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Transcript
Synapses and Synaptic Transmission • Dr. Donald Allen Learning Objectives • Describe the basic features of a synapse. • Describe the events that occur at a synapse from the time an action potential reaches the synapse to the time when the neurotransmitter is released. • Describe the electrical changes that occur at the postsynaptic terminal. • Describe the mechanism for presynaptic facilitation and presynaptic inhibition. • Explain the differences between ligand-gated ion channels and Gprotein mediated receptors. • Identify the major second messenger systems in the nervous system. • Identify the major neurotransmitter systems in the nervous system and their major functions. • Identify the primary excitatory and inhibitory neurotransmitters in the brain and spinal cord. • Describe the stages that occur in the life of a neurotransmitter molecule, (including storage in vesicles, release into the synaptic cleft, binding to receptors and either degradation or reuptake by the presynaptic terminal) and identify drugs that may interfere at these stages. • Describe the mechanism and role of receptor regulation • Describe the pathology of Lambert-Eaton syndrome and Myasthenia Gravis. What are synapses? • What is their function? Main Components of a Synapse • • • • Presynaptic terminal Postsynaptic terminal Synaptic cleft Vesicles – Neurotransmitters Where are Synapses located? • A synapse is between the axon of the presynaptic neuron and a region of the postsynaptic cell. • Where do we see synapses on the postsynaptic cell? • Do synapses with different locations have different functions? AxoAxoAxo- http://faculty.washington.edu/ chudler/synapse.html How Synapses Function 1. Action potential reaches presynaptic terminal 2. Calcium enters presynaptic terminal 1. Voltage-gated calcium ion channels 3. 4. 5. 6. Vesicles move toward release site Presynaptic terminal releases neurotransmitter Neurotransmitter binds to postsynaptic receptors Membrane channel changes configuration and ions enter postsynaptic cell 1. Can also activate intracellular messengers What determines how much neurotransmitter is released? Electrical Potentials at the Synapse • Neurotransmitter binding to receptors can open ion channels • At the neuromuscular junction or at axosomatic and axodendritic synapses, ion channel opening can generate a local postsynaptic potential • The potentials can be depolarizing or hyperpolarizing Postsynaptic potentials • Excitatory postsynaptic potential – EPSP – – – – De- or hyper-polarization Nicotinic ACh receptor – _____________ _____________ channels _____________ channels • Inhibitory postsynaptic potential – IPSP – De- or hyper-polarization – _____________ ion channels – _____________ ion channels Actions of EPSPs • In nervous system – EPSPs can summate to generate an action potential • _____________ • _____________ • At neuromuscular junction – Each action potential in motor neuron produces a sufficient EPSP in muscle that there is muscle contraction Actions of IPSPs • IPSPs can inhibit the generation of an action potential • What happens when there are both EPSPs and IPSPs at a postsynaptic neuron Presynaptic Facilitation • Where are the synapses – Axo- • Depolarization – – Makes an action potential last ________ at the second axon presynaptic terminal • The number of calcium ions that enter the presynaptic terminal is _____________ Presynaptic Facilitation • The change in calcium ions causes more vesicles to release their neurotransmitter Presynaptic Inhibition • Hyperpolarization – – Makes an action potential last ________ at the second axon presynaptic terminal – The number of calcium ions that enter the presynaptic terminal is _____________ – The change in calcium ions causes less vesicles to release their neurotransmitter Neurotransmitters and Neuromodulators • Neurotransmitter – Excite or inhibit postsynaptic neuron – Effect lasts less than 1/10th of a second • Neuromodulator – Effect G-proteins which activate second messengers – Longer lasting (minutes to days) Functional and Anatomical Organization of Neurochemical Systems • Local circuits • Diffuse systems • Relay systems Classification of Neurotransmitters and Neuromodulators • • • • • Acetylcholine Amino acids Monoamines Peptides Other Acetylcholine • Cholinergic systems • Receptors –N –M Amanita muscaria http://www.du.edu/~kinnamon/3640/neurotransmitters/ Acetylcholine Metabolism • Acetyl-Coenzyme A and Choline – Choline acetyltransferase (CAT) • Acetylcholine – Acetylcholinesterase (AChE) • Acetate and Choline Peripheral ACh • Neuromuscular junction – Receptor: – Function: • Autonomic nervous system – Receptors: – Function: Central ACh • Receptors – Both nicotinic and muscarinic • Function – Autonomic regulation – Selection of objects of attention Amino Acids • Main neurotransmitters of central nervous system • Excitatory amino acids – Aspartate – Glutamate • Inhibitory amino acids – Glycine – Gamma-aminobutyric acid (GABA) Glutamate • Principal fast neurotransmitter • Functions – Learning – Development – Neuronal death after CNS injury Inhibitory Amino Acids • Glycine – Inhibits postsynaptic membranes, particularly in brainstem and spinal cord • GABA – Major inhibitory neurotransmitter in CNS – Interneurons in spinal cord – Receptors: GABAA and GABAB • Both act to prevent excessive neural activity • Blocking the effects of these neurotransmitters can produce seizures Monoamines • Moderate sized group – – – – Norepinephrine (noradrenaline) Dopamine Serotonin Histamine • Cell bodies of these neurons? • Overall functions? Catecholamines: Dopamine and Norepinephrine • Phenylalanine • Tyrosine • Dihydroxyphenylalanine (l-DOPA) • Dopamine Further metabolism of catecholamines • Dopamine • Norepinephrine • Epinephrine Structure of some catecholamines Dopamine • Motor activity (Parkinson’s Disease) – l-DOPA • Cognition (Schizophrenia) – Dopamine receptor blockers • Motivation – Addiction • Cocaine • Amphetamine Norepinephrine • Autonomic nervous system – Fight or fight response – Panic disorder • Attention and Vigilance Serotonin • AKA 5-hydroxytryptamine Serotonin functions • Regulation of blood vessels • Low levels of serotonin associated with depression and suicide – SSRI – selective serotonin reuptake inhibitors • Fluoxetine (Prozac) • Sleep Histamine • Concentrated in hypothalamus • Helps regulate hormonal function Peptides • • • • Very broad category Many different functions More modulators than neurotransmitters There are several families of peptides Peptide release • Many neurons contain both a peptide neuromodulator and a more traditional neurotransmitter • With low stimulation, usually the neuron releases just the neurotransmitter • With high levels of stimulation, both the peptide and the neurotransmitter are released Endogenous opioid peptides • Bind to the same receptors that opiate drugs bind to • Three families – – – – Endorphins Enkephalins Dynorphins Each family comes from a different gene • In general, involved in pain inhibition • Endorphins and enkephalins involved in ‘runner’s high’ • Also important in regulation of hormonal systems Substance P • P is for pain • Substance P acts as a neurotransmitter in some of the neurons in the sensory pathways that relay pain sensation Other peptides • • • • • ACTH (pituitary) Vasopressin (pituitary) Neurotensin Cholecystokinin Somatostatin (hypothalamus) Miscellaneous Neurotransmitters • Nitrous oxide – – – – Neuromodulator Regulates vascular systems Cell death of neurons Changes in postsynaptic neuron in response to repeated stimuli • Carbon monoxide – Short-lasting, rapid effects – Affects neurotransmitter release Receptors • Most neurotransmitters and neuromodulators act by binding to specific proteins on the postsynaptic membrane termed receptors • Substances which bind to receptors are called ligands • Most receptors named after the ligand that binds to them – Some important exceptions Types of Receptors • Ligand-gated ion channels • G-protein mediated receptors Ligand-gated ion channels • Receptor and ion channel are the same complex • Actions usually rapid and brief • Mechanism – – – – Ligand binds to receptor Ion channel opens Ions travel through channel Local membrane depolarization or hyperpolarization Nicotinic Acetylcholine Receptor • Located at neuromuscular junction • Best studied receptor • Made up of 5 subunits Nicotinic AChR • Two molecules of ACh bind to the receptor • Ion channel opens – Permeable to both Na+ and K+ – Overall effect is depolarization • More Na+ enters than K+ leaves the muscle fiber – Channel open for only a few milliseconds • Action at the receptor ends when: – Neurotransmitter diffuses away from the synaptic cleft – Neurotransmitter is broken down into an inactive form • Acetylcholinesterase (ACh) • Monoamine oxidase (monoamines) • Peptidases (peptide neuromodulators) – Neurotransmitter is taken up into the presynaptic terminal G-protein mediated receptors • AKA: 7-transmembrane receptor – Picture next slide • Effects slower and longer lasting – – – – Open/close ion channel Activate/inhibit enzymes Regulate calcium levels in cell Activate/inactivate genes Beta-2 adrenergic receptor Mechanism of Action • Can be stimulatory, inhibitory or modulatory • Involve activation/inhibition of second messenger systems – Note that this can give us amplification of the ligand. One