Neurotransmitters and Their Receptors

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Categories of NT. Small molecule neurotransmittersBiogenic aminesAmino acidsNeuropeptides (3-36 AAs). Acetylcholine (ACh). The first identified NTUsed at the NMJ and Used in the parasympathetic nervous systemVagus nerve and cardiac muscle fibersUsed in the visceral motor systemFunction in CNS is not well known.

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Neurotransmitters and Their Receptors

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1. Neurotransmitters and Their Receptors

2. Categories of NT Small molecule neurotransmitters Biogenic amines Amino acids Neuropeptides (3-36 AAs)

3. Acetylcholine (ACh) The first identified NT Used at the NMJ and Used in the parasympathetic nervous system Vagus nerve and cardiac muscle fibers Used in the visceral motor system Function in CNS is not well known

5. AChR Nicotinic receptors are ionotropic and found at the NMJ Agonists of the nicotinic receptor can produce euphoria and addiction nAChRs are nonselective cation channels Many toxins interfere with this receptor Muscarinic receptor is metabotropic Organophosphates inhibit AChE Sarin gas Can lead to paralysis The toxin muscarine is from the red mushroom Amanita muscaria. The toxin muscarine is from the red mushroom Amanita muscaria.

6. Myesthenia gravis Autoimmune disorder that destroys nAChRsAutoimmune disorder that destroys nAChRs

7. Immobilizing prey and altering minds Alpha-bungarotoxin is from the banded krait, Bungarus multicinctus, binds irreversibly to the nicotinic receptor, leading to paralysis. Other toxins that bind to this receptor are the cobra toxin cobra-a-neurotoxin and sea snake peptide erabutoxin. The plant toxin, delta-turbucurarine also blocks nAChRs. Cone snails have 100s of neurotoxins, many which target synaptic transmission. Toxins block AChRs and glutamate receptors as well as Na+ and Ca2+ channels. Alkaloid plant toxins such as atropine from belladonna and scopolamine from henbane act on muscarinc ACh receptors. Betel nuts produce a stimulant similar to nicotine that acts on the same nAChRs. Chewing betelnuts for the compound arecoline is common in southeast asia Alpha-bungarotoxin is from the banded krait, Bungarus multicinctus, binds irreversibly to the nicotinic receptor, leading to paralysis. Other toxins that bind to this receptor are the cobra toxin cobra-a-neurotoxin and sea snake peptide erabutoxin. The plant toxin, delta-turbucurarine also blocks nAChRs. Cone snails have 100s of neurotoxins, many which target synaptic transmission. Toxins block AChRs and glutamate receptors as well as Na+ and Ca2+ channels. Alkaloid plant toxins such as atropine from belladonna and scopolamine from henbane act on muscarinc ACh receptors. Betel nuts produce a stimulant similar to nicotine that acts on the same nAChRs. Chewing betelnuts for the compound arecoline is common in southeast asia

8. Structure of the nAChR at NMJ Structure—each subunit crosses through the membrane 4 times. 5 subunits come together to form a pore. The openings are either end are large. The alpha subunit binds the NT and the alpha toxins. In the CNS there are only 2 subunits 3alpha:2beta, however the beta does not bind alpha-bungarotoxin. The opening of the channel is ~3 nm at its larges point and 0.6 nm at its most narrow. A Na+ channel has an opening about 0.3 nm. Electron micrograph of nAChR Structure—each subunit crosses through the membrane 4 times. 5 subunits come together to form a pore. The openings are either end are large. The alpha subunit binds the NT and the alpha toxins. In the CNS there are only 2 subunits 3alpha:2beta, however the beta does not bind alpha-bungarotoxin. The opening of the channel is ~3 nm at its larges point and 0.6 nm at its most narrow. A Na+ channel has an opening about 0.3 nm. Electron micrograph of nAChR

