THE CENTRAL NERVOUS SYSTEM (CNS)

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THE CENTRAL NERVOUS SYSTEM (CNS)

Post  counselor on Mon Oct 15, 2012 12:00 pm

THE CENTRAL NERVOUS SYSTEM (CNS)


NEURONS
The majority of neurons has only one axon (or axis-cylinder).
Have short extensions called dendrites.
At the end of the axon is a dense localization of synaptic vesicles containing neurotramettitori.

The synaptic neurons can establish relationships with a number of possible spatial arrangements:
dendro-dendritic synapses
assodendritiche
assosomatiche

Interconnections NEURONAL
1) Organizations neuronal hierarchical long. Transmission of information sequential.
2) Connections Only in the immediate vicinity of the neuron.
3) Connections pluriramificate and diverging towards different regions of the 'brain different from that in which is located the neuron. (For example by the hypothalamus or the midbrain towards cortex, bulb etc.).

CELL neuroglial
I'm not nervous cells

• astrocytes: are cells with many extensions. Cover the walls of the capillaries of the CNS. Are believed to be involved in the transport of nutrients from the blood to the neurons.
• oligodendrocytes: files are in between the fibers and are important for the formation of myelin.
• Microglia: magrofagi stray.
• ependymal cells: they form a continuous layer similar to the epithelium.

NEUROTRANSMITTERS
Substances contained in the presynaptic neuron and released it to transmit an information to its postsynaptic target.
On this target can evoke excitation or inhibition

Criteria for identifying a neurotransmitter:
1) must be present in the neuron and presynaptic terminals.
2) must be released from the presynaptic neuron simultaneously to its activation.
3) The effects of exogenous neurotransmitter must be equal to those of the stimulation of the presynaptic neuron.
4) Both responses can be blocked by a single antagonist.

Neuromodulators
Influencing neuronal activity in a different way compared to neurotransmitters.
• From just cause only little or no change in membrane potential or ion conductance. But can enhance or inhibit the response to classical neurotransmitters.
• Their actions are rather slow.
• They can not be released from synaptic sites, while influencing synaptic activity.
• They may also have synaptic actions.

Are considered neuromodulators various peptides, steroid hormones, prostaglandins, adenosine.

Neurohormones
In this case the transmitter processed by nerve cells is poured into the bloodstream.
However, a neurotransmitter in certain sites of liberation can function as a neurotransmitter classic.

Neuromediators
Substances which contribute to evoke a postsynaptic response: cAMP, cGMP, IP3


Blood-brain barrier

Anatomically the blood-brain barrier can be identified mainly vascular endothelium without intercellular spaces and in the neuroglia that surrounds them.

Overcoming the barrier is to:
1) Passive Diffusion for highly soluble molecules
2) active transport for some charged molecules such as neurotransmitters.

Various brain areas lacking blood-brain barrier. In them the vascular endothelium has large fenestration:
1) Organ sottofornicale
2) Area postrema
3) Median Eminence
4) Epiphyses

The elimination of drugs and metabolites from the CNS occurs mostly through the cerebrospinal fluid, rather than riversandoli in the blood.
Exchanges with the fluid are very intense in the choroid plexus.




MAIN CENTRAL NEUROTRANSMITTERS

GABA
It 'been identified in the CNS in 1950, but only in the 60s has been proposed as a neurotransmitter.

For glucose metabolism is formed -ketoglutarate, which is converted into glutamic acid by the enzyme GABA- chetoglutariltransaminasi of glial cells.
GABA is formed in specific neurons from glutamic acid by the action of GAD (glutamic acid decarboxylase)

GABAergic interneurons are mostly found in the cerebellum, hippocampus, olfactory bulb, lateral septum, cerebral cortex, basal ganglia, spinal cord.

There are known two subtypes of GABA receptors:

GABA A:
• Average the inhibitory responses faster.
• E 'for the Cl-ion channel
• The receptor consists of 5 subunits, each with 4 transmembrane domains. Have been described:
-6 Types of subunits 
-4 Types of 
-4 Types of 
-1 Of 
-1 Of 
-3 Of 
-1 Of 
• So there are many subtypes of GABA-A receptors with potentially different functional roles. In mammals predominate  and  subunits
• The binding of GABA to this receptor takes place on the  subunit
• The GABA increases the conductance for Cl-.
• The muscimol is a potent agonist, while the bicuculline is an antagonist.
• The receptor is typically a postsynaptic receptor, but at the level of the spinal cord is presynaptic

The receptor has also site for
• Benzodiazepines that increases the frequency of channel opening to chlorine. The site also binds compounds benzodiapinici.
• Barbiturates inside the channel increases the flow of Cl-
• pentylenetetrazole, Picrotoxin and TBPS. Reduce opening of the channel and are therefore convulsant
• General anesthetics and ethanol positively modulate the function of the GABA-A receptor
• neuroactive steroids of peripheral origin (derived allopregnanolone and tetraidrodeossicorticosterone, derived from progesterone) and central causes of neurosteroids modulate the channel

