NSC 4352 1st Edition Exam 3 Study Guide Lectures 12 16 Lecture 12 Neurotransmitters I Chemical signaling consists of A molecular signal neurotransmitter A receptor molecule transduces information provided by the signal A target molecule ion channel that is altered to cause electrical response in the postsynaptic cell Two types of Receptors Ionotropic ligand gated channels receptor IS channel Metabotropic G protein coupled receptors receptor modulates channel or other intracellular effects Ionotropic Receptors Membrane spanning region forms ion channel Comprised of 4 5 protein subunits Mediate rapid postsynaptic effects millisecond time scale Glutamate receptors NMDA AMPA Kainate nicotinic acetylcholine receptor nAChR 5 HT receptor GABA receptor Glycine receptor Purinergic 3 A receptors General features of metabotropic receptor G protein coupled receptors Monomeric proteins consisting of 7 transmembrane domains Domains II III VI and VII make up the neurotansmitter bind G proteins bind to both the loop between domains V and VI and the C terminus blue Acetylcholine the nicotinic AChR Consists of 5 subunits Each subunit consists of 4 in muscle transmembrane spanning helices in neurons subunits bind acetylcholine M2 subunit blue lines pore Binding of acetylcholine to the two alpha subunits results in the 15 rotation of all M2 helices The cytoplasm side of the nAChR receptor has rings of high negative charge that determine the cation specificity of the receptor and remove the hydration shell of the passing ions nAChR is non selective cation channel Higher driving force for Na typically results in an inward current and an EPSP Acetylcholine metabolism Precursors Acetyl coenzyme A and choline Enzyme choline acetyltransferase ChAT catalyzes Acetylcholine A vesicular ACh transporter loads ACh into vesicles 10 000 per vesicle After release Acetylcholinesterase breaks up ACh into acetate and choline ACh esterase is the target of nerve gases pesticides A Na choline transporter takes choline back up into the presynaptic terminal Irreversible Acetylcholinesterase inhibitors Insecticides so called organophosphates and nerve gases e g Sarin Soman Irreversible AChE inhibitors completely inhibit ACh breakdown The lethal effect results from overstimulation persistent depolarization of the postsynaptic membrane particularly muscle cells The main effect is neuromuscular paralysis leading to respiratory failure within 5 min preceded by cognitive and severe autonomic symptoms Treatment involves combined administration of a muscarinic receptor antagonist e g atropine and the AChE antagonist pralidoxime which paradoxically restores AChE function Pralidoxime attaches to the site where the cholinesterase inhibitor has attached then attaches to the inhibitor removing the organophosphate from cholinesterase allowing it to work normally again Glutamate most prevalent excitatory transmitter half of all synapses Precursor glutamine released by glia cells Enzyme glutaminase catalyzes glutamate from glutamine VGLUT vesicular glutamate transporter EAAT excitatory amino acid transporter 5 different types some on presynaptic terminals others on glia cells Lecture 13 Neurotransmitters II Biogenic Amines the Monoamines Catecholamines Dopamine Norepinephrine Noradrenaline Epinephrine Adrenaline Serotonin 5 HT Histamine DA as final common pathway in addiction Nearly all drugs directly or indirectly target the brain s reward system by flooding the circuit with dopamine Drugs of abuse typically release 2 to 10 times the amount of dopamine that natural rewards do Chronic drug use changes monoamine metabolites and uptake transporters Dopamine D2 receptors are down regulated to compensate for their druginduced overstimulation Thus the brain s capacity to experience pleasure is diminished tolerance Cocaine and amphetamines inhibit the re uptake of dopamine Cocaine blocks the dopamine transporter DAT i e blocks dopamine reuptake This increases the lifetime of dopamine in the synaptic cleft Amphetamines increase dopamine release and block re uptake Amphetamines enter the presynaptic terminal via DAT or through direct diffusion and release dopamine from the vesicles by making the dopamine transporters work in reverse Serotonin 5 HT Precursor Tryptophan essential amino acid Regulates Mood and Sleep Implicated in depression anxiety disorders schizophrenia i e can not be synthesized by body has to be part of diet plentiful in turkey poultry chocolate bananas milk Depression anxiety disorders Many antidepressants Prozac Zoloft are SSRIs Selective Serotonin Reuptake Inhibitors block the serotonin transporter SERT SERT is target for MDMA ecstasy Degraded by MAO Most 5 HT receptors are metabotropic only 5 HT receptor is ligand gated ion channel 3 Lecture 14 Intracellular Signaling Cells alter internal chemistry in response to external signals Signal transduction is the process by which extracellular signals are communicated to specific domains within the cell Requires 3 steps Signal receptor and target molecule that mediates the cellular response Signal Amplification and temporal control Most signal transduction pathways serve not only to communicate signals to specific intracellular domains but to amplify them as well In addition different signaling pathways allow for control of cellular responses on various time scales Extracellular signaling molecules Small soluble organic molecules e g Neurotransmitters amino acids sugars nucleotides 2 Inorganic ions e g Zn Diffusable gases e g CO NO Peptides Lipophilic organic molecules e g endocannabinoids Cell surface expressed proteins G Protein Coupled Receptors GPCR The human genome encodes roughly 800 G protein coupled receptors which detect photons light hormones growth factors drugs and other endogenous ligands Approximately 150 of the GPCRs found in the human genome have unknown functions Whereas G proteins are activated by G protein coupled receptors they are inactivated by RGSproteins Receptors stimulate GTP binding RGS proteins Regulators of G protein signaling orGAPs GTPase Activating Protein stimulateGTP hydrolysis via GTPases Heterotrimeric large G proteins G protein binds to the receptor G protein is composed of 3 subunits the alpha subunit binds either to guanosine triphosphate GTP or guanosine diphosphate GDP G proteins function as molecular switches They are on when they bind GTP they are off when they bind GDP There are several classes of G subunits G stimulatory s G