Neurotransmitter Systems III Neurochemistry Reading: BCP Chapter 6
Neurotransmitter Systems Normal function of the human brain requires an orderly set of chemical reactions. Some of the most important chemical reactions are those associated with synaptic transmission. Identification and Distribution Criteria Localization/function Receptors Subtypes Activation Neurochemistry Synthesis Cycling
Life Cycle of Neurotransmitters The life cycle of a neurotransmitter involves five major steps: synthesis in the cell body or in the terminal packaging into vesicles release into the synaptic cleft binding to a receptor (ionotropic or metabotropic) inactivation via diffusion or reuptake (with or without prior degradation) for re-packaging
Major Neurotransmitters Their exact number is unknown, but more than 100 chemicals have been identified as neurotransmitters. Neurotransmitters can classified as small (about the size of an amino acid) or large. Major neurotransmitters include: Acetylcholine Amino acids Glutamate (Glu) Gamma-amino butyric acid (GABA) Glycine (Gly) Biogenic amines Dopamine (DA) Norepinephrine (NE) Epinephrine Serotonin Histamine Neuropeptides (large) Hypothalamus Pituitary Gut
Acetylcholine 1 Acetylcholine is derived from acetyl COA, a common product of cellular respiration in mitochondria, and choline, which is important for fat metabolism throughout the body (available in the diet e.g., eggs; synthesized in the liver). (1) ACh synthesis requires a specific enzyme choline acetyltransferase (ChAT), which is manufactured in the soma and transported to the axon terminal. Only cholinergic neurons contain ChAT, so this enzyme is a good marker for cells that use acetylcholine. (2) Following its release, ACh is degraded in the synaptic cleft by the enzyme acetylcholinesterase (AChE), which is secreted by both axons and dendrites. (3) The pre-synaptic cell then takes up the choline via a choline reuptake transporter. The uptake of choline is the rate-limiting step in ACh synthesis.
Acetylcholine 2 The mechanisms for reuptake of transmitter molecules/parts and for packaging of transmitter molecules into vesicles are similar among transmitter systems. Reuptake transporters are large proteins that span the plasma membrane. There can be several different transporters for one transmitter. Plasma membrane transporters use a cotransport mechanism using the driving force for sodium to enter the cell to also bring in a transmitter molecule. By contrast, vesicular membrane transporters use a counter-transport mechanism that trades a transmitter molecule from the cytosol for a hydrogen ion from inside the vesicle. Vesicle membranes have ATP-driven hydrogen pumps that keep their contents very acidic, or high in protons (hydrogen ions).
Acetylcholine 3 Cholinergic neurons supply the input to both PNS and CNS targets including: all first-stage targets (ganglia) of the autonomic nervous system skeletal muscles (somatic nervous system) the target end-organs of the parasympathetic nervous system (smooth muscles, heart) and the brain (diffusely) with a projection to the hippocampus (learning and memory) Nicotinic (ionotropic) receptors are located at autonomic ganglia and the neuromuscular junction, whereas muscarinic (G-protein) receptors are located at the end-organs of the parasympathetic nervous system and in the brain including the hippocampus. Nicotinic Autonomic ganglia Smooth muscle Hippocampus M1-M3-M5 (Gaq) Heart M2-M4 (Gai) All CNS (K+ channels opened) Enhances LTP in hippocampus (Also, autoreceptor)
Amino Acids 1 The amino acids glutamate and glycine are synthesized in all cells from glucose and other precursors by the action of enzymes (during cellular respiration). Glutamate is converted to GABA by the enzyme glutamic acid decarboxylase (GAD), a good marker for GABAergic neurons. The synaptic actions of the amino acid neurotransmitters are terminated by selective uptake in the presynaptic terminals and glia.