GABA B:
• Average the inhibitory responses lens.
The structural form • fully functional receptor is a heterodimer consisting of 1 unit of GABA-BR1 and 1 unit of GABA-BR2.
• E 'a receptor associated protein G. In particular it comes to protein Gi and Go acting on adenilatociclasi (disabling), on K + channels (activating) or Ca + + (inhibiting them).
• The GABA has a low affinity for this receptor.
• The receptor is both presynaptic (auto-and hetero-receptor) and postsynaptic
• The baclofen is an agonist. For baclofen have been reported effect antispasmodic, analgesic, anticraving, antineurodegenerativi (increase NGF and BDNF).
• Benzodiazepines do not affect the GABA-B receptor.


The action of GABA ends mainly for neuronal reuptake and by glial cells, through specific carriers.


GLYCINE
• Glycine is synthesized by serine idrossimetiltransferasi (SHMT) and stored in synaptic vesicles
• After his release, the neuronal and glial reuptake it ends the action.
• It 'mainly located in the spinal cord and brainstem
• The receptor for glycine is a pentamer composed of subunits  (if they know 4 types) and subunit     gefirina The protein binds to the receptor cytoskeleton
• The receptor is associated with an ion channel for the Cl-
• Glycine evokes hyperpolarization of postsynaptic neurons to increased Cl-conductance.
• It also serves as co-transmitter with glutamate on NMDA receptor.
• The activity of the receptors for glycine is modulated positively by anesthetics and alcohols, while it is antagonized by strychnine.




GLUTAMATE

• Glutamate is the major excitatory neurotransmitter
• It originates in neurons from glutamine (formed glial cells) by the glutaminase. Can also be formed starting from '-ketoglutarate or ornithine.
• Glutamate is stored in synaptic vesicles from which it is released
• The activity of glutamate reuptake ends mainly neuronal and glial (notes are 5 different carrier proteins EAAT1-EAAT5).
• The glutamate receptors are divided into ionotropic and metabotropic.

Ionotropic receptors
3 are known ionotropic receptors, which mediate rapid excitation.


1. AMPA receptor
E 'consists of four different subunits.
The channel is permeable to Na + and K +, but very little to the Ca + +
Selective agonist is l '-amino-3-hydroxy-5-methyl-isoxazol-propionic acid (AMPA)
It 'widely localized in the hippocampus, cerebellum and glia.
It 'involved in synaptic transmission and rapid phenomena of neuronal plasticity (long-term potentiation, ie long-term potentiation of neurotransmission of particularly long)


2. Receptor for the kainate
Are notes 5 subunits that form the receptor. This is present at the presynaptic level (where it inhibits the release of glutamate), but also at the level postsynaptic.
The kainate is the selective agonist
It 'involved in long-term potentiation and neurodegeneration


3. NMDA receptor
The selective agonist is the NMDA (N-methyl D-aspartate)
And 'composed of two subunits, each of which can exist in different isoforms due to alternative splicing
The channel is permeable to Na + and Ca + +

The NMDA receptor has several binding sites for
1. Excitatory amino acids
2. Glycine
3. Mg + + (voltage-dependent block of the channel)
4. Phencyclidine (PCP), which also binds to non-competitive antagonists and dissociative anesthetics (ketamine)
5. Zn + + (voltage-dependent block of the channel)
6. Spermine, spermidine, putrescine
7. Site for H +




The NMDA receptor controls:
• synaptic transmission (activation of NO-synthase, phospholipase C activation, synthesis of polyamines that determine influence of Ca + +)
• processes of long-term potentiation
• processes of neuronal degeneration and necrosis

Metabotropic receptors
• 8 metabotropic receptors have been identified
• membrane receptors are characterized by a N-terminal portion bilobed, to which they bind agonists (which determine approaching and closing of the lobes) and antagonists (which take away the lobes)

All receptor subtypes form a dimer at the time of receptor activation.


Group I belong to the receptors mGlu1 / 5.
• They are located postsinapticamente
• They are coupled to Gq proteins that activate phospholipase C, to Gs proteins that stimulate adenilatociclasi or G proteins that stimulate channels for the Ca + +

Belong to group II mGlu2 / 3
• The mGlu2 has presynaptic localization of GABAergic neurons
• The mGlu3 is localized on astrocytes
• They are coupled to Gi or Go proteins that inhibit the adenilatociclasi, inhibit the channels for the Ca + + and stimulate the channels for the K +

The third group belong mGlu4/6/7/8
• They are located at the presynaptic level and operate a negative feedback on the release of glutamate.
• They are coupled to Gi or Go proteins


SEROTONIN

• The synthesis of serotonin in neurons part dall'aminoacido L-tryptophan, which is hydroxylated to 5-hydroxytryptophan
• The latter is decarboxylated to 5-hydroxytryptamine (serotonin alias)
• Serotonin is stored in synaptic vesicles which are released by exocytosis
• The metabolism of serotonin is implemented mainly by monoamine oxidase (MAO) type A of mitochondria, up to the formation of 5-hydroxyindoleacetic acid (5HIAA)
• After release into the synaptic cleft, the main mechanism of gating is the reuptake by the specific transporter (SERT)
• The SERT is a protein with 12 transmembrane domains (5 and 6 extracellular intracellular loops). The second extracellular loop is the largest and plays an important role for the purposes of the affinity for the substrate.