9. General ionotropic receptors Has either 3 or 4 transmembrane helices

10. mAChR Mediate most of the effects in the brain Found in striatum and forebrain—act against dopamine Mediate peripheral responses of visceral organs and exocrine glands Reduce HR Constrict pupil—atropine blocks this effect Constricts airways—Ipratropium blocks this effect and is used by asthmatics

11. General metabotropic receptors Monomeric proteins 7 transmembrane domains Domains I, II, VI, and VII bind NT G-proteins bind to loop between V and VI and the C-terminal

13. Glutamate Most important for brain function Over half of the synapses are glutamatergic Glutamate released during injury is toxic in high amounts Does not cross BBB Synthesized in the brain from local precursors Packaged into vesicles by VGLUT Removed from the synaptic cleft by EAATs Uses glutamine released by glial cells and it can transaminate 2-oxoglutarate, an intermediate of the citric acid cycle 5 EAATs exist, some in glial cells and others in presynaptic terminals. Glial cells convert glutamate to glutamine by glutamine synthetase.Uses glutamine released by glial cells and it can transaminate 2-oxoglutarate, an intermediate of the citric acid cycle 5 EAATs exist, some in glial cells and others in presynaptic terminals. Glial cells convert glutamate to glutamine by glutamine synthetase.

14. Glutamate-glutamine Cycle

15. Glutamate Receptors Ionotorpic receptors AMPA Kainate—some are presynaptic and thought to regulate glutamate release NMDA produces slower and long lasting currents Important in synaptic plasticity

16. NMDA-R

17. GABA 33% of brain synapses use GABA Used in local circuit interneurons Used by Purkinje cells, a projection neuron Synthesis: glucose ?glutamate ?GABA GAD converts glutamate to GABA Transported into vesicles by VIAAT Inactivation by GAT in neurons and glia Degradation by mitochondrial enzymes GAD requires pyridoxal phosphate, which comes from B6. Lack of B6 in infant formula led to seizures and death. A derivitive of breakdown of GABA-gamma hydroxybutyrate is a date rape drug that causes euphoria, memory deficits and unconsciousness.GAD requires pyridoxal phosphate, which comes from B6. Lack of B6 in infant formula led to seizures and death. A derivitive of breakdown of GABA-gamma hydroxybutyrate is a date rape drug that causes euphoria, memory deficits and unconsciousness.

18. GABAA and GABAC are ionotropic Benz. They also block Ca2+ channelsodiazepines and barbituates are used to treat epilepsy and are also used for sedation and anesthesia Benzodiazepines are anti-anxiety drugs Phenobarbitol and pentobarbital bind to alpha and beta subunits. Alcohol can also affect ionotropic GABA receptors GABAb receptors are metabotropic and do not activate Cl- channels but instead activate K+ channels.Benz. They also block Ca2+ channelsodiazepines and barbituates are used to treat epilepsy and are also used for sedation and anesthesia Benzodiazepines are anti-anxiety drugs Phenobarbitol and pentobarbital bind to alpha and beta subunits. Alcohol can also affect ionotropic GABA receptors GABAb receptors are metabotropic and do not activate Cl- channels but instead activate K+ channels.

19. The developing brain The electrical activity caused by the depolarizing effects of GABA may control proliferation, growth and maturation and possibly synaptic connectionsThe electrical activity caused by the depolarizing effects of GABA may control proliferation, growth and maturation and possibly synaptic connections

20. Glycine 50% of spinal cord synapses use glycine Synthesized from serine VIAAT transports glycine into vesicles Glycine transporters take up glycine Glycine receptors are ionotropic A mitochondrial enzyme serine hydroxymethyl transferase Mutations in the glycine transporter can result in hyperglycinemia, a neonatal disease characterized by lethargy, seizures and mental retardation. Strychnine acts on glycine receptors—an antagonistA mitochondrial enzyme serine hydroxymethyl transferase Mutations in the glycine transporter can result in hyperglycinemia, a neonatal disease characterized by lethargy, seizures and mental retardation. Strychnine acts on glycine receptors—an antagonist

21. Biogenic amines Regulate central and peripheral homeostatic functions Affect a wide range of behavior and are implicated in psychiatric disorders Catecholamines Indoleamines

