1. Hetero: different subunits
2. Homo: same subunits
3. Pseudo: all one piece joined together

1. Voltage Gated: when an action potential changes the charge of the membrane and it opens
2. Stretch: touch receptors on the skin help activate it (i.e., when you touch your skin and it stretches and the stretch opens the channel)
3. Ligand: when a NT binds to the channel (inside or outside) and causes it to open (e.g., capsaicin can go through the bilayer and binds on the inside.

1. Conformational/Regional: when one part of the gate changes shape to open
2. Conformational/General: when the entire gate changes shape to open
3. Blocking particle: when a particle tethered to the channel blocks and unblocks

1. Direct/Ionotropic: a NT binds directly to the channel and opens it
2. Indirect/Metabotropic: when a NT binds to a receptor which activates a g-protein coupled receptor which goes to open a channel

1. Salt: sodium goes straight through an open channel
2. Acid: H+ molecule goes and either blocks potassium channels are starts flowing through them, either way block the flow of K+ out
3. Bitter: quinine blocks K channels
4. Sweet/Umami/Bitter: uses g-proteins to activate channels

Nicotinic

8 nm at widest point, hole is only 0.7 nm.

It has beta, gamma, and delta. Alpha is the binding site.

• 4 Domains
• Big loop between subunits 5 and 6 is what gives the channel selectivity
• Subunit 4 is the voltage sensor: it is positively charged so when the membrane changes charge it causes a conformational change

It blocks VG Na channels, acetylcholine receptors, and VG Ca channels.

Causes a very quick death.

It's a homotetramer. It has one n gate that opens up shortly have depolarization.

The Na ion cannot pass through because the O groups cannot form proper bonds with the Na ion.

Voltage gated Ca channels open during depolarization and the Ca goes and binds to these K channels intracellularly, allowing K to flow out.

ACh can bind to Ca channels, letting Ca in which can go bind to K channels to open them.

There are 4 alpha subunits, that's all we need to know.

Some activate quickly and inactivate quickly, but some also inactivate very slowly.

1. Voltage gated
2. Inward rectifiers: help restore membrane potential
3. Purinergic: for cAMP and gAMP
4. Glutamate
5. Cyclic Nucleotide-Gated Channels

• Hyper: too much potassium in blood which is treated by a high carb, low K diet
• Hypo: too little potassium in blood which is treated by a low carb, high K diet

1. Yeast: hypertonicity
2. Nematodes: noxious chemicals
3. Male Mice: pheromones
4. Humans: sweet, bitter, umami, temperature, pain
5. Mechanosensation
6. Hearing

1. Metabotropic activation of PIP2 pathway from other receptors (i.e., other receptor gets activated and a g-protein comes over and activates channel)
2. Ligand Activation: a ligand binds directly to the TRP channel (e.g., capsaicin, icilin)
3. Direct Activation: changes in temperature and mechanical activation

Activated by heat greater than 43 degrees/spiciness. Heat or H+ can activate from the outside. Capsaicin goes through the bilayer and attaches to the inside.

Ca and Na are let through.

1. Bell Pepper: 0 Scovill units
2. Jalapeno: 2,000 - 5,000
3. Serrano: 5,000 - 15,000
4. Thai: 50,000 - 100,000
5. Habanero: 100,000 - 300,000

1. TRPM5: tastes bitter, sweet, and umami; this happens through downstream effects --> tastes activate transient receptors which cause 2nd messengers to activate TRPM5
2. TRPM8: temperatures below 26 degrees, methol, and icilin

• Noxious cold (not common)
• Horseradish
• Mustard Oil
• 9-tetrahydrocannibinol
• Cinnamaldehyde
• Ginger
• Mechanosensation
• Olfaction
• Osmosensation

It can interact with TRPV1

Pheromone detection in mice

Male mice that lack this receptor do not display correct behavior and will mate with male/females indiscriminately.

Lack of pheromone-evoked neuronal acitivity in the vomeronasal organ.

1. TRPC3: hey are photosensitve retinal ganglion cells.
2. TRPC5: in the amygdala; without these, mice exhibit diminished fear levels

• Sir John Eccles: brit that said predominant synapse would be electrical
• Bernard Katz: Eccles' student, he said no they were mostly chemical

The 2-3nm between two membranes. There are actual structures connecting them.

In a chemical synapse, it is more around 16-30, maybe even 40.

The are what connect two membranes and forms pores. Each membrane has half and it allows smaller substances to pass through.

Each connexon has 6 subunits, which are called connexins.

If all connexons are open, the coupling coefficient is 1. If half are open, the efficient is 0.5.

Depolarizing a cell can open up gap junctions, raising the CC.

With a normal CC, when the membrane is depolarized it will get higher.

In hysteresis, the CC remains constant regardless of the membrane potential.

One that allows current to flow only one direction (same concept as rectifying channels).

