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Neurotransmitter biochemistry

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Christian Paolo Balahadia

on 14 March 2013

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Transcript of Neurotransmitter biochemistry

Neurotransmitter Stimulus Response The neurons are the brain cells that are responsible for intracellular and intercellular signalling.
Action potential is large and rapidly reversible fluctuation in the membrane potential, that propagate along the axon.
At the end of axon there are many nerve endings (synaptic terminals, presynaptic parts, synaptic buttons, knobs). Nerve ending form an integral parts of synapse.
Synapse mediates the signal transmission from one neuron to another. BUT WAIT, THERE’S MORE… TRANSMISSION OF ELECTRICAL SIGNALS ACROSS SYNAPSE IS ACCOMPLISHED BY SMALL MOLECULES THESE SMALL MOLECULES ARE CALLED... Neurotransmitters 1. Identity
2. Synthesis
3. Release
4. Receptors
5. Inactivation
6. Pharmacology Substance must be found in neurons Cell has precursors and enzymes
necessary for synthesis Must be released from terminals; (collect substance from cleft after nerve stimulation) Cross desensitization between substance and suspected n.t.
Applicaton of suspected n.t. mimics action of nerve stimulation
Blockade of n.t. action by receptor antagonists Inactivation mechanism enzymatic degradation reuptake Same effect on ion channels; p.s.p.’s have same reversal potentials
Same effect on membrane resistance and potential
Applied substances must be effective in physiological concentrations
Inhibition of degrading enzyme prolongs action of both How were neurotransmitters discovered? Otto Loewi experiment in 1921
Simulated the vagus nerve of a frog’s heart
Slowed the heart down
Washed heart with solution, collected solution
Poured solution on a second heart
It slowed!!!! Biochemical Activity Called the substance vagusstoff
Acetylcholine
Later stimulated heart rate, similar method
Ended up with a sped up heart
Epinephrine Loewi and his frogs How neurotransmitters work? A chemical released by one neuron that affects another neuron or an effector organ
(e.g., muscle, gland, blood vessel) Acetylcholine 2-Acetoxy-N,N,N-trimethylethanaminium
Quaternary amine and a polyatomic cation
First known neurotransmitter
Neurotransmitter found in both peripheral and central nervous system
Found in neuromascular junctions, most synapses of autonomic nervous system, retina, and many parts of the brain. Performs as excitatory neurotransmitter between nerves and skeletal muscles
Inhibitory synapse in cardiac muscle which lowers heart rate
Can be excitatory of inhibitory neurotransmitter for smooth muscle and glands depending on location Functions Ach binds to ligand regulated ion gates that allow Na+ ions to enter the post synaptic neuron depolarizing its membrane causing a postsynaptic potential that triggers it to fire. Inhibited by acetylcholine Inactivates majority of acetylcholine released in the brain and in muscle Serine Serine Decarboxylase CO2 In Plants Sphingosine-1-P Multistep catabolism In Animals Related Disorders Most common form of dementia
Reduced Ach receptors preventing the action of acetylcholine
Drugs that inhibit acetylcholinesterase function can help Alzheimer's disease Autoimmune neuromuscular disease leading to muscle weakness and fatigability
Antibodies blocks the Ach receptors prevents excitatory effects of acetylcholine
Treated with acetylcholinesterase inhibitor and immunosuppresants Myasthenia gravis Gama-aminobutyric
acid 4-aminobutanoic acid
Amino acid neurotransmitter
Most common Inhibitory neurotransmitter of the brain
Although an amino acid it was never incorporated to a protein
Found in thalamus, hypothalamus, cerebellum, occipital lopes of cerebrum, and retina
Does not cross the blood brain barrier Functions Acts in the inhibitory synapses in the brain Two classes of receptor GABA A
Receptor coupled with a ligand regulated ion-channel that lets chloride ions pass thru the membrane of the postsynaptic neuron that hyperpolarizes or depolarizes the membrane inhibiting or exciting the neuron depending on the direction of the flow of ions.
GABA B
A metabotropic transmembrane receptor that are linked to G proteins that can activate potassium channels which can hyperpolarize postsynaptic neuron