ligand-activated receptor can produce multiple 2nd messengers. If the 2nd messengers activate enzymes, we have a further magnification of the response Second messengers • Cyclic AMP (cAMP) – Modulates ion channels (pain sensation in PNS) – Activates cAMP dependent proteins/enzymes • Arachidonic acid – derived from lipids – Produces prostaglandins – aspirin blocks PG synthesis • regulate vasodilation • Enhances inflammation • Inositol triphosphate – Regulates Calcium ion stores G-protein action cAMP as 2nd Messenger G-protein action Phosphoinositol as 2nd Messenger Types of Receptors • • • • • • Acetylcholine Aminoacid Norepinephrine Dopamine Serotonin Opioid peptide Acetylcholine Receptors • Nicotinic – ligand-gated ion channel – Neuromuscular junction – Autonomic ganglia – Some parts of CNS • Functions – Memory and learning • Alzheimer’s disease – Neuronal development Muscarinic Acetylcholine Receptors • G-protein linked receptors – Autonomic targets – heart – Selected areas of brain • Autonomic function – Parasympathetic – Slow heart Glutamate Receptors • Both ion channels and G-protein linked • Ion Channels – named for drugs that bind – AMPA – fast acting – Kainate – fast acting – NMDA – slow opening and closing of ion channels • G-protein – metabotropic receptors NMDA receptors • Function – Normal neurotransmission – Long-term changes in the CNS • Long-term potentiation (next section) • Learning and memory NMDA receptors and pathology • Neuronal cell death – Injury to part of the brain can produce cell death in surrounding regions • Overactivity may cause epileptic seizures • Phencylclidine (PCP, angel dust) acts on NMDA receptors • Other pathologies – Acute stroke, chronic pain, Parkinson’s disease, schizophrenia GABA receptors • GABA-A receptors – Chloride ion-channel linked – Effect on cell membrane? – Barbiturates bind • Sedation • Decrease anxiety (anxiolytic) • Anticonvulsants for treating seizures • GABA-B receptors – G-protein mediated – Linked to ion channels through 2nd messengers • Baclofen – muscle relaxant • All GABA receptors tend to be inhibitory Dopamine Receptors • Dopaminergic receptors – 5 types – D1, D2, D3, D4, D5 – Main types • D1, also D3, D5 • D2, also D4 • D1 and D2 can have the opposite effects Norepinephrine receptors • Alpha-receptors (alpha-1 and alpha-2) • Beta-receptors (beta-1 and beta-2) – Beta-1 • Heart: increase force and rate of contraction • Beta-blockers – Beta-2 • Lungs: bronchodilation • Inhalers for asthma Serotonin receptors • 5-HT receptors – Multiple types • • • • • Cognition Sleep Perception (including pain) Motor activity Mood Opioid peptide receptors • Several types – Mu – Delta – Kappa • Primary action is inhibition of slow pain information • Location: hypothalamus, spinal cord, and periaqueductal gray How can we change synaptic transmission? • Drugs can interfere at many different stages – – – – – – – Synthesis of neurotransmitter Packaging in vesicles Regulating calcium ions in presynaptic terminal Release of neurotransmitter from vesicles Binding of neurotransmitter to receptors Degradation of neurotransmitter Re-uptake of neurotransmitter Synthesis of Neurotransmitter • l-DOPA Packaging in vesicles • Reserpine Calcium Ion regulation • Lambert-Eaton syndrome Neurotransmitter release • Botulinum toxin poisoning – Blocks release of ACh at the neuromuscular junction – Used to treat (short-term) spasticity – Used for cosmetic reasons Receptor binding • Agonists • Antagonists • Myasthenia gravis Neurotransmitter Degradation • Monoamine oxidase inhibitors (MAO-I) • Acetylcholinesterase inhibitors Neurotransmitter Reuptake • Tricyclic antidepressants – Inhibit monoamine reuptake – Tend to act at cholinergic receptors also • Selective serotonin reuptake inhibitors – Prozac (serotonin) Lambert-Eaton Syndrome • Mostly seen in patients with cancer, usually small cell carcinoma of the lung • Antibodies are produced against voltage-gated calcium channel of the neuromuscular junction • Antibodies block calcium entry into presynaptic terminal • What affect will this have on ACh release and muscle strength? Myasthenia gravis • Antibodies to the nicotinic acetylcholine receptor • Antibody blocks the effect of ACh on the muscle – Increasing weakness seen with repeated use of a muscle – Initial sign in about 50% of patients • Weakness opening eyelids or moving eyes. Why? • Other muscles commonly affected – – – – Facial muscles Muscles for swallowing Proximal limb muscles Respiratory muscles • Demographics of onset – Women: 20-30 – Men: 60-70 Treatment • • • • Acetylcholinesterase inhibitors Removal of thymus gland Immunosuppressive drugs Plasmapheresis: removes antibodies Questions before Chapter 4
