Neurotransmitters and Receptors


Neurotransmitters and Receptors

Chemical neurotransmitters can be broadly classified into two groups: classical low-molecular-
weight transmitters and neuropeptide transmitters. The low-molecular-weight transmitters
are synthesized within the presynaptic terminal. The necessary synthesizing enzymes are
produced within the soma and transported to the terminal region. Neuropeptides, on the other
hand, are fabricated in the soma and carried via axonal transport mechanisms to the synaptic
terminal.


Although the processes of transmitter synthesis, release, degradation, uptake, and physiological
effect are not completely understood for the peptides, they are fairly well characterized for many
of the low-molecular-weight transmitters.

Classical Neurotransmitters

Acetylcholine 
 
One of the first low-molecular-weight transmitters to be studied was acetylcholine  (ACh).  It is found not only in the central nervous system but also in the peripheral nervous system, where it acts as the chemical transmitter between nerve and muscle.  ACh is synthesized from acetyl CoA and choline with the catalytic enzyme, choline acetyltransferase.  ACh is packaged and stored in vesicles within the presynaptic terminal, where is it positioned for release near the active zones.  The fusion of the synaptic vesicle with the presynaptic membrane causes the release of ACh into the synaptic cleft. It then diffuses across the cleft and binds with receptors on the postsynaptic membrane

 

In the central and peripheral nervous systems, there are two types of receptors for acetylcholine: nicotinic receptors and muscarinic receptors.  Nicotinic acetylcholine receptors are sensitive to nicotine, while muscarinic receptors respond to the drug muscarine.







Nicotinic Acetylcholine Receptors 

 

Nicotinic acetylcholine receptors have been well characterized and found to consist of five subunits: beta, gamma, delta, and two alphas. The five components are thought to be arranged so that an ion channel is formed at the central core of the receptor. The active binding sites for the nicotinic receptor are on the two alpha subunits. Both binding sites must be occupied by an acetylcholine molecule in order for the receptor to become activated. Once activated, the receptor opens its gate to permit the simultaneous influx of Na+ ions and the efflux of K+ ions.

As we have previously seen, the electrochemical driving forces for Na+ influx are much greater than for K+ efflux. Consequently, the excess positive charge movement into the cell causes the membrane to depolarize. The ion channel of the nicotinic receptor remains in the open state until ACh uncouples from its receptor. After ACh dissociates from its receptor, the receptor channel closes and Na+ and K+ are no longer able to pass through the ion channel. ACh is then free to diffuse within the synaptic cleft, where it binds with the membrane-bound enzyme acetylcholinesterase, AChE. The AChE enzyme degrades ACh by hydrolysis to produce choline and acetate. Choline is then taken up into the presynaptic terminal by a high-affinity choline transporter mechanism and recycled to be used again to synthesize ACh. This process of cholinergic nicotinic transmission is found in various areas of the brain and at the neuromuscular.

Muscarinic Acetylcholine Receptors 

 

The structure and function of the second type of acetylcholine receptor, the muscarinic receptor, are quite different from those of the nicotinic acetylcholine receptor. Two types of muscarinic receptors, M1 and M2, have been identified. Both are composed of 7 membrane-spanning domains and both exert their actions through a G protein. The activation of M1 receptors, however, results in a decrease of K+ conductance via phospholipase C, while M2 receptor activation causes an increase in K+ conductance via the inhibition of adenylate cyclase. As a consequence, when ACh binds to an M1 receptor it depolarizes the membrane, and when it binds to an M2 receptor it causes a hyperpolarization.




Biogenic Amines 

Biogenic amines are a class of low-molecular-weight transmitters characterized by the presence of an amine group. A subgroup of the biogenic amines, the catecholamines, have a catechol ring. This subgroup includes the transmitters dopamine, norepinephrine, and epinephrine. The synthesis of each catecholamine follows a similar biochemical pathway that starts with the synthesis of dopamine.


Dopamine 


 

 
Norepinephrine (NE) is another member of the catecholamine family that is found throughout the central nervous system and also at the junction between nerves and smooth muscles in the autonomic nervous system. Norepinephrine is synthesized from dopamine by the enzyme dopamine-beta-hydoxylase (DBH).

