Transcript Lecture 3
Neurotransmitters Glutamate Aspartate Glycine GABA Amino Acids Catecholamines Dopamine Epinephrine Norepinephrine Indolamines Serotonin Monoamines Nitric Oxide Carbon monoxide Soluble Gases Acetylcholine Acetylcholine Endorphins Neuropeptides Pituitary Peptides Gut Peptides Hypothalamic Peptides Misc. Peptides Next slide Endorphins Neuropeptides Dynorphin Beta-Endorphin Met Enkephalin Leu Enkephalin Pituitary Peptides Gut Peptides Misc. Peptides Angiotensin Bombesin Bradykinin Glucagon Insulin Neurotensin Cholecystokinin Gastrin Motilin Pancreatic polypeptide Secretin Substance P Vasoactive intestinal polypeptide Hypothalamic Peptides Coticotropin Growth Hormone Lipotropin Alpha-Melanocte stimulating hormone Oxytocin Prolactin Vasopressin Luteinizing hormone-releasing hormone Somatostatin Thyrotropin-releasing hormone Dopaminergic System (phenylalanine) Breakdown of monoamines Monamine oxidases (MAOs) -- Amino acids phenylalanine and tyrosine are precursors for catecholamines. -- Both amino acids are present in the plasma and brain in high concentrations. -- Tyrosine can be formed from dietary phenyalanine by the enzyme phenylalanine hydroxylase, found in large amounts in the liver. -- Insufficient amounts of phenylalanine hydroxylase result in phenylketonuria (PKU). -PKU is a genetic disease caused by mutations in the enzyme phenylalanine hydroxylase (PAH) that result in the loss of the enzyme’s ability to hydroxylate phenylalanine (Phe) to tyrosine, from which catecholaimine transmitters are synthesized. -If PAH levels are low or absent (as in PKU), blood levels of Phe are massively elevated. A tiny fraction of the increased Phe is converted to phenylpyruvic acid, which is excreted in the urine; hence the name of the disease. -Elevated Phe levels in PKU spare the body, but devastate the developing brain. Severe mental retardation can ensue unless steps are taken to limit dietary Phe intake. Regulation of Catecholamine Synthesis 1) Change in TH gene expression 2) Changes in translation 3) TH activity is regulated by specific kinases, leading to phosphorylated TH Noradrenergic System Serotonin System Monoamine oxidase and aldehyde dehydrogenase to the major metabolite, 5-hydroxy-indoleacetic acid (5-HIAA). -- Rate-limiting step in 5-HT synthesis is tryptophan hydroxylation. -- Availability of the 5-HT precursor tryptophan, an amino acid, is very important in regulating 5HT synthesis. -- Tryptophan is present in high levels in plasma, and changes in dietary tryptophan can substantially alter brain levels of 5-HT. An active uptake process facilitates the entry of tryptophan into the brain. However, other large neutral aromatic amino acids compete for this transporter. -- Although 5-HT is typically the final transmitter product of tryptophan synthesis, 5-HT in the brain and periphery can be metabolized to yield other important active products. -- In the pineal gland, 5-HT is metabolized through two enzymatic steps to form melatonin, a hormone that is thought to play an important role in both sexual behavior and sleep. -- Can also be metabolized to quinolinic acid, a potent agonist at NMDA glutamate receptors (cell loss and convulsions), and kynurenine an antagonist at NMDA receptors. Rate-limiting step in 5-HT synthesis is tryptophan hydroxylation. Cholinergic System Production of acetylcholine (choline acetyltransferase) Breakdown of acetylcholine (acetylcholinesterase) -- Synthesis of ACh is the simplest of any neurotransmitter because it has but a single enzymatic step. -- Acetyl-CoA that serves as a donor is derived from pyruvate generated by glucose metabolism. This obligatory dependence on a metabolic intermediary is similar to the situation present in GABA synthesis. -- Acetyl-CoA is localized to mitochondria. Because ChAT is cytoplasmic, acetyl-CoA must exit the mitochondria to gain access to ChAT. This exiting step may be the rate limiting step to ACh production. -- Enzymatic inactivation of Ach has been fertile ground for the development of potent neurotoxins (sarin, insecticides). Alpha-Ketoglutarate GABA-oxoglutarate transaminase (GABA-T) Glutamate Glutamic acid decarboxylase (GAD) GABA -- GABA is ultimately derived from glucose metabolism. -- Only GABA and Glutamate are taken up by glial cells as well as neurons. -- Intraneuronal GABA is