Question

The task is to develop new drugs to inhibit the delivery of proteins to specific cellular compartments as follows.

For each of the following describe 1) the cellular/molecular pathway involved and 2) indicate which step(s) in the pathway you would choose to control. .) 3) Indicate why you chose to inhibit this step and both the benefits and drawbacks of doing so for overall cellular health.

A) Release of neurotransmitter?

Answer 1

Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction from one neuron (nerve cell) to another "target" neuron, muscle cell, or gland cell. Neurotransmitter play a pivotal role in our REM sleep cycle, and can be understood by being broken down into two main types: REM-ON cells and REM-OFF cells. I will explain what these terms mean and how and why they affect our REM sleep.
Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available from the diet and only require a small number of biosynthetic steps for conversion.
In this section we will begin with overview of the neuron- the basic functional unit of our nervous system.
Their are various Neurotransmitter Pathways and Functions such as acetylcholine, dopamine, norephenephrine, serotonin, histamine, glutamate and GABA but will discus major five pathways in this
1. Acetylcholine Pathway:
Acetylcholine (ACh) is a neurotransmitter plays an important role in skeletal muscular movement and regulation of smooth and cardiac muscles in the peripheral nervous system. In the central nervous system, it is believed to be involved in learning, memory and mood.

Pathway of transmission
The two main receptors are involved in this neurotransmitter; ACh binds to the nicotinic and muscarinic receptors. When ACh binds to one of these receptors, it triggers a channels to open allowing positively charged sodium ions to enter the cell and negatively charged chloride ions to leave the cell. This makes “depolarises” the cell, which results in change in energy inside becomes it positive with respect to the outside. This generates an "action potential" and nerve signal transmission occurs.
The rate-limiting steps in ACh synthesis are the availability of choline and acetyl-CoA. Hence it can be chosen as controlling step as ACh binds only briefly to the pre or post synaptic receptors. Following dissociation from the receptor, the ACh is rapidly hydrolyzed by the enzyme acetylcholinesterase (AChE). This enzyme has a very high catalysis rate, one of the highest known in biology. AChE is synthesized in the neuronal cell body and distributed throughout the neuron by axoplasmic transport. The variation at the NMJ is a heteromeric protein composed of four subunits coupled to a collagen tail that anchors the multi-subunit enzyme to the cell membrane of the postsynaptic cell. These four-subunit form is held together by sulfhydryl bonds and the tail anchors the enzyme in the extracellular matrix at the NMJ.
Drugs can be used to inhibit ACh breakdown are effective in altering cholinergic neurotransmission. In fact, the irreversible inhibition of AChE by isopropylfluoroesters are so toxic that they can be incompatible with life inhibiting the muscles for respiration.

2. Norepinephrine pathway :
It is also known as noradrenaline is a neurotransmitter involved in the sympathetic nervous system. This neurotransmitter, along with epinephrine involved in the “flight-or-flight” response that our body makes under stressed or dangerous situations. It also involved in our sexual behaviour and control of appetite. The sympathetic nervous system is responsible for up or down regulating various homeostatic mechanisms in our bodies and the release of norepinephrine is correlated with an increase in the rate of contractions of the heart. Therefore this neurotransmitter represents in priming us for action and making us more physiologically vigilant.
Pathway : The amino acid tyrosine is transported into the sympathetic nerve axon. Tyrosine (Tyr) is converted to DOPA by tyrosine hydroxylase. DOPA is converted to dopamine (DA) by DOPA decarboxylase. Dopamine is transported into vesicles then converted to norepinephrine (NE) by dopamine β-hydroxylase (DBH); transport into the vesicle can by blocked by the drug reserpine.
Conversion of Tyrosine into DOPA is rate limiting step for NE synthesis. Which can be chosen for rate controlling step as it is based on DOPA Release.

3. Serotonin pathway :
Serotonin is another neurotransmitter in the brain plays important role in the regulation of mood, perception of pain and gastrointestinal functions. It binds to 5-HT receptors. There are 9 different types 5-HT receptars present in different regions in the brain.

5-HT synthesis is a two-step process catalyzed by tryptophan hydroxylase (TPH) and aromatic decarboxylase (DDC). TPH is the rate-limiting enzyme and exists in two isoforms TPH1 and TPH2. The TPH2 isoform is the predominant form in neuronal tissue. The 5-HT uptake into presynaptic storage vesicles is mediated by the vesicular monoamine transporter. This rate limiting step of TPH could be chosen as step for drugvdevelopment to inhibit delivery of protein.
4. Histamine pathway :
Our immune system trigger an anti-inflammatory response to certain foreign pathogens which invades to immune system. Histamines are released in this case. Histaminergic cell bodies that are involved in sleep are found primarily in the hypothalamus, from where they project throughout the brain, including regions of the cortex.
one-step enzymatic decarboxylation of l-histidine produces histamine hence HNMT inhibition can be chosen as rate limiting step for histamine pathway to trigger the inhibition of protein release to develop drug delivery system.

5. Dopamine pathway :
Dopamine is a neurotransmitter than has two different pathways.
A. The first pathway, which begins in the substantia nigra and projects to the basal ganglia is involved in movement.
B. The other pathway originates at the ventral segmental area and is commonly known as the reward or reinforcement pathway. This pathway is activated anytime when we are treated with “novel” stimulus. For better understanding when we drink water after a long race, or fall asleep after pulling an all-nighter. These actions are developed by learning with our nervous system and remembered as rewarding actions making us more likely to perform them again in the future.
Both steps were dependent on temperature and pH and were inhibited by enzymes as the reaction is enzymatic.
So enzyme inhibition can be selected as step for neurotransmitter release alteration.