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Chapter 07 The Nervous System Part 2 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. IV. Acetylcholine Acetylcholine (ACh) ACh is a neurotransmitter that directly opens ion channels when it binds to its receptor. In some cases, ACh is excitatory, and in other cases it is inhibitory, depending on the organ involved Excitatory in some areas of the CNS, in some autonomic motor neurons, and in all somatic motor neurons Inhibitory in some autonomic motor neurons Two Types of Acetylcholine Receptors Nicotinic ACh receptors 1) Can be stimulated by nicotine 2) Found on the motor end plate of skeletal muscle cells, in autonomic ganglia, and in some parts of the CNS Muscarinic ACh receptors 1) Can be stimulated by muscarine (from poisonous mushrooms) 2) Found in CNS and plasma membrane of smooth and cardiac muscles and glands innervated by autonomic motor neurons Agonists and Antagonists 1) Agonists: drugs that can stimulate a receptor a) Nicotine for nicotinic ACh receptors b) Muscarine for muscarinic ACh receptors 2) Antagonists: drugs that inhibit a receptor a) Atropine is an antagonist for muscarinic receptors. b) Curare is an antagonist for nicotinic receptors. Chemically Regulated Channels Binding of a neurotransmitter to a receptor can open an ion channel in one of two ways: 1. Ligand-gated channels 2. G-protein coupled channels Ligand-Gated Channels The receptor protein is also an ion channel; binding of the neurotransmitter directly opens the ion channel. Nicotinic ACh receptors are ligand-gated channels with two receptor sites for two AChs. Binding of 2 acetylcholine molecules opens a channel that allows both Na+ and K+ passage. 1) Na+ flows in, and K+ flows out. 2) Due to electrochemical gradient, more Na+ flows in than K+ out. Nicotinic ACh Receptors Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Extracellular Fluid 1. Channel closed until neurotransmitter binds to it Binding site Ion channel Na+ 2. Open channel permits diffusion of specific ions Acetylcholine Plasma membrane (a) Nicotinic ACh receptors Cytoplasm K+ (b) Ligand-gated channels Inward flow of Na+ depolarizes the cell, creating an EPSP (excitatory postsynaptic potential). 1) EPSPs occur in the dendrites and cell bodies. 2) EPSPs from the binding of several ACh molecules can be added together to produce greater depolarization summation of graded-potentials 3) This may reach the threshold for voltage-gated channels in the axon hillock, leading to action potential. Graded nature of EPSPs Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. mV Cell bodies and dendrites Axon Membrane potential +30 Action potential EPSPs Threshold –50 rmp –70 Time Relative amounts of excitatory neurotransmitter Comparison of EPSPs and Action Potentials G-Protein Coupled Channels Ligand-gated channels that do not directly open ion channels These channels are coupled to a G-protein located on the intracellular membrane surface Once ligand binds, G-protein separates and attaches to a nearby ion channel. This binding either opens or closes ion channels. Muscarinic ACh receptors interact with ion channels in this way as well as dopamine and norepinephrine receptors G-Protein Coupled Channels Associated with a G-protein 1) G-proteins have three subunits (alpha, beta, and gamma). 2) Binding of one acetylcholine results in the dissociation of the G-protein subunits. 3) Either the alpha or the beta-gamma diffuses through the membrane to bind ion channels. 4) This opens the channel for short period of time. 5) The G-protein subunits dissociate from the channel and it closes Steps in the activation and deactivation of G-proteins G-protein Coupled Channels Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ACh K+ 1. ACh binds to receptor Plasma membrane β α γ Receptor G-proteins 2. G-protein subunit dissociates β γ 3. G-protein binds to K+ channel, causing it to open K+ K+ channel G-protein couple channels Binding of acetylcholine opens K+ channels in some tissues (IPSP) or closes K+ channels in others (EPSP). 