IFF conditions:

a. synthesized in presynaptic neuron

b. present in presynaptic terminal and released in amount to cause defined action on post-syn.

c. exogenous addition to pre-synaptic mimics normal stimulation

d. mechanism  for removing from synaptic cleft              → eliminates NT-like molecules

each neuron releases only 1 neurotransmitter type

↓

not always true but generally useful

1. Name amino acid transmitters, calecholamine transmitters

2. Name other important transmitters

1. amino acid - Glutamate

            -GABA

               - Glycine

calecholamine - "fight or flight"

                 - dopamine

                        - norepinephrine

                    - epinephrine

2. - serotonin

    - acetylcholine

    - ATP

    - histamine

ionotropic - transmitter binding → direct opening of channel

                    - fast neurotransm. (NT) release (msec)

                 - many subunits, variable transmembrane domains

      metabotropic - transm. binding → G-protein coupling with receptor

- slow NT release

 - receptor = 1 protein with 7 domains

- All neuropeptide receptors are GPCRs

agonist - binds to receptor to activate

antagonist - binds to block agonist

modulator - binds at separate site from agonist/antag. to modulate receptor function

1. What is the most used NT in the brain?

2. How do the others compare?

1. Glu - 75% transmission

2. GABA or Gly - 20%

- all other NTs - 5%

- other NTs modulate transmission of first 3

Glutamate

1. synthesis

2. localization

3. transporter for vesicular release

4. transporter for reuptake

5. describe receptors (ionotropic and metabotropic)

1. general metabolic pathway

2. everywhere in brain

3. vGlut

4. EAAT

5. ionotropic - AMPA (NA, CA influx), NMDA (NA), kainate (NA)

- NMDA modulated by PCP

metabotropic - mGluR - use Gq and Gi proteins, 8 types

GABA

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

Glycine

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

1. general metabolism

2. as NT, only in brainstem, spinal cord

3. vGAT

4. GLYT

5. ionotr. - five subunits (Cl flow)

- antagonist - strychnine

NO METABOTROPIC

Acetylcholine

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

                        choline acetyltransferase (ChAT)

1. Acetyl CoA + choline      →         Ach

2. nucleus basalis, pedunculo-pontine nucleus

3. vAChT

4. NO reuptake - acetylcholinesterase (enzyme) breaks down Ach, reuptakes choline ONLY

- acetylcholinesterase blocked by Sarin (nerve gas)

5. ionotropic - nicotinic (NA)

- agonist: nicotine, curare, cobra venom

- metabotropic: muscarinic

- agonist: muscarine

- uses Gq and Gi

dopamine

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

- mood, cognition, movement, reward                  

Tyrosine hydroxylase       DOPA decarboxylase    

1. Tyrosine         →         L-Dopa      →   Dopamine

2. substantia nigra

3. VMAT

4. DAT - inhibited by cocaine

- amphetamine binds to either VMAT or DAT to reverse transport of dopa

5. NO IONOTROPIC

metabotropic - D1-5 (Gs, Gi)

- antagonist: haloperidol (antipsych. drug for schizophr.)

Norepinephrine / Noradrenaline

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

- regulates arousal, sleep, mood, cognition, memory ("flashbulb memory"- strong memory from emotion)

Dopamine β-hydroxylase

1. Dopamine       →     Norepinephrine

2. locus ceruleus

3. VMAT

4. NET - inhibited by cocaine, imipramine (anti-depressant)

- VMAT, NET bind to amphetamine (reverse transport)

5. adrenergic receptor

- NO IONOTROPIC

- metabotr. - Alpha - 1 (Gq), Alpha - 2 (Gi), Beta (Gs)

- Beta antagonist: beta blockers

Epinephrine/ Adrenaline

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

           PNMT

1. norepinephrine    →   epinephrine

2.ventrolateral medulla (VLM)

3. VMAT

4. NET - inhibited by cocaine, imipramine

- VMAT, NET bind to amphetamine (reverse transport)

5. adrenergic

-NO IONOTROPIC

metabotr. - Alpha - 1 (Gq), Alpha - 2 (Gi), Beta (Gs)

- beta antag. - beta blockers

Serotonin (5-HT)

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

arousal, mood, sleep, cognition       

    tryptophan hydroxylase                5-HTP decarboxylase

1. tryptophan     →     5-hydroxy tryptophan    →    5-HT

2. raphe nuclei

3. VMAT

4. SERT

- amphetamine binds (reverse transport)

