Neurons and Neurotransmitters

usually longer and few in # than dendrites

function: propagation of nerve impulse (intercellular communication)

                axonal transport (intracellular communication)

PNS, but not CNS neurons retain regeneration ability after nerve damage

axolema (plasma membrane)

microtubules: large tubulin and microtubule associated proteins (MAPS)-containing structures

neurofilaments: intermediate size filaments

microfilaments: small actin-containing filaments

mitochondria and vesicles

usually shorter and more ramified than axons

lack neurofilaments

finction: receive nerve impulse

specialized asymmetric structures for intercellular cell-to-cell communication via neurotransmitter release; chemically mediated

connect neurons with each other or with target tissues (ie: muscle)

axon-dendritic: most common

axon-axonic

presynaptic: important in modulation of synaptic transmission

function: modulation of synaptic transmission

structure: synaptic vesicles, ER, mitochondria, lysosymes, etc, plasma membrane (containing coltage-gated Ca channels and other molecules involved in exocytosis and membrane recycling)

INTRACELLULAR COMMUNICATION

transports vesicles from area of synthesis, down axon, to area of synaptic release

bidirectional communication between soma and terminal

fast vs. slow axonal transport

1 foot (200-400mm)/day

bidirectional: anterograde and retrograde

ATP-dependent (ENERGY)

requires microtubules

requires motor proteins (kinesin-anterograde and dynein-retrograde) affected by conditions that affect the energy state

delivery of vesicular material and mitochonfria to the terminals

transports membrane proteins, lipids, neurotransmitters (synaptic vesicles)

delivery of prophic factors and lysosomes to soma

trasports lysosomal enzymes, neutrotrophic factors, and the polio virus

~2 mm/day (100x slower than fast transport)

transports cytosketetal components (MT, MF, NF) and soluble proteins (glycolytic & biosynthesis enzymes)

unidirectional

NO ATP (passive diffusion)

does NOT require motor proteins or microtubules

retrograde trophic factors transported to cell body support neuronal survival

neurotoxins affect tansport = neuronal degradation

affected in neurodegenerative diseases

viruses enter peripheral nerve endings & infect cell via retrograde transport

green dots: trans-neuronal infections

viruses intially infect via retrograde transport; viruses can be transported by both anterograde AND retrograde transport = trans-neuronal infections

anterograde and retrograde: herpes simplex (HSV), herpes zoster, rabies, west nile virus, HIV, prion protein (mad cow disease)

retrograde: polio

electrical synapses: in neuronal populations with synchronized firing

neuroendocrine interactions

neuron-glia interactions

neuroimmune interactions

1. transport of precursors & NT synthesis

2. storage of NTs into synaptic vesicles (ATP H+ pump)

3. action potential invades presynaptic terminal

4. depolarization of presynaptic terminal causes opening of voltage gated Ca channels

5. Ca influx

6. Ca (with SNARE complex) causes fusion of vesicles and presynaptic membrane

7. NT release into synaptic cleft

8. binding of NT to postsynaptic receptors and presynaptic auto-receptors (inhibitory; - feedback)

9. activation of post-synaptic receptors (generation of new action potential)

10. opening or closing of post-synaptic channels

11. post-synaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the cell

RRP: close to presynaptic membrane; vesicles are ready to be loaded by NTs

recycling pool: can be reloaded by NTs

reserve pool: extra capacity necessary for daily activity;

*stationary pools can be recruited for release when the RRP is utlized

Acetylcholine (ACh)

amino acids

monoamines

peptides

postsynaptic effect: excitatory in NMJ (nicotinic), modulatory (muscarinic)

main enzyme: ChAT

inactivation mechanism: degraded by AChE

postsynaptic effect: excitatory (5HT3R); modulatory

precursor: tryptophan

inactivated by MAO

postsynaptic effect: major inhibitory in the CNS (brain and cerebellum)

precursor: glutamate

resticted localization; co-localize with other NTs

synthesized in the cell body and stored in large dense core vesicles

released at diffferent rates than classical NTs

cell bodies are restricted to specific regions of the CNS

can either be stimulatory or inhibitory depending on receptor interation

either excitatory (glutamate) or inhibitory (GABA)

responsible for setting the level of activity in the nervous system

NT released at ALL NMJs (formed by lower motor neurons, incl. brainstem)

in autonomic ganglia (pre-ganglionic neurons in symp. and pre- and post-ganglionic neurons in parasymp. system)

basal ganglia

participate in movement control

Acetyl-CoA + Choline -------------> Acetylcholine (ACh)

                      LR (diet)  ChAT  (choline acetyl transferase) --- enzyme in immediate precursors              cytoplasm at presynaptic terminals

*PC --PLC--> PA + Choline (reuse)

ACh ---Acetylcholinesterase (AChE)---> Choline + Acetate

2 step rxn: Choline release; hydrolysis (irreversible inhibition of AChE by nerve gases, pestisides; reversible inhibition by AChE carbamylation using theraeutic drugs)

RAPID degredation

linked to extracellular side of post-synaptic membrane by a covalently attached glycophospholipid; can also be released to synaptic cleft

similar to: butyryl- and pseudocholinesterase

mediate ACh action in NMJ, brain & ANS ganglia

non-selective transmembrane protein complex w/ 5 subunits (2 bound ACh molecules at alpha subunit are required for opening of ligand gated channel)

FAST

agonist: nicotine

antagonist: curare

mediate ACh action in peripheral tissues (ANS: smooth muscle, vasculature, heart, gland, GI, eye) & brain