1) In the heart, K+ channels are opened by the beta-gamma complex, creating IPSPs (hyperpolarization) that slow the heart rate. 2) In the smooth muscles of the stomach, K+ channels are closed by the alpha subunit, producing EPSPs (depolarization) and the contraction of these muscles. Acetylcholinesterase (AChE) AChE is an enzyme that inactivates ACh activity shortly after it binds to the receptor. Hydrolyzes ACh into acetate and choline, which are taken back into the presynaptic cell for reuse. Action of Acetylcholinesterase (AChE) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Presynaptic axon Presynaptic axon Acetylcholine Acetate Choline Acetylcholinesterase Receptor Postsynaptic cell Postsynaptic cell ACh in the PNS Somatic motor neurons form interactions called neuromuscular junctions with muscle cells. The area on the muscle cell with receptors for neurotransmitter is called the motor end plate. a. EPSPs formed here are often called end plate potentials. b. End plate potentials open voltage-gated Na+ channels, which result in an action potential. c. This produces muscle contraction Interruption of Neuromuscular Transmission Certain drugs can block neuromuscular transmission. Curare is an antagonist of acetylcholine. It blocks ACh receptors so muscles do not contract. 1) Leads to paralysis and death (due to paralyzed diaphragm) Used clinically as a muscle relaxant Drugs that Affect the Neural Control of Skeletal Muscles Alzheimer Disease Associated with loss of cholinergic neurons that synapse on the areas of the brain responsible for memory V. Monoamines as Neurotransmitters Introduction Monoamines are regulatory molecules derived from amino acids Catecholamines: derived from tyrosine; include dopamine, norepinephrine, and epinephrine Serotonin: derived from L-tryptophan Histamine: derived from histidine Monoamine Action and Inactivation Like ACh, monoamines are made in the presynaptic axon, released via exocytosis, diffuse across the synapse, and bind to specific receptors. They are quickly taken back into the presynaptic cell (called reuptake) and degraded by monoamine oxidase (MAO). Monoamine Action and Inactivation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Presynaptic neuron ending 1. Monoamine produced and stored in synaptic vesicles Action potentials Tyrosine Ca2+ Dopa 2. Action potentials open gated Ca2+ channels, leading to release of neurotransmitter Dopamine 5. Inactivation of most neurotransmitter by MAO Priming Norepinephrine Fusion 4. Reuptake of most neurotransmitter from synaptic cleft 3. Neurotransmitters enter synaptic cleft Norepinephrine Receptor Postsynaptic cell Monoamine Action None of the receptors for these signals are direct ion channels. All use a second messenger system. Cyclic adenosine monophosphate (cAMP) is the most common second messenger for catecholamines. Monoamine Action Binding of a catecholamine to its receptor activates a G-protein to dissociate and send the alpha subunit to an enzyme called adenylate cyclase which converts ATP to cAMP cAMP activates an enzyme called protein kinase, which phosphorylates other proteins. An ion channel opens. Norepinephrine Action & G-proteins Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1. Norepinephrine binds to its receptor Norepinephrine Adenylate cyclase Ion channel Plasma membrane Receptor α β G-proteins α α γ 2. G-protein subunits dissociate 3. Adenylate cyclase activated ATP Opens ion channels cyclic AMP Protein kinase (inactive) Postsynaptic cell Protein kinase (active) Phosphorylates proteins 4. cAMP activates protein kinase, which opens ion channels Serotonin as a neurotransmitter Used by neurons in the raphe nuclei (middle region of brain stem) Implicated in mood, behavior, appetite, and cerebral circulation The drug LSD and other hallucinogenic drugs may be agonists. Serotonin specific reuptake inhibitors (SSRIs) are used to treat depression. 