Dopamine is an organic compound synthesized from the amino acid tyrosine, which is converted to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase (TH). Tyrosine hydroxylase is the controlling enzyme that regulates the overall synthesis of dopamine. DOPA, in turn, is converted to dopamine by the enzyme DOPA decarboxylase.

Based on their pharmacological properties, two subtypes of dopamine receptors have been identified: D1 and D2. D1 receptors are coupled to Gas proteins, leading to the activation of adenylate cyclase (AC), while D2 receptors are coupled to Gai proteins, which cause a decrease in AC activity. The activation of D2 receptors has been shown to hyperpolarize the postsynaptic membrane by increasing potassium conductance. After uncoupling with the receptor, dopamine is transported by a re-uptake pumping mechanism back into the presynaptic terminal, where it is repackaged into synaptic vesicles. Eighty percent of the dopamine within the synaptic cleft is transported back to the presynaptic terminal. Thus, the re-uptake process is the main mechanism by which dopamine transmission is terminated. The remaining 20% of dopamine is degraded within the cleft by the enzyme catechol-O-methyl transferase (COMT).

The synaptic transmission of dopamine is greatly affected by commonly used illegal drugs. Cocaine, for example, inhibits the re-uptake of dopamine into the presynaptic terminal, and amphetamine  increases the release of dopamine into the synaptic cleft. Both drugs effectively increase the levels of dopamine within the cleft to activate dopamine receptors to induce their psychophysiological effects.


Norepinephrine 

 

 

A variety of amino acids also satisfy the conditions necessary to be classified as neurotransmitters. We will consider only glutamate and gamma amino butyric acid, since they are found in great abundance throughout the nervous system.

The formation of NE is quite labile and is regulated by mechanisms that can change the enzymatic activity associated with NE synthesis over either a short or long period of time. The short-term changes involve the modulation of tyrosine hydroxylase. Typically the activity of TH is regulated by both dopamine and norepinephrine by the process of end-product inhibition. When the enzyme undergoes phosphorylation, however, the process of end-product inhibition is less effective. In addition, the phosphorylation of tyrosine hydroxylase increases the affinity of the enzyme to the tyrosine substrate. Thus the phosphorylation of the tyrosine hydroxylase can increase its enzymatic activity. The phosphorylation of tyrosine hydroxylase has been shown to occur by cAMP-dependent protein kinase and Ca2+/calmodulin mechanisms. The short-term increases in the synthesis of NE occur within minutes and are easily reversible.

Long-term increases in NE can be caused by factors such as stress, since stress can lead to increases in tyrosine hydroxylase and dopamine beta-hydroxylase enzymes. Environmental factors can therefore play a significant role in modifying nerve cell function on a long-term basis.

The binding of NE to the adrenergic alpha receptor in the central nervous system opens K+ channels and causes a hyperpolarization of the postsynaptic cell. In the peripheral nervous system, two types of norepinephrine receptors have been identified: alpha receptors and beta receptors. Alpha-1 receptors are found on the smooth muscles of blood vessels. When they are activated, an increase in Ca2+ ion influx occurs, which in turn causes the contraction of smooth muscles. Alpha receptors also stimulate the hydrolysis of phosphatidylinositol, a lipid in the postsynaptic membrane that activates the intracellular messenger diacylglycerol (a.k.a. diglyceride). Diacylglycerol in turn activates protein kinase C, which initiates a variety of cellular functions.

Beta-2 receptors are also found on smooth muscles. Their activation, however, results in a relaxation of smooth muscles by mechanisms that remain to be determined. In addition to activating ionic channels, the binding of NE to beta-2 receptors activates metabolic pathways by converting ATP to cAMP. As previously discussed, this second messenger in turn activates a cAMP-dependent protein kinase, which regulates a number of important cellular. Beta-1 receptors are found in the heart, kidney, and adipose tissue, where they are responsible for the acceleration of heart rate, renin secretion, and lypolysis, respectively.