-reuptake blocked by cocaine, Prozac

5. ionotrop. - 5-HT3 (NA,CA flow)

agonist: LSD

metabotr - 5-HT1 (Gi), 2 (Gq), 4-7 (Gs)

agonist: LSD, for 1 (also Buspar - weak, partial)

Histamine

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

- arousal, cognition

histidine decarboxylase

1. histidine       →    Histamine

2. mesencephalic reticular formation (MRF), hypothalamus

3. VMAT

4. UNKNOWN

- amphetamine binds to VMAT (reverse transport)

5. NO IONOTROPIC

- metab. - H1-4 (Gq, Gs, Gi)

ATP

1. synthesis

2. localization

3. vesicular release

4. reuptake

5. describe receptors (ionotropic and metabotropic)

- coreleased with other NTs

1. general metabolism

2. everywhere

3. UNKNOWN

4. ATP pumps

5. purinergic receptors

-ionotropic - P2X (NA, CA flow)

-metab. - P2Y (Gq)

Opioid Receptors

1. ionotropic

2. metabotropic

3. agonists, antagonists

1. NONE

2. μ, δ, κ (Gi)

3. agonists - endorphins, heroin, morphine, vicodin

4. naloxone (counteracts opiate overdose)

1. directly causing depolarization, hyperpolariz.

2. regulating voltage-gated channels

3. allowing flux of Ca

1. alpha, beta, gamma

cycle: a. agonist stimulation

b. GDP-G complex binds with ch., GDP release

c. GTP binding to complex

d. beta/gamma release

e. gtp-apha complex released from ch.

f. alpha (GTPase) hydrolyzes GTP to GDP

g. cycle restarts

Describe Gs-coupled receptor signaling

a. role of Gs-alpha

b. secondary messengers

a. Gs-alpha named because stimulates enzyme that makes cAMP

b.  cAMP directly acts on channels and activates protein kinase A

- activating kinase makes cAMP secondary messenger for phosphorylation (regulates channel, changes activity)

- 1st messenger is NTs

-phosphorylation can be used for cross-talk between NTs (ie. norepinephr. uses to enhance glu NMDA-R)

Gi-coupled Receptor signaling

a. role of Gi-alpha

b. any other mechanisms

a. inhibits enzyme that makes cAMP

b. Gi receptors can couple with Go (does not affect cyclase enzyme, regulates ch. activity, promotes brain development/growth cones)

-Gi, Go inhibited by pertussis toxin ("whooping cough")

- beta/gamma can regulate channels (ie. GIRK)

Gq receptor signaling

a. role of Gq alpha

b. secondary messengers

a. activates phospholipase C (breaks down lipids into DAG, IP3)

b. DAG - activates protein kinase C to phosphorylate proteins in cell

- IP3 activates receptor in cell to release Ca from ER

- Ca levels regulated by binding prot. (ie. Calmodulin)

- Ca, CaM regulate kinases, phosphatases, proteases, etc.

- modulates glu synapse

excitotoxicity

1. definition

2. depends on what

3.  how can it be blocked

4. symptoms

5. i.e. in life

1. prolonged activation of neurons by NTs like glu to cause neuron injury, death

2. Ca overconcentration → overactivity of Ca-dependent enzymes

3. decrease Ca influx

4. brain damage

5. MSG

desensitization

a. definition

b. occurs where?

c. affect on ionotropic

d. affect on metabotropic

e. drug that alters rate of desens.in ionotropic

f. affect of phosphorylation

a. response to NTs, hormones decreases with prolonged, repeated stimulation

b. channels, enzymes downstream of receptors or receptors themselves

c. receptor state where agonist bound but ch. not open

- longer agonist bound to normal ch., the higher probability of desensit.

d. - desensitization (fast, seconds)

-internalization (slower, minutes) - removal of GPCR from cell surface to allow resensitization (dephosphorylates receptor, unbinds arrestin)

-down-regulation (very slow, hours) - internalyed recept. taken to lysosomes, degraded, recycled back to PM

-OR PKA/PKC move to nucleus to decrease receptor transcription

e. benzodiazepines (Valium)

f. activation of kinases (PKA, PKC) to phosphorylate results in homologous (of the activated receptor) desens. and heterologous (of other receptor types) desens.

-GPCR kinases (non-second messenger kinases) cause only homologous desens. using arrestin proteins (uncouple G proteins from GPCRs)