1) Prozac, Paxil, Zoloft Serotonin Over a dozen known receptors allow for diversity of serotonin function. Different drugs that target specific serotonin receptors could be given for anxiety, appetite control, and migraine headaches. Dopamine as a neurotransmitter Neurons that use dopamine (dopaminergic neurons) are highly concentrated in the midbrain in two main areas: a. Nigrostriatal dopamine system: involved in motor control b. Mesolimbic dopamine system: involved in emotional reward Nigrostriatal Dopamine System Neurons from the substantia nigra (part of the basal nuclei) of the brain send dopaminergic neurons to the basal nuclei (caudate nucleus, putamen, globus pallidus). Important step in the control and initiation of movements Parkinson disease is caused by degeneration of these neurons. Patients are treated with L-dopa and MAOIs (monoamine oxidase inhibitors). Mesolimbic Dopamine System Regions of the midbrain send dopaminergic neurons to regions of the forebrain. Involved in emotional reward systems and associated with addictions such as nicotine, alcohol, and other drugs Schizophrenia is associated with too much dopamine in this system. Drugs that treat schizophrenia are dopamine antagonists. Norepinephrine as a neurotransmitter Used in both the CNS and PNS Sympathetic neurons of the PNS use norepinephrine on smooth muscles, cardiac muscles, and glands. Used by neurons of the CNS in brain regions associated with arousal Amphetamines work by stimulating norepinephrine pathways in the brain. VI. Other Neurotransmitters Amino acids as NTs Excitatory NT – glutamate An amino acid used as the major excitatory neurotransmitter in the brain Produces EPSPs in 80% of the synapses in the cerebral cortex Energy required for all the EPSPs constitutes the major energy use in the brain Astrocytes take glutamate from the synaptic cleft to increase glucose uptake and increase blood flow by vasodilation Glutamate Receptors All glutamate receptors also serve as ion channels a) NMDA receptors b) AMPA receptors c) Kainate receptors NMDA and AMPA receptors work together in memory storage. Inhibitory NTs Glycine Amino acid used as a neurotransmitter to produce IPSPs Binding of glycine opens Cl− channels, causing an influx of Cl−. Makes it harder to reach threshold Important in the spinal cord for regulating skeletal muscle movement. This allows antagonistic muscle groups to relax while others are contracting (e.g., biceps relax while triceps contract). Glycine Also important in the relaxation of the diaphragm, which is necessary for breathing The poison strychnine blocks glycine receptors, which produces death by asphyxiation. GABA Gamma-aminobutyric acid is the most common neurotransmitter in the brain and is used by 1/3 of the brain’s neurons. It is inhibitory, opening Cl− channels when it binds to its receptor. It is involved in motor control. Degeneration of GABA-secreting neurons in the brain results in Huntington disease. GABA receptors contain a chloride channel Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. GABA Chloride ion (Cl–) Plasma membrane I 1. Channel closed until receptor binds to GABA Channel closed GABA receptors 3. Diffusion of Cl– into cell causes hyperpolarization (IPSP) 2. GABA receptor binds to GABA, Cl– channel opens Polypeptides as neurotransmitters Neuropeptides Many chemicals used as hormones or paracrine signals are also found in the brain acting as neurotransmitters. CCK: involved in a feeling of satiety after a meal Substance P: mediates sensations of pain Neuromodulators 1) Neurons that release a classical NT like Ach or norepinephrine along with a polypeptide 2) Can release either under different conditions 3) Called synaptic plasticity – capacity for alteration at the molecular level Endogenous Opioids Opioid receptors were discovered to bind with drugs such as opium and morphine, resulting in pain relief. Endogenous opioids are polypeptides produced by the brain and pituitary gland; includes enkephalin, β-endorphin, and dynorphin Opioids also produce euphoria so they may mediate reward pathways; may be related to feeling of well-being after exercise Neuropeptide Y Most abundant neuropeptide in the brain Plays a role in stress response, circadian rhythms, and cardiovascular control Powerful stimulator of hunger; leptin inhibits neuropeptide Y release to suppress appetite Works by inhibiting the release of glutamate in the hippocampus (excess glutamate release can cause convulsions) Endocannibinoids Neurotransmitters that bind to the same receptors that bind to the active ingredient in marijuana (THC) Short fatty acids produced in the dendrites and cell bodies and released directly from the plasma membrane (no vesicle) Retrograde neurotransmitters released from the postsynaptic neuron; inhibit further neurotransmitter release from the presynaptic axon Endocannibinoids Endocannibinoids can inhibit IPSP-producing NTs from