Alpha-2 and beta-2 receptors are located on the membrane of the presynaptic terminal and appear to regulate the amount of NE that is released (Panel b). These receptors are often referred to as autoreceptors. As the amount of NE within the synaptic cleft is increased, more alpha-2 autoreceptors become activated. These autoreceptors then inhibit the release of NE from the presynaptic terminal in a process of feedback inhibition. The activation of beta-2 receptors, on the other hand, increases the release of NE in a process called feedback excitation.

After uncoupling from its receptor, NE is taken back up into the presynaptic terminal, where it is repackaged into vesicles in preparation for release again into the synaptic cleft. As with dopamine, this re-uptake process removes approximately 80% of the NE from the synaptic cleft and is the main mechanism that terminates NE synaptic transmission. The remaining NE is degraded within the cleft by the enzyme COMT.


Serotonin 

Another common biogenic amine is 5-hydroxytryptamine (5-HT), or serotonin. It is found throughout the brain, but is primarily synthesized in the region of the brain stem. The synthesis of 5-HT begins with the amino acid tryptophan, which is converted to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase. In turn, 5-HTP is converted to serotonin by 5-HTP decarboxylase.

After its release into the synaptic cleft, serotonin can interact with several types of serotonin receptors. The best characterized serotonergic receptors are the 5HT-1A, 5HT-1C, 5HT-2, and 5HT-3 receptors. Activation of either the 5HT-1A or 5HT-1C receptors results in IPSPs. The inhibitory potential of 5HT-1A receptor activation, however, is mediated by an increase in K+ conductance via cAMP as the second messenger, while that produced by 5HT-1C activation is carried out by an increase in Cl- conductance via IP3. Activation of either the 5HT-2 or 5HT-3 receptors results in the generation of EPSPs. The excitatory potential produced by the activation of the 5HT-2 receptor is due to a decrease in K+ conductance via IP3, while the 5HT-3 receptor is directly coupled to an ion channel that allows the influx of Na+ ions and the efflux of K+ ions.

After uncoupling from its receptor, serotonin is transported back into the presynaptic terminal. As with NE and DA, approximately 80% of the serotonin within the synaptic cleft is removed by this re-uptake process. The remainder of the serotonin is degraded by an enzyme called monoamine oxidase (MAO).


Amino Acids Neurotransmitters 

A variety of amino acids also satisfy the conditions necessary to be classified as neurotransmitters. We will consider only glutamate and gamma amino butyric acid, since they are found in great abundance throughout the nervous system.

Glutamate 


 

 

Glutamic acid or glutamate is synthesized from alpha-ketoglutarate by way of the citric acid cycle. It is one of the most potent excitatory neurotransmitters in the nervous system. There are three subtypes of glutamate receptors: kainate, AMPA, and N-methyl-D-aspartate (NMDA). Activation of the kainate and quisqualate receptors produces excitatory postsynaptic potentials by opening ion channels that increase Na+ and K+ conductance. NMDA receptor activation results in an increase in Ca2+ conductance. This receptor, however, is blocked by Mg2+ when the membrane is in the resting state and becomes unblocked when the membrane is depolarized. Thus the NMDA receptor can be thought of as both a ligand and a voltage-gated channel.

Synaptic transmission by glutamate is terminated in part by its re-uptake into the presynaptic terminal. Much of the glutamate within the synaptic cleft, however, is transported into glial cells. There, it is converted to glutamine by the enzyme glutamine synthase. Neuropeptides are chemical transmitters that consist of chains of amino acids. The processing of neuropeptides differs considerably from that of low-molecular-weight transmitters. Neuropeptides are synthesized in the soma of neurons rather than in the synaptic terminal. In addition, neuropeptides are created when large proteins, or polyproteins, are broken down. The various peptides are packaged within secretory vesicles and carried to the terminal area by mechanisms of fast axonal transport. Within the synaptic terminal, vesicles containing peptides are found to co-exist with vesicles containing low-molecular-weight transmitters. It is thought that the released neuropeptide modulates the actions of the low-molecular-weight neurotransmitter.. The glutamine in turn is transported back into the presynaptic terminal, where it is then reconverted to free glutamate and repackaged into vesicles. Glial cells, therefore, play a critical role in regulating glutamate neurotransmission.


