Student 3 Chemical Signaling SP25 PDF

Module 1: Foundations Principles of Pharmacology Structure and Function of the Nervous System Chemical Signaling of Neurotransmitters Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation C. Neurotransmitter Rec...

Module 1: Foundations Principles of Pharmacology Structure and Function of the Nervous System Chemical Signaling of Neurotransmitters Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together Chemical Signaling Between Neurons  Chemical Signaling between Neurons Neurons are not physically connected Synapse The point of communication between neurons. Transmission of AP occurs in only one direction* From the presynaptic cell to the postsynaptic cell. Terminal boutons of the presynaptic cell contain synaptic vesicles Vesicles contain thousand molecules of neurotransmitters (NT) Chemical Signaling between Neurons The synapse is surrounded by processes from astrocytes (glial cells). Chemical Signaling between Neurons 1. Axodendritic synapses The terminal bouton of one neuron synapses on the dendrite of another neuron At the conclusion of an action potential, neurotransmitter is releases from the pre-synaptic neuron into the synapse and can bind to receptors on the dendrites of the post-synaptic neuron. Chemical Signaling between Neurons 2. Axosomatic synapses The terminal bouton of one neuron synapses on the soma of another neuron At the conclusion of an action potential, neurotransmitter is releases from the pre-synaptic neuron into the synapse and can bind to receptors on the soma of the post-synaptic neuron. Chemical Signaling between Neurons 3. Axoaxonic synapses The terminal bouton of one neuron synapses on the terminal bouton of another neuron At the conclusion of an action potential, neurotransmitter is releases from the pre-synaptic neuron into the synapse and can bind to receptors on the terminal bouton of the post- synaptic neuron. This permits the presynaptic cell to alter neurotransmitter release from the postsynaptic cell directly at the terminal bouton. Chemical Signaling between Neurons 3. Axoaxonic Synapses Presynaptic Inhibition Reduced transmitter release from the terminal bouton into the axosomatic (pictured here) or the axodendritic synapse. Presynaptic Facilitation Enhanced release of transmitter from the ternal bouton into the axosomatic (pictured here) or the axodendritic synapse. Chemical Signaling between Nerve Cells Neurons may terminate on another neuron, a muscle cell, or a cell specialized to release a hormone or other secretory product. Neuromuscular junction: synapse between a neuron and a muscle cell Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation 1. Classes of NTs 2. Synthesis 3. Release 4. Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together Neurotransmitter Basics More than 100 neurotransmitter chemicals have been identified. Classes of neurotransmitters: Amino acids Monoamines Acetylcholine Neuropeptides Lipids Gases Alcohol: Dopamine Glutamate GABA CRF Hallucinogens: Serotonin Dopamine Opioids: Dopamine Endorphins and Enkephalins Norepinephrine CRF Cannabis: Anadamide 2-AG Dopamine Process of Addiction: Dopamine CRF Glutamate Chapter 3: Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation 1. Classes of NTs 2. Synthesis 3. Release 4. Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together  Neurotransmitter Synthesis An individual neuron can make one or up to several different neurotransmitters. Vesicles can hold one or more transmitters. Small vesicles usually contain classic NTs Large vesicles typically contain neuropeptides and classic NTs  Figure 3.3 Axon terminal of a neuron that synthesizes both a classical neurotransmitter and a neuropeptide Neurotransmitter Synthesis Two types of synthesis: Neuropeptides (Image C. Peptide) Precursors proteins are synthesized in the soma Packaged in large vesicles with enzymes Enzymes cleave the precursor proteins into functional neuropeptides All other neurotransmitters (Image B. Sm Molecule) Enzymatic reactions occurring within the cell Chapter 3: Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation 1. Classes of NTs 2. Synthesis 3. Release 4. Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together Neurotransmitter Release When a wave of depolarization reaches the axon terminals: Voltage-gated Ca2+ channels open and Ca2+ enters the cell. Ca2+ necessary for neurotransmitter release. Vesicles “dock” with the cell membrane at the active zone and are primed for release (various proteins are involved in these steps) Exocytosis: Ca2+ aids the vesicle membranes to fuse with the cell membrane releasing neurotransmitter molecules into the synaptic cleft. Neurotransmitter Release- Application: Botulinum Toxin Some of the proteins involved in exocytosis are targets for drugs or toxins. Botulism: bacterial toxin blocks transmitter release at neuromuscular junctions, causing paralysis. Enzymes in the toxin attack proteins involved in exocytosis of acetylcholine from presynaptic motor neurons. Work in four areas: Neuromuscular junction Autonomic ganglia Postganglionic parasympathetic nerve endings Postganglionic sympathetic nerve endings Neurotransmitter Release Glutamate Neuromodulators Substances that play an indirect role in neurotransmission DA, 5-HT, and NE are often neuromodulators of glutamate and GABA Enhance, reduce, prolong the primary NTs action Dopamine GABA Neurotransmitter Release Neurotransmitter release is regulated by: 1. Rate of neuron firing 2. Probability that vesicles will undergo exocytosis Not all action potential that allow Ca++ into the cell result in NT release Not clear why 3. Autoreceptors (two types) Receptors for the same transmitter released by the neuron. Some drugs block or stimulate autoreceptors Located on regions of the PRE-synaptic receptor. Neurotransmitter Release 1. Terminal autoreceptors: Activated by the neurotransmitter On terminal boutons Reduces further transmitter release. Cell can continue to fire 2. Somatodendritc autoreceptors: Activated by the neurotransmitter On cell bodies or dendrites Slows the rate of neuron firing Reduces amount of NT released Somatodendritc Autoreceptors Terminal Autoreceptor s Neurotransmitter Release Dale’s Principle: A neuron performs the same chemical action at all of its synaptic connections to other cells, regardless of the identity of the target cell (i.e., one neuron, one neurotransmitter) Principle discarded in 1984 Co-Release: Single action potential releases all NTs into the synapse Co-Transmission: Allows for different NTs to be released from different areas of the axon terminal Co-release Co-transmission Action potential releases both NTs 1. Differential Ca++ sensitivity: Release controlled by different local depolarization, resulting in two different signals 2. Spatial segregation: Action potential releases both NT, but message sent to two locations Chapter 3: Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation 1. Classes of NTs 2. Synthesis 3. Release 4. Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together Neurotransmitter Inactivation To stop signal transmission, the neurotransmitter molecules must be removed from the synaptic cleft. Transmitter may be: 1. Broken down in the synapse by enzymes 2. Be taken back into the cell via transporters and recycled Neurotransmitter Release Inactivation 1. Enzymatic Degradation Neurotransmitters are broken down in the synapse by enzymes Common for ACh, lipid and gaseous transmitters, and neuropeptides. Neurotransmitter Synthesis, Release, and Inactivation 2. Reuptake: Transporter proteins in the cell membrane of the pre-synaptic neuron take the neurotransmitter molecules back into the cell Transmitters are taken back up by the cell that released them. This re-uptake can be executed by the pre-synaptic cell or by glia cells Neurotransmitter Inactivation Some psychoactive drugs block the transporters, and signal transmission is enhanced. Application: Cocaine blocks transporters for DA, 5-HT, and NE. Many antidepressants block the 5-HT transporter (SSRIs), the NE transporter (SNRIs), or both SSRI: Selective serotonin reuptake inhibitor NERI: Selective norepinephrine reuptake inhibitor Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together Neurotransmitter Receptors Neurotransmitter receptors are proteins located in cell membranes. The transmitter binds to the receptor to activate it. The resulting effect may be excitatory or inhibitory. Neurotransmitter Receptors and Second- Messenger Systems Neurotransmitters bind to more than one type of receptor—receptor subtypes. Drugs can be designed to affect specific subtypes, which can result in fewer side effects. There are two major categories of transmitter receptors: 1. Ionotropic 2. Metabotropic Video on ionotropic/metabotropic receptor function 1 Video on ionotropic/metabotropic receptor function 2 Neurotransmitter Receptors and Second-Messenger Systems 1. Ionotropic receptors Consist of 4 or 5 subunits with an ion channel in the center. When transmitter binds to the receptor, the channel opens and allows ion