# Structural Biochemistry/Signaling Within Neurons

Signaling allow neurons to communicate with each other. This usually involves long and complex signaling pathways, which results in an action being taken. Examples of different intracellular signaling include paracrine signaling, endocrine signaling, and both chemical and electrical synapses. In paracrine signaling, chemicals are secreted onto local target cells. In contrast, endocrine signaling secretes the chemicals or hormones directly into the bloodstream, which then delivers the chemicals to their intended targets.
A general purpose of chemical signal transduction is to allow for the amplification of a signal. A single ligand can binding to a receptor, which then releases proteins to bind to other signaling molecules and receptors, can exponentially increase the amount of molecules trying to reach a target protein, thereby greatly increasing the binding of the molecules to the targets and the potency of the signal.
Signaling molecules are grouped into three classes: cell-impermeant molecules, cell-permeant molecules, and cell-associated signaling molecules.
Cell-impermeant molecules are molecules that are unable to cross the lipid bilayer plasma membrane and must therefore bind to extracellular receptors. Neurotransmitters are considered cell-impermeant molecules.
Cell-permeant molecules are molecules that are relatively insoluble and are able to cross the lipid bilayer plasma membrane to bind to intercellular receptors. Steroids are considered cell-permeant molecules.
Cell-associated signaling molecules are able to only bind to receptors that are in direct contact with the target.

## Receptors

There are several types of receptors that receive these different signaling molecules. The binding of a molecule to a receptor will initiate a conformational change within the receptor, which allows signaling to occur.

### Channel-linked Receptors

These receptors are also called ligand-gated ion channels. These receptors function by opening or closing their channels when a signal binds to the receptor site. The opening of the channel allows ions to flow across the membrane which leads to an ion gradient across the membrane.

### Enzyme-linked Receptors

Enzyme-linked receptors are comprised primarily of protein kinases, which phosphorylate target proteins inside the cell. A signal first binds to an inactive enzyme. This activates the enzyme, which allows a product to be made.

### Intracellular Receptors

Intracellular receptors are usually activated by cell-permeant or other molecules that can pass through the membrane. When the signalling molecule transverses the lipid bilayer plasma membrane and binds to the receptor, the inhibitory complex dissociates and becomes the activated form of the receptor. This begins a signaling cascade that regulates the transcription of DNA.

### G-Protein-Coupled Receptors

G-Protein-Coupled receptors (GPCRs) are activated when a signal molecule binds to the receptor, which then binds a G-protein, thereby activating it. There are two types of G-proteins: heterotrimeric G-proteins and monomeric G-proteins.

#### Heterotrimeric G-proteins

Heterotrimeric G-proteins contain three subunits: α, β, and γ. These three subunits are normally inactive when binded together. When a signalling molecule binds to the receptor, phosphorylation occurs and the GDP turns into GTP, which then allows the α subunit to dissociate, thus activating the G-protein. The α subunit then binds to an effector protein and allows for difference responses and mechanisms throughout the cell.

#### Monomeric G-proteins

Monomeric G-proteins are also known as small G-proteins. They use a similar mechanism to heterotrimeric G-proteins. However, instead of the three subunits, a G-protein called ras (named for its discovery in rat sarcoma tumors) is used. The binding of a signaling molecule to the receptor phosphorylates GDP to GTP and actives ras, allowing it to transmit a signal to its target proteins.

## Second Messengers

Second messengers are used as signaling molecules between neurons.

### Calcium

The calcium ion (Ca$^{2+}$) is one of the most abundant second messengers seen in neurons. The influx of Ca$^{2+}$ into the cell depolarizes the cell so many mechanisms may occur.

#### Sources

There are four methods of increasing Ca$^{2+}$ in the interior of the cell:
* Voltage-gated calcium channels open in response to the initial depolarization, which allows a further Ca$^{2+}$ influx.
* Ligand-gated calcium channels open in response to ligand attachments.
* Ryanodine receptors, which are bound to the endoplasmic reticulum are activated in response to the rise in intracellular levels of Ca$^{2+}$. This causes the channels to open and an efflux of Ca$^{2+}$ from the endoplasmic reticulum into the interior of the cell.
* Inositol trisphosphate (IP$^3$) receptors, also bound to the endoplasmic reticulum, are activated by IP$^3$ binding to its receptor. Similarly to the ryanodine receptor, this causes to the channels to open and an efflux of Ca$^{2+}$ from the endoplasmic reticulum to flow into the cell.