inactivated by the actions of GABA-T, which appears to be associated with mitochondria. -- Thus, GABA-T is both a key synthetic enzyme and a degradative enzyme! -- GABA-T metabolizes GABA to succinic semialdehyde, but only if alpha-ketoglutarate is present to receive the amino group that is removed from GABA. This unusual shunt serves to maintain supplies of GABA. Alpha-Ketoglutarate GABA-oxoglutarate transaminase (GABA-T) Glutamate Glutamic acid decarboxylase (GAD) GABA Peptide Transmitters -- Peptide transmitters differ from classical transmitters by being synthesized in the soma rather than the axon terminal. -The active transmitter is transported in vesicles to the nerve terminal. -This suggests that transmitter release must be regulated carefully so that depletion of an important intercellular communication molecule does not occur. -The termination of peptides is much less specific than classical neurotransmitters. Unconventional/Retrograde Neurotransmitters 1) Nitric Oxide 2) Carbon Monoxide Excitatory - Ach, the catecholamines (dopamine, norepinephrine, epinephrine), glutamate, histamine, serotonin, and some neuropeptides. Inhibitory - GABA, glycine, and some peptides Serotonin Receptor Subtypes Of the chemical neurotransmitter substances, serotonin is perhaps the most implicated in the etiology or treatment of various disorders, particularly those of the central nervous system, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea. A major factor in our understanding of the role of 5-HT in these disorders is the recent rapid advance made in understanding the physiological role of various serotonin receptor subtypes. 5-HT1A This represents perhaps the most widely studied 5-HT receptor subtype. These receptors are located primarily in the CNS. Agonists facilitate male sexual behavior in rats, hypotension, increase food intake, produce hypothermia, and act as anxiolytics. This receptor has also been widely implicated in depression. 5-HT1B These may serve as autoreceptors; thus, activation causes an inhibition of neurotransmitter release. Agonists inhibit aggressive behavior and food intake in rodents. These receptors, which have been identified only in rodents and are apparently absent in humans, are thus only of theoretical interest at present. These receptors may be the counterpart of the 5-HT1D receptor found in other species. 5-HT1C These receptors belong to the same receptor subfamily as the 5-HT2 receptor and have been recently renamed as 5-HT2C receptors. This receptor is located in high density in the choroid plexus and may regulate cerebrospinal fluid production and cerebral circulation. This subtype is speculated to be involved in the regulation of analgesia, sleep, and cardiovascular function. 5-HT1D Located primarily in the CNS, this receptor may play a role presynaptically or as a terminal autoreceptor, being thus involved in the inhibition of neurotransmitter release by mediating a negative feedback effect on transmitter release. While the role of activation of this receptor sub-type is not fully understood, agonists at this site are effective in treating acute migraine headaches. 5-HT2 receptors Located primarily in the vascular smooth muscle, platelets, lung, CNS, and the GI tract, these appear to be involved in gastrointestinal and vascular smooth muscle contraction, platelet aggregation, hypertension, migraine, and neuronal depolarization. Antagonists have potential use as anti-psychotic agents. Because these receptors belong to the same receptor subfamily as the former 5-HT1C receptors, they have been recently renamed as 5-HT2A receptors. 5-HT3 receptors (ionotropic) Located primarily in peripheral and central neurons, these receptors appear to be involved in the depolarization of peripheral neurons, pain, and the emesis reflex. Potential use of agents acting at this site include migraine, anxiety, and cognitive and psychotic disorders. 5-HT4 receptors These receptors are found in the CNS, the heart, and the GI tract. Their activation produces an increase in cyclic adenosine monophosphate (AMP) and appears to involve activation of neurotransmitter release. Agonist - Any drug (exogenous ligand) that enhances the actions of a specific neurotransmitter. Antagonist - Any drug (exogenous ligand) that inhibits the action of a specific neurotransmitter.