flow Ligand-gated channel receptors. Neurotransmitter Receptors and Second-Messenger Systems Ionotropic receptors allow ions to flow across the membrane of a cell according to electrostatic pressure or concentration gradient. Ionotropic Na+ channels Results in depolarization and an excitatory response Example: Acetylcholine binds to receptor, allows Na+ into the cell Example: Voltage change open Na+ channel, allows Na+ to enter the cell Ionotropic Ca2+ channels Results in depolarization and an excitatory response Example: Glutamate binds to receptor, allows Ca++ into the cell Ca2+ can act as a second messenger. Ionotropic Cl- channels Results in hyperpolarization and an inhibitory response Example: GABA binds to receptor, allows Cl- to exit the cell Neurotransmitter Receptors and Second- Messenger Systems 2. Metabotropic receptors: Act more slowly, but response lasts longer. Consist of 7 trans-membrane domains (7-TM receptors). Work by activating G-proteins (G protein- coupled receptors). There are many different G-proteins Effects of the metabotropic receptor on the post-synaptic cell depends on which G-protein(s) the receptor activates Neurotransmitter Receptors and Second-Messenger Systems Two major classes of Metabotropic G proteins: 1. Those that interact with neighboring ion channels Inhibit or activate ion channels Example: K+ channels open, K+ moves out of cell and hyperpolarization results. 2. Those that interact with effector enzymes Stimulate or inhibit effector enzymes in the cell membrane that synthesize or break down second messenger molecules. Neurotransmitter Receptors and Second- Messenger Systems Second messengers Activate protein kinases Results in phosphorylation of substrate proteins. Ion channel Enzyme involved in NT synthesis or degradation Transporter proteins Phosphorylation of nuclear proteins can turn gene expression on or off. Second messengers can initiate transcription and the synthesis of new proteins, including neurotransmitter receptors Second messengers can promote upregulation or downregulation of neurotransmitter receptors at the cell membrane Application: Second Messenger and Psychiatric Disorders Epigenetics: how cells regulate gene activity without changing DNA sequence Second messengers can promote chromatin remodeling, change the expression of proteins, and provide a possible mechanism for psychiatric disorders  Application: Second Messenger and Psychiatric Disorders Epigenetic Mechanisms Application: Second Messenger and Psychiatric Disorders Schizophrenia Psychiatric disorders that impacts who people think, feel, behave Hallmark Symptoms: Delusions, hallucinations, disorganized thinking and speech, unusual physical behavior (flat or inappropriate affect) Impacts 1% of the population Monozygotic twins have 50% chance of diagnosis if their twin receives diagnosis Ps with schizophrenia have alterations in several neurotransmitter system, including GABA Application: Second Messenger and Psychiatric Disorders Premise: Schizophrenia is a caused by environmental and gene interaction If the environment encourages an altered genetic response (e.g., excessive, unpredictable stress), a risk for developing a disorder is increased. Histone modification DNA methylation Change in genetic response alters expression of proteins necessary for the synthesis and activity of NT systems Changes in NT systems produce behavioral effects of schizophrenia, including GABA and Glutamate https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC8616184/ Application: Second Messenger and Psychiatric Disorders Candidate Gene: Glutamate decarboxylase 1 (GAD1) GAD1 codes for an enzyme involved in the synthesis of the neurotransmitter GABA GABA is an inhibitory neurotransmitter (binding of the GABA receptor allows entry of Cl- into the cell) Ps with schizophrenia show deficits of GABA, including decreased expression of GAD1 GAD1 gene was hypermethylated in the neurons of the prefrontal cortex of Ps with schizophrenia, as compared to controls Hypermethylation associated with decreased gene expression and increased mutation rates Application: Second Messenger and Psychiatric Disorders Blue: hypoactivation in controls vs patients w/ schizophrenia Orange: patients w/ schizophrenia fail to deactivate as compared to controls https://www.nature.com/articles/ Chemical Signaling by Neurotransmitters A. Chemical Signaling Between Neurons B. Neurotransmitter Synthesis, Release, and Inactivation C. Neurotransmitter Receptors and Second-Messenger Systems D. Putting it all Together