#### Removal

There are several ways to remove Ca$^{2+}$ from the cell:
* Na$^+$/Ca$^{2+}$ exchanger on the plasma membrane exchanges inflowing Na$^+$ for outflowing Ca$^{2+}$.
* Membrane Ca$^{2+}$ pumps use ATP for active transport to transport Ca$^{2+}$ out of the cell.
* Ca$^{2+}$ binding proteins bind to Ca$^{2+}$ and remove their activating abilities.
* Intracellular Ca$^{2+}$ pumps on the endoplasmic reticulum use ATP to pump Ca$^{2+}$ back into the endoplasmic reticulum.
* Mitochondria also remove calcium from the cell.

#### Intracellular Targets

These are some examples of targets will initiate some sort of response when bound and activated by Ca$^{2+}$.
* Calmodulin will bind to other targets. It is one of the main initiator targets of downstream signaling cascades.
* Protein kinases add phosphate groups to proteins (phosphorylation).
* Protein phosphatases remove phosphate groups from proteins (dephosphorylation).
* Ion channels
* Synaptoptagmin is an essential protein involved in trafficking synaptic vesicles, containing neurotransmitters, to the surface of the presynaptic terminal for release.

### Cyclic AMP and Cyclic GMP

Cyclic adenosine monophosphate (cAMP) is produced when adenylyl cyclase, which is activated by G-proteins in the plasma membrane, acts on ATP to remove two phosphate groups. The most common target of cAMP is the cAMP-dependent protein kinase (PKA) which is often triggers many mechanisms and responses. Cyclic guanosine monophosphate (cGMP) is produced in a very similar process as cAMP, where guanylyl cyclase acts on GTP to remove two phosphate groups. Also similarly to cAMP, the most common target for cGMP is the cGMP-dependent protein kinase (PKG) which also serves a similar function as PKA.

### IP$^3$ and Diacylglycerol (DAG)

In both the cases of IP$^3$ and DAG, phosphatidylindositol bisphosphate (PIP$_2$) is cleaved by an enzyme called phospholipase C, which is activated by calcium ions and G-proteins. The result of this cleaving produces IP$^3$ and DAG. DAG goes on to target protein kinase C (PKC), within the cell, which causes phosphorylation to occur in its targets, triggering a signaling cascade. IP$^3$ binds to the IP$^3$ receptors, which then allow a calcium efflux from the endoplasmic reticulum.

### Modulation

- modulation refers to the synaptic transmission that modifies effectiveness of EPSPs generated by other synapses with trasmitter gated ion channels such as activating NE beta receptor. -The mechanisms are: 1. NE, the neurotrasmitter, binds to the corresponding receptors on posynaptic neurons, which activates G-protein in membrane 2. The G-Protein then activates the enzyme, adenylyl cyclase 3. Adenylyl cyclase then converts ATP into second messenger, cAMP. 4. cAMP activates a protein kinase that causes a potassium channel to close by attaching a phosphate group to it.
* File:Modulation.jpg

## Dendritic Information Processing

- A Cell with an axon can have local ouputs through its dendrites (back propagation) - Dendrites can carry out complex computations with mostly passive properties - Distal dendrites can be closely linked to axonal output (ie. large diameter apical dendrite) - Many neurons show a separation of their dendritic fields

## Population Coding

- population coding hypothesis states that information within brain is carried by pools of neurons not by a single neuron system
1. The Independent-Coding Hypothesis - each neuron contributes to the pool independently - the "vote" of each neuron gives a population vector
2. The Coordinated-Coding Hypothesis - the relationships among the neurons in a population is an important part of the signal - the signal cannot be decoded without considering spike synchrony, oscillations, or some other relationship among the neurons in the population.
* Characteristic Patterns of Activity

## References

Purves, Dale, et al. Neuroscience, 4th Edition. Sunderland, MA: Sinauer Associates, Inc., 2008. Purves, Dale, "Principles of Cognitive Neuroscience", Sinauer Associates, Inc., 2008