Neuro Lecture #5 PDF

Cell Signaling Lecture 012825 Neuromodulation and Neurotransmission Ch 4 (ionotropic versus) metabotropic receptors “The doogie mouse” G protein coupled receptors (G proteins)...

Cell Signaling Lecture 012825 Neuromodulation and Neurotransmission Ch 4 (ionotropic versus) metabotropic receptors “The doogie mouse” G protein coupled receptors (G proteins) Pharmacology: focus on Ach receptors skeletal muscle, heart, and CNS Second messenger systems cAMP, cGMP (cyclic nucleotides) phosphatidyl inositol Ca2+ / calmodulin protein kinases Synaptic plasticity homo-synaptic and hetero-synaptic functional significance of neuromodulation Cell Signaling: Local, in Tissue direct neurochemical Endocrine, in Bloodstream paracrine or autocrine hormonal neurotransmission - fast neurosecretory neuromodulatory - slow Ligand-gated Receptors Last time: ionotropic receptor gated by ligand Fast chemical transmission ion channel part of receptor directly affect VM by ionic flux ionotropic receptor nAchR metabotropic receptor gated by ligand; GTP binding (G) protein activated with ligand binding Metabotropic receptors are G protein coupled receptors mAchR is metabotropic Ach receptor Slow chemical transmission (1) ex. mAchR inhibits cardiac muscle 1 2 Slow chemical modulation (2) neurohormonal, modulatory second messenger production activation of protein kinases “2nd and 3rd messengers” are biochemical signals IONOTROPIC receptor / channel METABOTROPIC G-coupled receptor nAch mAchR (nicotinic) (muscarinic) * * The nAchR actually permits K+ flux as well Example: skeletal muscle Example: cardiac muscle  Ach receptor pharmacology ionotropic = nicotinic AchR directly gated - ion channel neuromuscular junction agonist (+) = nicotine antagonists (-) = curare, bungarotoxin metabotropic = muscarinic AchR indirectly gated - G protein cardiac muscle agonist (+) = muscarine Ach acts on CNS: antagonists (-) = atropine, skeletal muscle: excitatory both types of AchR scopolamine cardiac muscle: inhibitory Nicotinic Ach pharmacology Muscarinic agonists antagonists (curare)  Ach receptor Pharmacology: heart Otto Loewi’s Dream: “vagustuffe” metabotropic = muscarinic AchR indirectly gated - G protein cardiac muscle Ach activates G protein G protein activates K channel cardiac muscle hyperpolarizes heartbeat slows down Ach receptor Pharmacology: Sympathetic ganglion of autonomic nervous system (A) Ach nicotinic receptor (B) Ach muscarinic receptor Fast, ionotropic receptor channel Slow, metabotropic G protein-coupled receptor Ach activates fast EPSP G protein blocks “M” type K channel (A) (B) Blocking the “M” current: An example of decreased conductance (decreased permeability) EPSP Slow EPSP increases response to arriving signals Neurotransmission vs. Neuromodulation - nuts and bolts A. ionotropic receptors: 4 TM subunits ligand binding to receptor ionic flux altered VM neurotransmission B. metabotropic receptors: 7 TM segments ligand binding to receptor G protein activation enzyme activation second messenger production protein kinase activation Slow response neuromodulation phosphorylation of targets: Amplified response ion channels pumps receptors other second messenger systems DNA binding proteins phosphatases terminate signals G protein-coupled receptors extra-cellular domain - bind ligand intra-cellular domain - activate GTP binding protein G protein tri-mer - binds GDP, inactive G protein a subunit binds GTP and dissociates, active a subunit directly gates ion channel. Rare event. a subunit activates next enzyme. More common. - adenylate or guanylate cyclases, phospholipases C or A. enzyme  Cyclic AMP signaling system (cyclic adenosine monophosphate) First messenger (ligand) binds receptor Activation of G protein Activation of adenyl cyclase: production of second messenger cAMP Activation of protein kinase A Phosphorylation of: Enzymes Ion channels Nuclear proteins  Phosphatidyl Inositol signaling system First messenger (ligand) binds receptor Activation of G protein Activation of: phospholipase C Production of 2 second messengers: inositol trisphosphate diacyl glycerol Increase in Ca INT Activation of: * protein kinase C calmodulin (other*) Phosphorylation: Enzymes Ion channels Nuclear proteins  cGMP (photoreceptors) Other biochemical systems: Ca++/ calmodulin / CamK II (learning) nitric oxide, arachidonic acid Synaptic plasticity 1. Homo(same)-synaptic Homo-synaptic facilitation (during stimulation) Homo-synaptic potentiation (post-tetanic potentiation) Homo-synaptic depression Mechanism: Levels of nerve terminal calcium More or less NT release as a consequence of AP input train acting on Ca++ channels “residual calcium hypothesis” New Studies on Homo-Synaptic Plasticity in Mammalian Learning LTP = long term potentiation Pre-Synaptic Learning and memory: Terminal cerebral cortex hippocampus NMDA GluR NMDA Glu receptor: Ca2+ activates calmodulin Kinases activate enzymes for Dendritic arachidonic acid, nitric oxide (NO) Spine Postsynaptic Diffusion (retrograde signal) enhances NT release increased synaptic efficacy Hetero-synaptic plasticity - increase or decrease in synaptic efficacy a. pre-synaptic facilitation - interneuron increases NT release augment pre-synaptic AP... b. pre-synaptic inhibition - interneuron inhibits NT release inhibit pre-synaptic AP. Enkephalin in spinal cord modulation of pain Example of pain stimuli cause release of substance P neuromodulation: pre-synaptic interneurons release enkephalin enkephalins reduce release of substance P Pain receptor enkephalin = 5 amino acids the ascending pain pathway will be discussed in module III  INHIBIT: Pre-synapatic AP duration shorter: How does hetero-synaptic increased IK+, or decreased ICa++ plasticity work to alter NT release? AUGMENT: Pre-synapatic AP duration longer: decreased IK+, or increased ICa++ (enkephalin example - inhibit) (serotonin example – augment) With enkephalin: pre-synaptic dorsal root ganglion (DRG) action potential is shorter Result: less Ca influx into terminal Result: less Substance P released