Transmission of nerve impulses from nerves to muscles and Importance of nicotinic receptors at neuromuscular junction

1. Transmission of nerve impulses from nerves to muscles
Importance of nicotinic receptors at neuromuscular junction

2. Synapses: areas where signals or action potentials are transmitted
from a presynaptic to a postsynaptic structure (e.g., neurons, muscle).
Different types of synapses according to the synaptic structures:
 Axodendritic synapses: signaling between axons and dendrites
 Axoaxonic synapses: signaling between axons
 Axosomatic synapses: signaling between axons and the cell body
of neurons
 Dendrodendritic synapses: signaling between dendrites

3. Axodendritic (between axon
and dendrite); axosomatic
(between axon and
perikaryon); axoaxonic
(between two axons) and
axodendrosomatic (between
axon, body, and dendrites).

4. 1. Electrical synapse
2. Chemical synapse

5.  Characterized by direct flow of current through cells via gap
junctions
 Found in the heart and smooth muscle
 No chemical synapse is required → no delay during synapsis

7.  Transfer of signals from a neuron to another cell (e.g., neuron,
muscle cell) with the aid of a neurotransmitter
 Composed of presynaptic membrane, synaptic cleft, and
postsynaptic membrane
Example that is related to the case:
 Neuromuscular junction is an example of chemical synapse.
 Definition: a chemical synapse between alpha motor
neurons and skeletal muscle
 Motor unit: an alpha motor neuron together with the group of
muscle fibers it innervates

8. After dividing into several
branches, the α-motor
neuron axons (shown in red
or blue) and individual
muscle fibers form the
motor endplate, where
impulses are transmitted to
the muscle. In this area, the
axon further divides into
several axon terminals,
where neurotransmitters
are released. The sum of all
muscle fibers innervated by
a single α-motor neuron is
called a motor unit
(analogous to the α-motor
neurons shown here in red
and blue)

10.  Soluble NSF Attachment protein REceptor complex
 Consists of several SNARE proteins, which are attached to either:
 The vesicle membrane (v-SNARE proteins; e.g., synaptobrevin)
 The presynaptic target membrane (t-
SNARE proteins; e.g., syntaxin 1, SNAP 25 )
 v-SNARE and t-SNARE proteins combine at the presynaptic
membrane to form the SNARE complex

11.  Exocytosis is mediated through proteins on the vesicle membrane (synaptotagmin, v-
SNARE) and the presynaptic membrane (t-SNARE).
 Action potential causes depolarization of the presynaptic membrane, and calcium ions
enter the cell through voltage-gated calcium channels. SNARE proteins are activated
and mediated by fusion of the vesicle and presynaptic membrane. ACh is exocytosis into
the synaptic cleft.

12. Presynaptic neuron:
 action potential → depolarization of the presynaptic membrane → opening of voltage-
gated Ca2+ channels → influx of Ca2+ into the presynaptic terminal → SNARE complex-
mediated fusion of vesicles with the presynaptic membrane → release
of acetylcholine (ACh) from vesicles into the synaptic cleft
Muscle fiber:
 binding of ACh to its receptor on the postsynaptic membrane of muscle (motor end plate)
→ depolarization of the postsynaptic membrane → end-plate potential (EPP) → stimulation
of voltage-sensitive dihydropyridine receptors (DHPR) → coupling with ryanodine
receptors (RR) → release of Ca2+ from the sarcoplasmic reticulum (SR)
→ tropomyosin releases the myosin-binding site on actin → binding
of myosin and actin → muscle contraction
Synaptic cleft:
 acetylcholinesterase (AChE) breaks down ACh → acetate + choline → reuptake of choline
into the presynaptic membrane → resynthesis of ACh

13. Nicotinic acetylcholine receptors (nAChRs):
 ligand-gated ion channels
 divided into two groups:
1. muscle receptors (found at the skeletal neuromuscular junction
where they mediate neuromuscular transmission)
2. neuronal receptors (found throughout the peripheral and central
nervous system where they are involved in fast synaptic
transmission)