Serotonergic receptors
The receptors for serotonin are classified into seven families (5-HT1 to 5-HT7) in which there are various subtypes.
It is metabotropic receptors.
Only the 5-HT3 receptors are associated with ion channel

5-HT1A receptors
It is both presynaptic receptors, both postsynaptic, coupled to Gi / o protein, which exert their effects by inhibiting the adenilatociclasi or influencing K + channels.
In the raphe nuclei are presynaptic autoreceptors located on soma and dendrites.
They postsynaptic localization in limbic areas (hippocampus, septum, amygdala)
Play an important role in controlling anxiety.

5-HT1B receptors
Are presynaptic receptors with strong localization in the cortex and basal ganglia.
Sumatriptan, agonist-receptor 5HT1D/1B is a drug for migraine.

5-HT2 receptors
We can distinguish three subtypes (A, B and C)
Are coupled to Gq/11 protein that influence the metabolism of membrane phosphoinositides.
The serotonin 5-HT2A and 5-HT2C receptors are believed to play an important role in psychosis (antipsychotics are antagonists of 5-HT2 receptors).

5HT3 receptors
Are associated with ion channel that controls the flow of Na +, Ca + + and K +.
Are located mainly in the medulla oblongata, where play an important role in the control of emesis.


Role of serotonin in the central nervous
• The serotonergic neurons have their somata in the raphe nuclei of the medulla oblongata.
• From the start rostral nucleus neurons directed to the cortex, amygdala, hippocampus, basal ganglia. These neurons have an important role in the control of emotions (anxiety and depression) and motivation, memory, sense of hunger.
• hypothalamus neurons interact with serotonergic neurons by CRF-positive and these affect the hypothalamic-pituitary-adrenal axis.
• From the start rostral nucleus neurons directly to the spinal cord, involved in the control of pain.



OXIDES OF NITROGEN

The nitrogen monoxide (NO) is produced by enzymes called NO synthase (NOS), which form NO and citrulline from L-arginine and NADPH

There are three types of NOS:
• nNOS (neuronal NOS)
It 'constitutively expressed in the CNS and skeletal muscle
E 'Ca + + dependent, because the calmodulin binds only after increase of intracellular calcium (for example by stimulation of NMDA receptors)
Linked to Ca-calmodulin and in the presence of tetrahydrobiopterin translocates to the cytoplasm where it is dephosphorylated by calcineurin and therefore activated.
In the CNS function has neuromodulator.
Excessive production of NO neurotoxicity due to the formation of superoxide and peroxynitrite

• iNOS (inducible NOS)
Interferon gamma and other cytokines, proteins trasduttrici by means of the signal, will induce gene expression.
E 'Ca + + independent, as it binds to calmodulin normal concentazioni of Ca + +, so its activation can last long.
Exerts antimicrobial and anti-cancer mechanisms radicatici.
However, is also involved in inflammatory processes (rheumatoid arthritis, septic shock, etc.)
• eNOS (endothelial NOS)
It 'constitutively expressed
E 'Ca + + dependent
Under conditions at rest is bound to the caveolin; interaction with the Ca-calmodulin separates it from caveolin, activating it.
Evokes vasodilatation, especially activating the guanilatociclasi. Mediates the vasodilatory effects of acetylcholine and substance P.
Are in the studio NO-NSAIDs to reduce the toxicity gastric, exploiting the properties of NO to increase the blood flow on the gastric mucosa


Several drugs (organic nitrates) behave as donors of NO groups, as a result of metabolic processes.

Other compounds (nitroprusside, triossidinitrato and compounds derived dell'ossatriazolio study and furossano) release NO spontaneously without metabolism.

Have been developed competitive inhibitors of NO synthase (eg. The L-NAME).




PEPTIDES

There are several families of peptides in the CNS, which regulate neurotransmission or neuromodulation:
1) Opioids
2) Tachikinine
3) Angiotensin
4) Vasopressin
5) Cholecystokinin etc.
Numerous peptides are synthesized in the form of propeptides in the rough endoplasmic reticulum.
The propeptide is cleaved and subsequently transported in vesicles to the nerve endings.
Not 'been documented for peptides reuptake mechanism.
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