fusion of the synaptic vesicles and release of neurotransmitter (Acetylcholine; ACh) by exocytosis
- ACh diffuses across the synaptic cleft and binds to post-synaptic ACh receptor (AChR) located on the muscle fiber at the motor endplate (ligand gated cation channels is the receptor)
- Binding of ACh to AChRs opens the channels causing an influx of Na+ (K+ flux out)
- depolarization of the sarcolemma that travels down the t-tubules and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum - CONTRACTION.
- How Ach is removed: Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE) to acetic acid and choline (choline put back in terminal for the resynthesis of acetylcholine)
Tell me some NMJ disorders?
- Myasthenia gravis
- Lambert-Eaton myasthenic syndrome
- Neuromyotonia (Isaac’s syndrome)
Tell me about myasthenia gravis
- “grave muscle weakness”
- Autoantibodies to the nicotinic AChR on the motor end-plates of muscles.
- Binding of ACh is blocked and muscle activation is inhibited.
- The autoantibodies also induce complement-mediated degradation of the AChRs, resulting in progressive weakening of the skeletal muscles.
Autoantibodies to MuSK, which is important for the tight clustering of AChRs at the neuromuscular junction .
Tell me the symptoms to the NMJ disorder myasthenia gravis
Tell me about the NMJ disorder Lambert-Eaton myasthenic syndrome
- Autoantibodies to presynaptic voltage-gated calcium channel (VGCC)
- These antibodies interfere with the calcium-dependent release of ACh from the presynaptic membrane and subsequently cause a reduced endplate potential on the postsynaptic membrane, resulting in NMJ transmission failure.
Tell me about the NMJ disorder Neuromyotonia (Isaac's syndrome)
- Autoantibodies to presynaptic voltage-gated potassium channel (VGKC)
- Autoimmune neuromyotonia is typically caused by antibodies that bind to potassium channels on the motor nerve resulting in continuous/hyper-excitability.
What is the neurotransmitter always used as the NMJ?
A client with myasthenia gravis asks the nurse why the disease has occurred. The nurse bases the reply on the knowledge that there is…?
A decreased number of functioning acetylcholine receptor sites
Katrina a client with myasthenia gravis is to receive immunosuppressive therapy. The nurse understands that this therapy is effective because it...?
Decreases the production of autoantibodies that attack the Ach receptors
Drugs working on NMJ
In the 16th century, what did south americans find out?
What was the active compound for this?
In the 16th century, European explorers found that south America natives in the amazon basin were using an arrow poison, curare to produce skeletal muscle paralysis in the animals there were hunting
Active compound- d-tubocurarine
NM blocking drugs
Name 2 toxins that bind with high affinity to nicotinic acetylcholine receptor and cause postsynaptic block at the NMJ
What effects do NMJ blocking agents cause?
paralysis - small rapidly moving muscles (eyes, fingers), then limbs, last is respiratory muscles (recovery in reverse order)
Name a competitive NMJ blocking agent and how it works
Competitive (non-depolarizing) agents e.g. Curare
- compete with ACh for binding to receptor
- flaccid, relaxed paralysis
- non-NMJ effects: ganglia, muscarinic blocking, histamine release
- NMJ block CAN be reversed by AChE inhibitors
Name a non-competitive NMJ blocking agent and how it works?
Non-competitive (depolarizing) agents
- Phase 1 block:
- membrane depolarization
- transient fasciculations followed by paralysis
- Phase 2 block:
- membrane repolarizes, hyposensitive to ACh
- NMJ block NOT reversed by AChE inhibitors
Tubocurarine is also another competitive NMJ blocking agent. Tell me how this works and at what concentrations certain effects are caused?
Tubocurarine, dimethyltubocarine (metacarine)
- No effect on nerve transmission
- Muscle can still be stimulated
- 5-10 mg (iv) produces flaccid paralysis
- 10-20 mg (iv) can produce apnea, not active orally
- Can cause histamine release (mast cells)
- Can block ganglionic receptors [high concentration]
Pancuronium is another competitive NMJ blocking agent. Tell me about it?
- more potent than tubocurarine (x5)
- reduced histamine release than curare
- lack of ganglionic blockade
Name 3 other NMJ competitive blocking agents