This is the point at which 50% of the receptors are occupied.

It can be interpreted however as how well the affinity is of the ligand. A lower K_d represents a higher affinity of the ligand, because it takes less drug to cause receptor binding.

What is the K_i?

The K_i is found by adding a competitive drug to already saturated receptors/ligands. When half of the receptors have had their ligand replaced with the new competitive drug, you have reached the K_i.

Interpretation: the lower the Ki, the more potent/competitive the drug

Potency refers to the dose needed for a drug to have an effect. For example, if one drug requires a smaller amount to have an effect than a competeting drug, it will be more potent.

The drug with a lower K_d will have a higher potency because it will take less of the drug to bind to 50% of the receptors, making it much likely to bind. 

Dose response curves graph the amount desired effect of the drug vs. the concentration of the drug administered.

A DRC shifted to the left represents higher potency because less of the drug was used to cause the desired effect. A higher dose response curve represents a higher efficacy, because it has a higher overall effect.

Most DRCs are an inverted U- at the extremes, the drug has no/starts to lose effect. In the middle, the effect is the highest.

A therapeutic window is the range in which a drug can be effective without being dangerous (i.e., when a drug starts producing desired effects to the does at which it is starts to become dangerous). A larger therapeutic window represents a safer drug. 

They are tiny actin filaments coming off the dendrite that reduce space inbetween dentrites and axons, making them close enough to have an actual physical connection.

They are so important because they are only part of the adult brain the remains plastic through your lifetime. Their ability to be constantly changing and increasing/decreasing their number makes it possible for us to create more/less synapses and create more/less connections.

• Resistance refers to the ease at which ions can cross the membrane, which is dependent on the amount of ion channels contained in the membrane.
• Capacitance refers to the ability of the membrane to store a charge, which is dependent upon physical membrane properties (e.g., area, thickness, etc.).

They are responsible for the initial depolarization of a membrane, letting Na flow into the cell at will.

Certain drugs can sow down the recovery of Na channels from their inactive state, making it harder for them to open. This limits the firing rate of neurons (used to prevent seizures in epilepsy).

They are responsible for cell signaling. Ca flows into the cell and activates vesicle binding and NT release, leading to second messenger cascades, muscle contraction, etc.

They open at about -50 mV, so they require enough Na to flow in before triggering the release of NTs.

L, T, P/Q, N, R. P/Q and N are most responsible for NT release.

Transient receptor potential channels: they are Ca, Na, and Mg permeable. They are extremely important in sensory perception.

Chloride channels are included in these; they help damp electrical excitability in cells by keeping the negative charge.

Linking the drug to a molecule that has the ability to bind to and open a transporter molecule can get it through.

Ex: TfR receptors and transferum- transferum binds to iron and gets it into the brain through the TfR receptor. Linking a drug to this can get it into the brain with the iron.

1. Dopamine
2. Norepinephrine
3. Epinephrine

Endogenous peptides that already exist in the body. However, we come up with creative ways to administer them because most peptides get chewed up in the gut before even getting into the blood stream.

All endogenous peptide sequences have active sequences that can be cleaved out and identified, along with different properties (e.g., hydrophobic, polar, acidic, basic, etc.).

1. They can be broken down by an enzyme, then transported back into the neuron in that state. Ex: aceytlcholine is borken down into choline by acetylcholineasterase.
2. NT Transporters reuptake the NT back into the cell to be repackaged and resued (e.g., serotonin).

1. Docking
2. Priming
3. Fusion
4. Endocytosis
5. Recycling

v-SNARES are vesicular SNARES, and t-SNARES are target SNARES.

The v-SNARE protein is called synaptobrevin. After the vesicle is primed, it can interact with the t-SNARES on the membrane, SNAP-25 and syntaxin. They zip together and pull the vesicle into the membrane, fusing it and releasing NTs.

1. Ionotropic/ligand gated ion channels
2. Metabotropic/g-protein coupled receptors
3. Tyrosine kinases
4. Steroids and steroid receptors inside the membrane (steroids can traverse the membrane)

It has two different jobs:

1. Ca can activate NO synthase, which is used to help make GTP.
2. Ca can bind to calmodulin. This compound can then activate various CaMPK (Ca/calmodulin protein kinases).

There is phospholipase C-β and phospholipase C-γ. Beta is activated by the G_αq subunit.

Gamma is activated exclusively by receptor tyrosine kinases due to the presence of the SH2 domain.

They can regulate adynylyl cyclase, gunaylyl cyclase, ion channels, protein kinases, and other cellular proteins.

Antiinflammatory medicines can turn of cyclooxygenases, stopping their production. However, too much of these is bad.

1. Voltage gated ion channels (action potentials depolarize these and let Ca in).
2. Ligand gated ion channels (MMDA receptors open them)
3. Na/Ca exchanges: Na in, Ca out.
4. Ca Pumps: use gradient to get Ca out and H in
5. Ryanodine: lets Ca out
6. ATP/ADP Pump: Ca in
7. Ca binding buffer proteins
8. IP3: binds to IP3 receptor to let Ca in

The MAP-K and ERK pathways

PKA, PKG, and PKC pathways

No, many phosphotases dephosphorylate proteins that PKA/G/C may phosphorylate. Phosphotases are dominate, so to generate a signal you have two options:

You can inhibit the phosphotases, which is extremely difficult.

Or you can activate much more kinases than phosphotases.