22. Dopamine (DA) Loaded into vesicles by VMAT Transported by DAT Inactivated in presynaptic cell by MAO and COMT Metabotropic receptors Some antidepressants work on inhibiting MAO and COMT Receptors G-protein coupled receptors that activate or inhibit adenylyl cyclase Behaviors elicited by DA agonists Hyperactivity Repetitive, sterotypical behaviors Inhibit vomiting (antagonists can stimulate vomiting) Catalepsy—difficulty initiating movement Cocaine and amphetamine block DAT and may reverse the transporter Dopamine is implicated in addiction. Release of dopamine acts on critical brain regions involved in motivation and emotional reinforcement. Produces feelins of well-being, self-confidence and satisfactionSome antidepressants work on inhibiting MAO and COMT Receptors G-protein coupled receptors that activate or inhibit adenylyl cyclase Behaviors elicited by DA agonists Hyperactivity Repetitive, sterotypical behaviors Inhibit vomiting (antagonists can stimulate vomiting) Catalepsy—difficulty initiating movement Cocaine and amphetamine block DAT and may reverse the transporter Dopamine is implicated in addiction. Release of dopamine acts on critical brain regions involved in motivation and emotional reinforcement. Produces feelins of well-being, self-confidence and satisfaction

23. Norepinephrine (NE) Loaded into vesicles by VMAT Transported by NET Inactivated in presynaptic cell by MAO and COMT Metabotropic receptors Behavioral effects Sleep and wakefulness Attention Feeding behavior NET can also take up DA The first metabotropic receptor identified was the b-adrenergic receptor. The two alpha1 receptors produce slow depolarization through inhibition of a K+ channel, while the alpha 2 produce a slow hyperpolarization through the opening of a K+ channel There are 3 subtypes of the beta adrenergic receptors that are a target of beta blockers such as propanolol. They treat arrhythmia and migraines and they act on the smooth muscles of arteries and the cardiac musclesBehavioral effects Sleep and wakefulness Attention Feeding behavior NET can also take up DA The first metabotropic receptor identified was the b-adrenergic receptor. The two alpha1 receptors produce slow depolarization through inhibition of a K+ channel, while the alpha 2 produce a slow hyperpolarization through the opening of a K+ channel There are 3 subtypes of the beta adrenergic receptors that are a target of beta blockers such as propanolol. They treat arrhythmia and migraines and they act on the smooth muscles of arteries and the cardiac muscles

24. Epinephrine (Epi) Loaded into vesicles by VMAT No specific transporter but NET is capable Metabotropic receptors Uses the same alpha and beta receptors The first metabotropic receptor identified was the b-adrenergic receptor. The two alpha1 receptors produce slow depolarization through inhibition of a K+ channel, while the alpha 2 produce a slow hyperpolarization through the opening of a K+ channel There are 3 subtypes of the beta adrenergic receptors that are a target of beta blockers such as propanolol. They treat arrhythmia and migraines and they act on the smooth muscles of arteries and the cardiac musclesUses the same alpha and beta receptors The first metabotropic receptor identified was the b-adrenergic receptor. The two alpha1 receptors produce slow depolarization through inhibition of a K+ channel, while the alpha 2 produce a slow hyperpolarization through the opening of a K+ channel There are 3 subtypes of the beta adrenergic receptors that are a target of beta blockers such as propanolol. They treat arrhythmia and migraines and they act on the smooth muscles of arteries and the cardiac muscles

25. Histamine Loaded into vesicles by VMAT No transporter identified Inactivated in presynaptic cell by MAO and COMT Metabotropic receptors Found in neurons of the hypothalamus Histamine mediates arousal and attention and vestibular function Histamine is also released from mast cells during an allergic reaction. Histamine may influence blood flow Histamine is produced from histadine by histadine decarboxylase Anti histamines are histamine antagonists and are used in allergic responses. H2 receptors regulate secretion of gastric acid. Found in neurons of the hypothalamus Histamine mediates arousal and attention and vestibular function Histamine is also released from mast cells during an allergic reaction. Histamine may influence blood flow Histamine is produced from histadine by histadine decarboxylase Anti histamines are histamine antagonists and are used in allergic responses. H2 receptors regulate secretion of gastric acid.