14.  Nicotinic acetylcholine receptors belong to a superfamily of ligand-
gated ion channels that play key roles in synaptic transmission
throughout the central nervous system.
 Neuronal nicotinic receptors, however, are not a single entity, but
rather there are many different subtypes constructed from a variety
of nicotinic subunit combinations that compose channel-receptor
complexes with varied functional and pharmacological
characteristics.
Ionotropic receptors: A group of transmembrane ion channels that open or close in
response to the binding of a chemical messenger (ligand) such as a
neurotransmitter

15. This structural diversity and the presynaptic, axonal, and
postsynaptic locations of nicotinic receptors contribute to the varied
roles these receptors play in the central nervous system:
1. Presynaptic and preterminal nicotinic receptors enhance
neurotransmitter release
2. Postsynaptic nicotinic receptors mediate a small minority of fast
excitatory transmission.
3. Nonsynaptic nAChRs modulate many neurotransmitter systems
by influencing neuronal excitability.
4. Some nicotinic receptor subtypes have roles in synaptic plasticity
and development.
5. Nicotinic mechanisms participate in learning, memory, and
attention.
6. Nicotinic receptors are distributed to influence many
neurotransmitter systems at more than one location, and the
broad, but sparse, cholinergic innervation throughout the brain
ensures that nicotinic acetylcholine receptors are important
modulators of neuronal excitability.

16.  The nicotinic acetylcholine receptor is a transmembrane allosteric
protein that mediates transduction of chemoelectric signals
throughout the nervous system by opening an intrinsic ionic
channel, in which stimulated by Acetycholine.
 This rapid pore opening enables flow of Na+, K+, and, in several
instances, Ca2+ ions across the cell membrane.
 As a consequence, nicotinic acetylcholine receptors elicit fast
changes in the membrane electric potential, but they also regulate
transmission of electric signals by closing the pore through slower
desensitization transitions.

17. In the central nervous system: nAChRs contribute to the pathological mechanisms
of neurodegenerative disorders, such as Alzheimer and Parkinson diseases.
Case-related pathology:
In the peripheral nerve-muscle synapse: the vertebrate neuromuscular junction,
"classical" myasthenia gravis (MG) and other forms of neuromuscular transmission
disorders are antibody-mediated autoimmune diseases.
In MG, antibodies to the nAChR bind to the postsynaptic receptors and activate the
classical complement pathway culminating in the formation of the membrane
attack complex, with the subsequent destruction of the postsynaptic apparatus.
Divalent nAChR-antibodies also cause internalization and loss of the nAChRs. Loss
of receptors by either mechanism results in the muscle weakness and fatigability
that typify the clinical manifestations of the disease.
Other targets for antibodies, in a minority of patients, include muscle specific
kinase (MuSK) and low-density lipoprotein related protein 4 (LRP4).

18. nAChRs play a significant role in nicotine addiction.
 Nicotine happens to imitate the neurotransmitter acetylcholine, and binds to
those receptors. However, unlike acetylcholine, nicotine is not regulated by your
body. While neurons typically release small amounts of acetylcholine in a
regulated manner, nicotine activates cholinergic neurons (which would normally
use acetylcholine to communicate with other neurons) in many different regions
throughout your brain simultaneously.
 Because of all of that unregulated stimulation and disruption, your body increases
its release of acetylcholine, leading to heightened activity in cholinergic pathways
throughout your brain. Activity in the cholinergic pathways calls your body and
brain into action, and you feel re-energized. Stimulating those cholinergic neurons
also increases how much dopamine gets released by the limbic system, which
activates reward pathways in your brain. When drugs like cocaine or nicotine
activate the reward pathways, it reinforces your desire to use them again because
it feels good.

19.  https://next.amboss.com/us/article/lp0vpS#L9ac500b0b1450f36759faf05a954aec3
 https://pubmed.ncbi.nlm.nih.gov/11230867/
 https://pubmed.ncbi.nlm.nih.gov/17009926/
 https://science.howstuffworks.com/nicotine3.htm
 https://pubmed.ncbi.nlm.nih.gov/30916550/
 https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology
_(Boundless)/10%3A_Overview_of_the_Nervous_System/10.5%3A_Neurophysiology/10.5J%3A_Ionot
ropic_and_Metabotropic_Receptors