Amino Acids 2 The amino acid transmitters account for the vast majority of synaptic connections in the CNS. glutamate: primary excitatory GABA: inhibitory; brain glycine: inhibitory; brainstem and cord Glutamate fast excitation: AMPA ionotropic receptor; learning and memory (hippocampus): NMDA ionotropic receptor (ligandvoltage gated leads to Ca +2 influx) autoreceptor: presynaptic metabotropic mglur2/3 (Gai reduced Ca +2 influx) GABA fast inhibition: GABA-A ionotropic channel autoreceptor: presynaptic GABA-B metabotropic receptor (Gbg blocks Ca +2 ) AMPA Gi NMDA
Catecholamines 1 The amino acid tyrosine is the precursor for three different amine neurotransmitters (dopamine, norepinephrine and epinephrine in that order), collectively called the catecholamines. The enzyme tyrosine hydroxylase, which catalyzes the first step in the process, is the rate limiting factor. Interestingly, dopamine is synthesized in the cytosol, norepinephrine in vesicles and epinephrine back in the cytosol. The actions of catecholamines in the cleft are terminated by selective uptake of the transmitters back into the axon terminal by sodium-dependent transporters. There they may be re-loaded into vesicles, or enzymatically destroyed via monoamine oxidase (MAO) in mitochondria or catecholamine-o-methyl transferase (COMT), located in cytoplasm.
Catecholamines 2 Catecholamines are used in both the CNS and PNS, and all receptors are of the metabotropic G-proteincoupled kind. Dopamine: CNS There are five dopamine subtypes (D1-D5) movement selective the substantia nigra excites some neurons in the striatum (with D1 receptors) and inhibits others (D2) reward the ventral tegmental area excites D1 neurons in the nucleus accumbens (basal forebrain) Norepinephrine (NE): CNS+PNS Epinephrine (E): PNS There are two classes of adrenergic receptors, a and b. NE and E act at both receptors; NE is more potent than E at a adrenergic receptors and vise versa for the b receptors. alertness, attention the locus coeruleus excites neurons in cortex (with a1, b receptors) autoreceptor: presynaptic metabotropic (a2) activate sympathetic nervous system target organs (fight-or-flight; a1, b receptors) Closes K+ channels Opens K+ channels
Indolamines 1 The amino acid tryptophan is the precursor for two different amine neurotransmitters (serotonin and melatonin in that order), collectively called the indolamines. The synthesis of serotonin (5-hydroxytryptamine; 5-HT) occurs in two steps. Its synthesis appears to be limited by the availability of tryptophan in the extracellular fluid bathing neurons (essential amino acid in diet: grains, meat, dairy products, chocolate) The actions of serotonin in the cleft are terminated by selective re-uptake of the transmitter back into the axon terminal. There it may be re-loaded into vesicles, or enzymatically destroyed via monoamine oxidase (MAO) in mitochondria.
Indolamines 2 Serotonin is found primarily in the gastrointestinal tract (motility and secretion), but also broadly distributed in the CNS. In the CNS, serotonin is released by neurons located in the Raphe nuclei of the reticular formation. Serotoninergic axons distribute widely in the brain, and regulate a variety of behaviors including mood and appetite. Most serotonin receptors are metabotropic (excluding the 5-HT3 receptor): mood: the serotonin 5-HT2A receptor is expressed in the amygdala, an area known to affect mood. Serotonin appears to excite GABAergic interneurons to control the activity of the principal cells. appetite: the serotonin 5-HT2C receptor is expressed in the arcuate nucleus of the hypothalamus, an area that controls appetite autoreceptors: 5-HT1 and 5-HT5
Histamine Histamine is synthesized from the amino acid histadine, an essential amino acid (diet: poultry, fish, dairy products). The actions of histamine in the cleft are terminated by degradation by enzymes after selective re-uptake by glia. Histamine is found predominantly in tissue-resident mast cells (a type of white blood cell: immune/inflammatory function), but also in the CNS. In the CNS, histamine is released by the tuberomamillary nucleus of the hypothalamus, and regulates (among other functions) the sleep-wake cycle. All histamine receptors are metabotropic: arousal: H1 receptors are found in thalamus, an area that controls arousal autoreceptors: H3 receptors
Neuropeptides Neuropeptides are small protein-like molecules (chains of 2-40 amino acids). Unlike small neurotransmitters, they are synthesized as large precursors (called propeptides) in the soma, and transported to the axon terminal. There, they are cleaved (post-translational processing) into their active forms. Other differences from small transmitter processing include: stored in dense-core vesicles far from the presynaptic membrane after release, they are often modified by extracellular peptidases to alter activity they are not recycled back into the cell once secreted, but are either inactivated by peptidases or simply diffuse away Peptides act at metabotropic (G-protein-coupled receptors), and tend to affect gene expression. Different neuropeptides are involved in a wide range of brain functions, including arousal, reward, appetite, metabolism, reproduction, social behaviors, mood, learning and memory.