26. Serotonin (5-HT) Loaded into vesicles by VMAT Trasnported by SERT Inactivated in presynaptic cell by MAO and COMT One ionotropic receptor (5-HT3), the rest are metabotropic 5-HT Regulate sleep and wakefulness Emotions Circadian rhythms Motor behaviors State of mental arousal Satiety Appetite Serotonergic drugs that target the transporter and receptors are used to treat Eating disorders Anxiety Depression OCD Postoperative nausea Chemotherapy induced emesis Irritible bowel syndrome Impairment of receptors 5-HT Regulate sleep and wakefulness Emotions Circadian rhythms Motor behaviors State of mental arousal Satiety Appetite Serotonergic drugs that target the transporter and receptors are used to treat Eating disorders Anxiety Depression OCD Postoperative nausea Chemotherapy induced emesis Irritible bowel syndrome Impairment of receptors

27. ATP and other purines Enzymes and nucleoside transporters are used for removal Receptors are widely distributed One family of ionotropic receptor May play a role in mechanosensation and pain Two families (A and P type) of metabotropic receptors Caffeine and theophyline block adenosine receptors—produce stimulation Found in brain, heart, adipose tissue, and kidney All synaptic vesicles have ATP and it is released with other NT Excitatory at motor neurons of the spinal cord and sensory and autonomic ganglia Postsynaptic actions of ATP seen in hippocampus and dorsal horn neurons Receptor location: All synaptic vesicles have ATP and it is released with other NT Excitatory at motor neurons of the spinal cord and sensory and autonomic ganglia Postsynaptic actions of ATP seen in hippocampus and dorsal horn neurons Receptor location:

28. Peptides Pre-propeptides are produced in the cell body ER removes secretion sequence Travel to Golgi as propeptides and are packaged into vesicles and processed Propepetides can produce more than one peptide Act on metabotropic receptors Are released in small amounts Processing includes proteolytic cleavage, ,odification of the peptide ends, glycosylation, phosphorylation, and disulfide bonds formed Processing includes proteolytic cleavage, ,odification of the peptide ends, glycosylation, phosphorylation, and disulfide bonds formed

30. Brain-gut peptides Substance P—found in neocortex, hippocampus and GI tract Released from C-fibers in the periphery that convey info on pain and temperature. Opioid peptides presynaptically inhibit release

31. Opioid peptide Bind to receptors that also bind opium Discovered during search for endorphins 3 classes—endorphins, enkephalins and dynorphins Prepeptides are enzymatically processed in vesicles Colocalized with GABA and 5-HT and are depressants May underly acupuncture induced analgesia Opioids are involved in complex behaviorsxyual attraction, aggressive/submissive behavior--se Prepeptides are enzymatically processed in vesicles Colocalized with GABA and 5-HT and are depressants May underly acupuncture induced analgesia Opioids are involved in complex behaviorsxyual attraction, aggressive/submissive behavior--se

32.

33. Unconventional NTs Endocannabinoids Produced by breakdown of membrane lipids Inactivated by carrier mediated tranport to postsynaptic cell and degraded by fatty acid hydrolase. Function in synaptic regulation Inhibits GABA release Chemicals include anadamide and 2-arachidonylglcerol and it is thought that they are produced by enzymatic breakdown of membrane lipids. The hydrophobic molecules may diffuse through the lipid bilayer,e although release mechanism is not clear. They are Chemicals include anadamide and 2-arachidonylglcerol and it is thought that they are produced by enzymatic breakdown of membrane lipids. The hydrophobic molecules may diffuse through the lipid bilayer,e although release mechanism is not clear. They are

34. Endocannabinoid release of GABA

35. NO Signal lasts seconds or less

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