• Grb2: an adaptor protein with an SH2 domain (enables the binding of Sos)
• Sos: a GEF for Ras 
• Ras: a GEF for Raf
• Raf: a serine-threonin kinase that runs on MEK
• MEK: a dual specificty kinase that turns on ERK
• ERK: a MAP kinase that turns on transcription factors

1. SH2 Domains: these like to interact with phosphotyrosine binding sites (ex: PLCgamma or Grb2)
2. SH3 Domains: these like to interact with polyproline rich sequences (ex: sos, the GEF for Raf)

DNA is stored in tightly wound around proteins called histomes. The single unit of a histome and its surround DNA is called a nucleosome. The entire wound up DNA strand is called chromatid.

This structure is the cells natural way to inhibit transcription of genes unless specifically activated by signaling cascades.

1. Active: chromatin is acetylated and unwound, and transcription is ocurring
2. Permissive: histomes are heaveily acetylated and chromatin is ready for transcription to beging
3. Repressed: the chromatin is primarily methylated
4. Inactive: histomes and the DNA itself are methylated, furthest from transcription

1. DNA Binding Domain: this is what recognizes the DNA sequence
2. Protein Dimerization Domain: this connects the transcription factors, creating a dimer
3. Transcriptional Activation Domain: this can be phosphorylated by certain protein kinases at phosphorylation sites, however the primary job of these is to recruit proteins such as HATs.

1. Gq receptors can generate calcium, which can combine with calmodulin to create CaMK, which can phosphorylate CREB
2. Gs receptors activate AC, which makes cAMP, which activates PKA, which through more steps activates CREB
3. Tyrosine kinases can go through Ras, Raf, MEK, and ERK (the normal MAP-K pathway), but then instead activate RSK which can activate CREB

1. kB
2. FOS
3. JUN

1. Upstream of TATA, there's a CRE (which binds CREB). CREB activates c-Fos. CREB has to be phosphorylated by either glutamate (or other neuromodulaters) or RSK to be activated.
2. Further upstream of CRE, there's a serum response element (SRE), which can also activate CREB. SRE needs to be activated (somehow) for c-Fos expression.
3. Upstream of SREs, there's a group of cytokines (compounds excreted my inflammatory cells), which signal through the tyrosine kinase pathway (however cytokines are not an actual tyrosine kinase, they activate one lower downstream, which then activates STATS).

1. They can get taken directly back in by EAAC1 receptors as glutamate.
2. GLAST or GLT-1 receptors on astrocytes take glutamate back up into glial cells. They then turn it into glutamine, which can be put back out and taken up again into the pre-synatpic cell.

1. Ionotropic: glutamate binds directly to a ligand gated channel and ions flow in
2. Metabotropic: g-proteins

1. AMPA
2. Kainate
3. NMDA

They are all cation channels, meaning they pump sodium in and potassium out. They are all also technically tetramers (AMPA isn't fully)

There are only three transmembrane domains. The fourth, located between T1 and T2, does not go all the way through. This is the Q/R-site. There is also a "flip-flop" region, which is two spliced variants of each subunit.

Glutamate binds to the extracellular regions of T1 and T2.

Group 1 receptors are coupled to Gq receptors and are primarily located on the post cell.

Group 2 and 3 receptors are coupled to Gi and Go, and are found on pre cell terminals

• PSD-95: NMDA
• Stargazin!: AMPA
• Homer: will bind to all mGluR (metabotrobic) receptors.

In chronic LTP, you also have CAMKinaseIV made, activating PKA and CREB, which transcribes genes and causes an increase in AMPA and growth proteins that caues big changes in synapse architecture.

Acute last minutes, while chronic lasts hours, to days, to weeks

It is synthesized from glutamate by glutamic acid decarboxylase.

GABA can be converted to α-ketoglutarate or succininc acid through GABA-transferase. Basically this means GABA-T tends to decrease GABA levels, even though it can also create it.

• GABA A: ionotoropic receptors- they let Cl in
• GABA B: metrabotropic receptors

1. The GABA Site: GABA binds here, or bicuculline to inhibit it
2. The Barbituate Site: agonists will bind here, allowing Cl to go through and hyperpolarize the cell; this is what anesthetics target
3. The Picrotoxin Site: picrotoxin is another convulsant that can block the channel. However, it is not competitive because it binds at a different site than gabbing, just reducing the conduction of Cl.
4. The Benzodiazepine Site: compounds that increase channel affinity for GABA bind here, increasing the probability of opening (e.g., valium)
5. Steroid Site: he didn't care about these, but it seems they can bind both antagonists and agonists (e.g.., anesthetics or anxiogenics)

They are agonists of the GABA A receptors. They have their own unique binding site and are often anxiolytics (decrease anxiety), anticonvulsants, or sleep aids (sedative).

Ex: valium, ativan, xanax

Gi and Go proteins. They open the K channels and block the calcium channels, inhibiting adneylyl cyclase.

They are primarily inhibitory autoreceptors

GABA-transaminase. It chews up GABA.

Vigabatrin can target GABA-T so it doesn't eat up as much, prolonging GABA in the cleft.

They are MAO inhibitors.

• Selegiline is used for PD
• Irponiazid can treat depression, but SSRIs work better

The substantia nigra to the striatum, this controls and coordinates motor movements (PD).

The VTA to the nucleus accumbens (reward and addiction behavior)

D2,3,4 to Gi

D 1,5 to Gs

Alpha agoneric receptors

a1 are coupled to Gq, a2 are coupled to Gi

Beta agonergic receptors

couples to Gs