one neuron so EPSP-producing NTs from another neuron can have a greater effect. Endocannibinoids may enhance learning and memory and have been shown to induce appetite; depolarization-induced suppression of inhibition Marijuana use impairs learning and memory because the action of THC is widespread and not controlled. Nitric Oxide and Carbon Monoxide Nitric oxide a. A gas produced by some neurons in the CNS and PNS from the amino acid L-arginine b. Diffuses across the presynaptic axon plasma membrane (no vesicle) c. Diffuses into the target cell and activates the production of cGMP as a second messenger d. Causes blood vessel dilation and helps kill bacteria e. May also act as a retrograde NT Nitric Oxide In the PNS, nitric oxide is secreted by autonomic neurons onto cells in the digestive tract, respiratory passages, and penis, causing muscle relaxation. Responsible for an erection The drug Viagra works by increasing NO release. Carbon Monoxide (CO) Another gas used as a neurotransmitter Derived from the conversion of heme to biliverdin Also activates the production of cGMP in target cells Used in the olfactory epithelium and cerebellum ATP & Adenosine as NTs Used as cotransmitters released via vesicles with another neurotransmitter Classsified chemically as purines; bind to purinergic receptors a. P1 receptor for ATP b. P2 receptor for adenosine Released with norepinephrine to stimulate blood vessel constriction and with ACh to stimulate intestinal contraction Released by nonneural cells; act as paracrine regulators in blood clotting, taste, and pain Chemicals that are or may be NTs VII. Synaptic Integration Introduction Neural pathways Divergence of neural pathways: Axons have collateral branches, so one presynaptic neuron can form synapses with several postsynaptic neurons. Convergence of neural pathways: Several different presynaptic neurons (up to a thousand) can synapse on one postsynaptic neuron. Summation Spatial summation occurs due to convergence of signals onto a single postsynaptic neuron. All of the EPSPs and IPSPs are added together at the axon hillock. Temporal summation is due to successive waves of neurotransmitter release that add together at the initial segment of the axon Spatial Summation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 Action potential +30 mV 2 –55 mV Threshold EPSP –70 mV EPSP EPSP Release of neurotransmitter from neuron 1 only Release of neurotransmitter from neurons and 1 2 Synaptic Plasticity Repeated use of a neuronal pathway may strengthen or reduce synaptic transmission in that pathway. When repeated stimulation enhances excitability, it is called long-term potentiation (LTP). Found in the hippocampus of the brain where memories are stored Associated with insertion of AMPA glutamate receptors Long-term potentiation Improves the efficacy of synaptic transmission that favors transmission along frequently used pathways Seen in learning and memory in the hippocampus Synaptic Plasticity Long-term depression (LTD) occurs when glutamate-releasing presynaptic neurons stimulate the release of endocannibinoids. This suppresses the further release of neurotransmitter. Due to removal of AMPA receptors Short-term (20-40 sec) is called DST, depolarization-induced suppression of inhibition Synaptic plasticity Both LTP and LTD depend on a rise in calcium ion concentration within the postsynaptic neuron Rapid rise leads to LTP Smaller but prolonged rise leads to LTD Synaptic plasticity involves enlargement or shrinkage of dendritic spines Synaptic Inhibition Postsynaptic inhibition is produced by inhibitory neurotransmitters such as glycine (spinal cord) and GABA (brain). Hyperpolarizes the postsynaptic neuron and makes it less likely to reach threshold voltage at the axon hillock Synaptic Inhibition Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 2 –55 mV –70 mV Threshold for action potential IPSP EPSP –85 mV Inhibitory neurotransmitter from neuron 1 Excitatory neurotransmitter from neuron 2 Presynaptic Inhibition Decreased in excitatory NTs being released from one presynaptic axon through axoaxonic synapse from another presynaptic axon Calcium ion channels are inactivated Seen in the action of endogenous opioids in pain reduction; inhibits the release of substance P that promotes pain transmission