GPCR (NOT an ion channel) --- acts through phospholipase c with Ca

agonist: muscarine, pilocarpine

antagonist: atropine, scopolamine

botulism toxin (BOTOX)

black widow spider venom (alpha-latrotoxin)

snake BETA-neurotoxins (beta-bungarotoxin)

lambert-eaton syndrome

inhibitors of AChE (nerve gases, organic phosphates)

congenital AChE deficiency

snake ALPHA-neurotoxins (alpha-bungarotoxin)

myasthenia gravis

congenital defects of ACh receptor structure

affects cholinergic transmission at presynaptic NMJ

toxins cleave presynaptic proteins important for release

results in PARALYSIS of muscles

ex: botulism from food poisoning; cosmetic BOTOX

affects cholinergic transmission at presynaptic NMJ

local muscle twitching first, ANS problems; later onset of paralysis

alpha-bungarotoxin: affects cholinergic transmission at postsynaptic NMJ; blocks nicotinic receptors

beta-bungarotoxin: affects cholinergic transmission at presynaptic NMJ; blocks ACh release

affects cholinergic transmission at presynaptic NMJ

autoimmune reaction against a protein present at the presynaptic membrane, the voltage-dependent Ca channel

diminishes ACh release

affects cholinergic transmission at postsynaptic NMJ

autoimmune reaction against a protien present at the postsynaptic membrane affecting the nAChR

neostigmine, used in MG, is an AChE inhibitor that does not cross the BBB

affects cholinergic transmission at junction

decreased enzyme activity = buildup of ACh in cleft; increased ACh release = persistant depolarization and no repolarization

affects cholinergic transmission at postsynaptic NMJ

slow closing channel results in prolonged muscle depolarization

release stimulated by black widow spider venom (alpha-latrotoxin)

release blocked by botulinum toxin and snake beta-neurotoxins

AChR are activated by cholinergic agonists and cholinesterase inhibitors

nicotinic receptors are blocked by curare and alpha-bungarotoxin (snake venom)

muscarinic receptors are clocked by atropine and scopolamine

located in the substansia nigra pars compacta (red), ventral tegmental area (blue), and arcuate nucleus (orange) of the hypothalamus

nigrostriatal (red)

mesolimbic (short blue)

mesocortical (short\\long blue from VTA)

tuberhypophysial (green)

indolamine

raphe nuclei and a moderate cluter in the brain stem

locus coeruleus

*also released by adrenal gland*

circulating norepinephrine does not affect the brain because it does not cross the blood brain barrier

medullary epinerphrine neurons

*also released by the adrenal gland*

circulating epinerphrine does not affect the brain becuase it does not cross the blood brain barrier

L-Tyrosine ---TH w/ BH4 cofeactor---> L-DOPA ---AAAD w/ vitamin B6 cofactor---> dopamine                  RL enzyme

TH: tyrosine hydroxylase

AAAD: aromatic amino acid decarboxylase

*Tyr transport is compromised in PKU patients*

dopamine

allosteric inhibition in the cytosol

1: monoamine oxidase (MAO)

*MAO-B is more selective for dopamine*

2: catechol O-methyl-transferase (COMT) -- methylation

main product of enzymes: homovanillic acid (HVA) instead of VMA for dopaminergic degredation

dopamine ---DBH w/ ascorbic acid cofactor---> norepinephrine (OH) ---PNMT and SAM-----> epinephrine (CH3)

DBH: dopamine beta-hydroxylase; only enzyme found in synaptic vesicles

large neutral amino acid transporter (LNAAT)

Phe, Trp, L-DOPA, etc.

re-uptake mechanisms and recycling

selective re-uptake systems that re-uptake specific monoamines from the synaptic cleft; mediated by specific monoamine transporters localized at the presynaptic membrane

tryptophan ---tryptophan hydroxylase w/ BH4 cofactor---> 5-hydroxytryptophan ---aromatic amino acid decarboxylase (AAAD) ---> serotonin (5-HT) ----> melatonin (in pineal gland)

* serotonin is inactivated only by MAO, specifically MAO-A*

midbrain raphe nuclei

project diffusely in brain to striatum, dentate gyrus of hippocampus, and cortex

all GPCR or metabotropic receptors (EXCEPT SEROTONIN)

single subunit w/ 7 transmembrane domains

activation affects cAMP levels in the cell: (+) or (-)

some receptors are presynaptic auto-receptors that inhibit release

EX: D1R, D2R, alpha2R, betaR

located in the tuberomammillary nucleus of the hypothalamus

project throught brain (released in cortex) & spinal cord; increases state of arousal of the CNS = drowsiness w/ OTC H1 receptor blockers

diamine; biogenic amine, NOT a monoamine

L-histidine ---histidine decarboxylase (HDC)---> histamine

histamine ---histamine methyl transferase (HMT)---> METABOLIZED

parkinson's disease

schizophrenia

mood disorders

depression

substance abuse

aggresive behavior

sleep disorders

neurotransmitters in the brain

present in synaptic vesicles and released during synaptic transmission; binds to its own receptor; converted to UTP and adenosine to bind to their specific receptors

GPCR

A1

A2A

A2B

inhibitory

coupled to G_i/o

anxiolytic, anticonvulsant, analgesic, sedative actions

coupled to G_s

highly expressed in dorsal striatum, nucleus accumbens, and olfactory tubercle

antagonizes dopamine D2R affect in stratum

contribute to vasodilation

coupled to G_s

present in endothelial cells

regulate vascular permeability

contribute to vasodilation

agonist: neuroprotective drugs in stroke treatment (adenosine-A1R binding inhibits glutamate release and A1R activation opens K/CL channel and hyperpolarizes cell)

antagonist: methylxanthines (caffeine, tea, and chocolate) act as stimulates