The nerve in crayfish that allows them to flick their tails so quickly.

1. Gray's Type I: asymmetrical and typically excitatory; there is more density in post cell and vesicles are circular
2. Gray's Type II: symmetrical and typically inhibitory; they have qual density everywhere and vesicles are flatter

1. Enzymatic degradation (e.g., ACh by cholinesterase)
2. Diffusion
3. Re-uptake

1. Must be synthesized in pre neuron
2. Must be found in a high enough concentration to be considered meaningful
3. Have same effect when applied externally
4. It can be blocked by pharmacological substances
5. Must be removed in specific way from synapse

1. Docking
2. Priming (needs ATP)
3. Exoctyosis (needs Ca)
4. Endocytosis
5. Translocation
6. Endosome Fusion
7. Budding
8. NT Uptake
9. Translocation

• Vesicle Side: snyaptobrevin and synatotagmin
• Membrane Side: SNAP-25 and syntaxin

Put tissue in a tube and it would slide down while exocytosis was occuring and freeze i t in the middle of the process. Can then view it with microscopy.

The views of vesicle as they are bound and exocytosing.

Miniature end plate potentials

They are the muscle's equivalent of EPSP.

Heteropentimer. Only binds to the two alpha subunits.

ACh receptors are permeable to Na ions when activated.

1. Direct
2. Presynaptic
3. Shunting

• Mainly amines
• Produced in relatively short biosynthetic pathways. This allows reconversion of inactivated transmitter substances at the actual axon terminal

• Tyrosin
• L-DOPA
• DA
• NE
• Epinephrine

• Serotonin
• Histamine

A pentamer receptor

It is a ligand gated ion channel that lets Cl- in. It hyperpolarizes the postsynaptic nerve (inhibitory).

It is metabotropoic!!

On pre cell, it inhibits Ca channels, preventing vesicular release.

On post cell, it activates potassium channels, which hyperpolarizes the cell.

• NO: promotes cGMP production
• CO: promotes cGMP production and potassium channels
• H₂S: promotes cAMP and potassium channels

1. Amino Acids (glutamate)
2. Amines and Purines (catecholamines and indolamines)
3. Peptides

• Nicotinic ACh
• GABA
• Glycine
• AMPA
• NMDA

• G-protein coupled receptors
• a and B adrenergic
• Serotonin
• Dopamin
• Muscarinic ACh

• Leading disability worldwide
• 9.5% adult Americans
• Twice as many women as men

1. Abnormality of mood: up-mania, down-depression
2. Vegetative Features: sleep, appetite, weight gain/loss, sex drive
3. Cognitive Features: attention span, frustration tolerance, memory
4. Impulse control: suicide, homicide
5. Behavior Features: motivation, pleasure, interests, fatigability
6. Physical: headaches, stomach aches, muscle tension

When treatment improves at least 50% of symptoms. Not cured, but better.

Remission is when all symptoms all clear for several months.

Recovery is when symptoms stay gone for more than 6 months

Relapse is when symptoms return following remission.

• Monopolar/Major: 17% lifetime risk; intense sadness, disruption of circadian rhythms, suicidal behavior, good response to drugs
• Dysthymic: low grade but chronic depression that lasts more than 2 years
• Bipolar: depression, full mania, lesser mania, mixed episodes; can cycle 4 times in 12 months

67% respond after 8 weeks, but the other 33% don't response at all.

All antidepressants have the same response rate.

Placebos are THE OPPOSITE, 33% respond within 8 weeks, 67% do not respond at all.

• Multiple prior episodes
• Incomplete recoveries
• Sever episodes
• Chronicity
• Bipolar/psychotic

• 1 of 7 with recurrent depression commits suicide
• 70% of suicides of depression
• 70% of suicides see their primary care physician within 6 weeks of suicide
• Suicide is 7th leading cause of death in US

• Women: menstrual cycle, pregnancy, postpartum depression, miscarriage, pre-menopause, menopause
• Men: less like to admit it, 4 times the suicide rate, increased risk or coronary disease

• Shock therapy to increase NE and 5HT
• Trephination
• Frontal lobotomies
• Deep brain stimulation (still used)
• CBT and IPT (still used)
• Drugs (still used)

• Use began in 1950's for a ton of disorders
• They are nonselective MA reuptake inhibitors (5HT and NE, but can affect more)
• Extremely easy to overdose on, leading cause of death by drugs in US; can also cause cardiac complications
• Side effects: dry mouth and eyes, unusual taste in mouth, blurry vision, weight gain, restlessness, anxiety constipation
• Examples: imipramine, amitriptyline, desipramine, clomipramine, limbitrol

• They inhibit the enzyme that break down monoamines (MAOs)
• MAO A: breaks down 5HT, NE, tyramine; clorgiline blocks this
• MAO B: DA; selegiline blocks this

• Tranylcypromine and phenelzine (block both A and B)
• They have serious side effects and interactions --> low blood pressure, light headedness, insomnia, sleepiness, dry mouth, weight gain, reduced alcohol tolerance, headache, CNS stimulation, venous pooling, sexual disturbances
• Cannot eat tyramine while on these --> it's an amino acid present in many foods and you cannot metabolise it when on MAOIs. It will displace NE and E from nerve endings and adrenal glands. This leads to headache, cardiac arrhythmias, cardiac failure, and cerebral hemorrhage.