Found in the central and peripheral autonomous nervous system 2 isoforms in mammals Participates in 5 metabolic pathways Related Disorders Spastic diplegia Little’s Disease (form of cerebral palsy)
Unable to properly absorb GABA in nerve
especially high and constant "tightness" or "stiffness“ in the muscles of the lower extremities of the human body Autosomal recessive disorder found mostly in consanguinoeus families
Suffers neurological conditions such as delayed intellectual, motor, and speech
succinic semialdehyde is reduced to gamma-hydroxybutyric acid (GHB) by gamma-hydroxybutyric dehydrogenase which causes the neurological disorders Succinic semialdehyde dehydrogenase deficiency Serotonin 5-hydroxytryptamine (5-HT)
monoamine neurotransmitter
primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans
popularly thought to be a contributor to feelings of well-being and happiness Function regulates intestinal movements
regulates mood, appetite, and sleep
cognitive functions, including memory and learning
serves as a vasoconstrictor 
helps regulate hemostasis and blood clotting
growth factor for some types of cells Synthesized from L-tryptophan by tryptophan Hydroxylase (TPH) and amino acid decarboxylase
TPH-mediated reaction as the rate-limiting step
TPH exists in two forms
TPH1: found in several tissues
TPH2: a neuron-specific isoform  
Mainly metabolized to 5-HIAA, which is excreted by the kidneys Related Disorders Depression and anxiety
Obsessive-compulsive disorder
Addiction
Treatment: drugs that increase the amount of serotonin synthesized or help to increase the lifetime of serotonin Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers.
Levels of these substances may be measured in the urine to test for these tumors. Nitric Oxide a diatomic free radical (NO)
lipid soluble and very small
diffuses readily through membranes
high reactivity limits range of diffusion to ~1 mm radius from site of synthesis
previously known mainly as a component of smog Function Activates guanylyl cyclase, which catalyzes cGMP production
As neurotransmitter, NO
Signals inhibition of smooth muscle contraction
Facilitates adaptive relaxation and localized vasodilation
Plays a role in long term memory
A bactericidal agent Synthesized from arginine in an NADPH-dependent reaction
Catalyzed by nitric oxide synthase (NOS)
dimeric enzyme
structurally related to NADPH cytochrome P-450 reductase
each subunit of enzyme contains one bound molecule of each of four different cofactors: FMN, FAD, tetrahydrobiopterin, and Fe3+ heme
stimulated by interaction with Ca2+/calmodulin
A five-electron oxidation Related Disorders NOS inhibitors
interact with the arginine-binding site (e.g. derivatives and close analogues of arginine)
mimic the tetrahydrobiopterin cofactor
interact directly with the heme or with calmodulin or flavine cofactors sexual stimulation triggers NO secretion
NO activates guanylate cyclase
cGMP, blood flow into erectile tissues, bringing about an erection
erection subsides when cGMP is broken down by phosphodiesterase
to prevent it to subside too soon, prevent cGMP from breaking down so fast
use phosphodiesterase inhibitors (Viagra, etc.) Erectile Dyfunction Involved in numerous pathological situations
hypotension accompanying septic shock
essential hypertension
atherosclerosis
Increase formation of NO has neurotoxic effects and contributes to the pathogenesis of
stroke and other neurodegenerative disorders
both acute and chronic inflammatory processes Choline 1,2 DAG Phospholipase De Novo Synthesis Salvage Pathway Thank you for Listening! Biochemistry of Addiction Serious worldwide problem with strong genetic and environmental influences
Identified 1,500 human addiction-related genes*
Developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface*
*Li, Mao and Wei (2007). Genes and (Common) Pathways Underlying Drug Addiction
Key Players:
Parts of the Brain
Major: VTA (Ventral Tegmental Area of the midbrain) and NAc (Nucleus Accumbens)
Several other brain areas:
Amygdala
Hippocampus
Hypothalamus
Frontal cortex
All of which have traditional memory system ~ powerful emotions /memories
Mechanism All abuse converge on a common circuitry in the brain limbic system
Most attention has been given to the mesolimbic dopamine pathway
Where VTA and NAc are major parts
Full transcript