Gamma Amino Butyric Acid 


 

 

Another amino acid neurotransmitter found throughout the central nervous system is gamma amino butyric acid (GABA). GABA is a potent inhibitory neurotransmitter synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD).

There are two types of GABA receptors: GABAA and GABAB. The GABAA receptor is a ligand-gated Cl- channel, and its activation produces inhibitory postsynaptic potentials by increasing the influx of Cl- ions. This receptor is composed of 2 alpha and 2 beta subunits, each of which spans the membrane 4 times. Its activation requires the binding of GABA to the beta subunits. The increase in Cl- conductance is facilitated by drugs called benzodiazepines, which bind to the alpha subunits. Benzodiazepines such as librium are used as anticonvulsants and sedatives.

The activation of the GABAB receptor also produces inhibitory postsynaptic potentials. With this receptor, however, the IPSP results from an increase in K+ conductance via the activation of a G protein. The synaptic transmission of GABA is terminated by its re-uptake into the presynaptic terminal and by its transport into glial cells. The mitochondria within glial cells convert GABA into succinic semialdehyde by the enzyme GABA-T. At the same time, this enzyme is coupled to the conversion of alpha-ketoglutarate to glutamate. Glutamate in turn is converted to glutamine by glutamine synthase and is then transported to the presynaptic terminal. Within the presynaptic terminal, glutamine is converted into glutamate and subsequently into GABA to be packaged into synaptic vesicles.

Neuropeptide Neurotransmitters 

Neuropeptides are chemical transmitters that consist of chains of amino acids. The processing of neuropeptides differs considerably from that of low-molecular-weight transmitters. Neuropeptides are synthesized in the soma of neurons rather than in the synaptic terminal. In addition, neuropeptides are created when large proteins, or polyproteins, are broken down. The various peptides are packaged within secretory vesicles and carried to the terminal area by mechanisms of fast axonal transport. Within the synaptic terminal, vesicles containing peptides are found to co-exist with vesicles containing low-molecular-weight transmitters. It is thought that the released neuropeptide modulates the actions of the low-molecular-weight neurotransmitter.

At the terminal ending, the process of synaptic transmission of peptides is different from that of low-molecular-weight transmitters. Once they are released into the synaptic cleft, there are no re-uptake mechanisms to recycle the neuropeptides. Therefore the process of peptide transmission cannot be sustained as it is for the low-molecular-weight transmitters.

Neuropeptides can be classified in one of several families of peptides based on their amino acid sequence and function. The family of neurohypophyseal peptides is structurally similar to those found in the posterior pituitary and function to regulate plasma osmolarity and lactation. Secretins and gastrins are peptides that are structurally similar to the peptides and hormones found in the gastrointestinal system. The family of insulins is similar in structure to the insulin hormone and is responsible for the growth and maintenance of nerve cells, while the somatostatins are structurally similar to growth hormone.

Opiates are peptides that bind to opioid receptors. They appear to be involved in the regulation of pain information. Opioid peptides include met-enkephalin, leu-enkephalin, dynorphin, and beta-endorphin. Structurally, they share homologous regions consisting of the amino acid sequence Tyr-Gly-Gly-Phe. The opiates are derived from three propeptides: proenkephalin, pro-opiomelanocortin, and prodynorphin. Proenkephalin gives rise to met- and leu-enkephalin; pro-opiomelanocortin gives rise to beta-endorphin; and prodynorphin is the precursor of dynorphin. There are several opioid receptor subtypes. Beta-endorphin binds preferentially to mu opioid receptors; enkephalins bind preferentially to delta opioid receptors, and dynorphin binds preferentially to kappa receptors. The enkephalins are metabolized by two enzymes: aminopeptidase, which hydrolyzes the Tyr-Gly bond, and enkephalinase, which hydrolyzes the Gly-Gly bond.

From our discussion of chemical neurotransmitters, it can be seen that nerve cells are capable of producing a variety of transmitters. Individual nerve cells, however, are able to synthesize only specific combinations of low-molecular-weight and peptide transmitters based on the enzymes they have available. This defined set of chemical transmitters is used by a neuron at all of its synapses to transduce the action potentials it generates into chemical signals that are detected by target cells.


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