Beer, ale, Chianti wine, vermouth, whiskey and liqueurs

Banana peels, bean curd, soy bean, cheese, ginseng, sausage, bologna, pepperoni, salami, shrimp paste, soups, yeast extracts

1. Trazodone: it's nonlethal overdose; effects are sedation, hypotension, preapism, dry mouth, blurred vision, nausea, headache, weight gain
2. Buproprion: anxiety, insomnia, weight loss; start in low doses and taper up

• Fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram
• They are better tolerated then TCAs and MAOIs, but can cause anxiety, insomnia, more appetite, tremors, GI symptoms, headache, rashes, sexual dysfunction

Raphe Nucleus

When serotonergic drugs are taken together, can lead to fever, agitation, hypertension, hyperthermia, rigidity, myoclonus, seizure, coma, death.

• Depression, bulimia, and OCD
• SSRI, it also upregulates GABA-B receptors and may have very small effects on 5HT receptors
• Anxiety, insomnia, weight loss, mania, siezures

• Depression, panic disorder, OCD, and PTSD
• Inhibits 5HT reuptake in CNS, weak effects on adrenergic synapses, downregulates NE receptors
• Dependence, extreme agitation, hostility, aggression, suicide; it's very controversial and there has been a lot of law suits

• Depression
• Most potent SSRI, also has slight affinity for muscarinic and NE receptors
• Nausea, somnolence, sweating, tremor, dizziness, dry mouth, insomnia, male sexual dysfunction

• Depression, panic disorder, OCD, eating disorder, chronic tension headaches
• SSRI
• Dry mouth, constipation, decreased appetite, nausea, insomnia, drowsiness, dizziness, headache, agitation, sleep disorders, diarrhea, weakness, hypomania, nervousness, sexual problems

• Depression
• Very specific SSRI
• Mania/hypomania, serotonin syndrome symptoms

• Depression, anxiety, motor retardation, cognitive and sleep disturbances
• Targest specific 5HT receptors, enhances 5HT and NE transmission, excites 5HT1 and inhibits 5HT2/3, antagonist for histamine sometimes
• Drowsiness, increased appetite, weight gain, dizziness; should not be used with other antidepressants or MAOIs, painkillers, or antihistamines.

It's specificity causes fewer serotonergic effects

• Depression, GAD, and fibromyalgia
• SNRI
• More effective than fluoxetine

• Depression, first melatonergic antidepressant
• Relieves sleep complaints by agonist on MT1/2 (melatonin receptor); not approved in US

• Depression, panic disorder, ADD/ADHD
• NRI, stimulates alpha-2 and beta-NE receptors
• No good reviews

• Depression, panic disorder, ADD/ADHD
• Blocks 5HT2a receptors and inhibits 5HT and NE reuptake
• Discontinued in some countries because of liver damage

What is venlafaxine used to treat? What is its MOA? Side effects?

"Prozac with a punch"

• Depression: 6th most popular antidepressant
• Inhibits reuptake of NTs nonselectively (like tricyclics) but has no effect on muscarinic, alpha adrenergic, or histaminergic receptors

• Low grade depression or dysthymia
• SDRI
• Not in US

• Depression
• Reduces glutamate release and increases reuptake
• Liver damage

• Symptoms of bipolar disorder (depression, mania, mixed state)
• SSRI/SNRI

• Inflated self-esteem
• Severe insomnia
• Excessive talkativeness
• Racing thoughts
• Distractibility
• Activities done to excess
• Pursuit of risky behaviors

• Lithium
• Valproate
• Olanzapine
• Geodon
• Seroquel
• Lamotrigin, gabapentin, topiramate

Yes, but usually by accident.

Nausea, vomiting, diarrhea, tremor, confusion, arrhythmias, convulsions

Tremor, sedation, ataxia, aphasia, thyroid enlargement, polyuria, salivary gland dysfunction, arrhythmias, edema, leucocytosis

• Bipolar disorder
• Blocks D2 and 5HT2 receptors

• Bipolar, schizophrenia, add-on for depression
• High affiniy for D2/3, 5HT1/2a receptors

• Bipolar
• It's very specific

New and treats depression very quickly. Also works on bipolar and suicidal behavior

Blocks the NMDA receptor and enhances AMPA receptor