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Ionotropic and Metabotropic Receptors Recall the 2 Kinds of Synapses? Electrical • 2 neurons linked together by gap junctions • Function in nervous system: - rapid communication - bidirectional communication - excitation/inhibition at the same synapse • Some between neurons and glia cells • • • • • Chemical Signal transduction Excitatory Inhibitory Slower communication Unidirectional communication Recall where chemical synapses are found? Recall the Chemical Synapse? Communication Across a Synapse 1. Action Potential 2. Voltage-gated Ca channels open 3. Ca triggers exocytosis 4. Nt diffuses and binds to receptor 5. Response in cell Response is terminated by removing nt from synaptic cleft 6. Degradation 7. Reuptake 8. Diffusion Signal Transduction at Synapses • Rate of the response is due to the mechanism by which the signal is received and transferred at the plasma membrane. • Fast responses at ionotropic receptors (channel-linked). • Slow responses at metabotropic receptors (G-protein-linked). Ionotropic Receptors • The receptor is a ligand-gated ion channel. • Ligand binding directly opens ion channel. • Fast action, short latency between nt binding and response. • Response is brief. Ionotropic Receptors • 5 subunits form the pore through the membrane. • Binding of ligand opens the pore. • Ions flow into or out of the cell. • Produces EPSP or IPSP (depending on the ion channel). • Rapid desensitization (loss of activity) if continuously exposed to nt. • Limits postsynaptic responding when presynaptic neurons are highly active for a period of time. Ionotropic Receptors Sensitization High Ion Flow Low Time, ms, in exposure to neurotransmitter Ionotropic Receptors • Can have multiple binding sites for various neuromodulators. • Can enhance or inhibit binding of endogenous ligands. • Are good targets for drugs. Fast Responses at Ionotropic Receptors Metabotropic Receptors • Most common type of receptor. • Coupled to G protein. • No direct control of ion channels. • Second messengers. Metabotropic Receptors • Single subunit with 7 transmembrane spanning domains. • Highly conserved across the “receptor superfamily”. • Ligand binds in cleft on external face. • Ligand binding activates G protein • G protein activate various effectors. • Sometimes the effectors are the ion channels. β-adrenergic receptor N Extracellular space TM3 TM2 TM4 Asp - TM1 NE + TM7 TM5 TM6 αs C i3 loop Cytoplasm γ β GTP GDP ATP Gs GDP protei cAMP cAMP n cAMP cAMP 4)6) 2) 3) 1)The 5) Binding Activated After The GTP-bound ß-adrenergic hydrolysis of i3 NE adenyl tocauses the αof subunit receptor αGTP subunit to third GDP, is a s cyclase sthe intracellular of dissociates 7-transmembrane produces the theαG many from loop returns the molecules results (i3)spanning βofsubunit to the inits aof s subunit s protein receptor conformation and protein. cAMP original from from to conformation, the A change negatively ATP. βAR change receptor conformation incharged dissociates αs, and Asp rd and causing binds residue from bind to AC GDP adenyl on to (which the the to dissociate cyclase GDP-bound 3then becomes (AC). and α (Click to see animation; clicks subunit GTP (Meanwhile, transmembrane inactive), to bind. of the and norepinephrine Greforms regionthe (TM3), may s protein. again for next step) dissociate along with trimeric Gfrom other protein the charged, receptor, complex. polar but (Click to sees animation; click the residues, αs subunit allows canaremain positively active again (Click for tonext see animation; step) click for charged many seconds norepinephrine after this (NE) again for next slide) dissociation.) molecule to bind to the hydrophobic core of the receptor. (Click to see animation; click again(Click for next to see step) animation; click again for next step) Slow Responses at Metabotropic Receptors: Direct G-Protein Coupling Slow Responses at Metabotropic Receptors: Second Messenger Coupling Postsynaptic Potential • Change in membrane potential in response to neurotransmitter binding to receptor. • Can be excitatory or inhibitory: - Excitatory: likely to elicit action potential: Deporalization -Inhibitory: less likely to elicit action potential: Hypoerpolarization Membrane Stabilization Excitatory Synapses • Depolarize postsynaptic cell -Brings membrane potential closer to Threshold by opening or closing ion channels. • Channels affected are: - Open Na channels - Close K channels - Open channels that are equally permeable to Na and K Causes depolarization because of the stronger force of Na to flow into the cell • Depolarization = EPSP (excitatory postsynaptic potential) Fast EPSPs Slow EPSPs EPSPs are Graded Potentials • Higher freq of APs (presynaptic) • More neurotransmitter released (presynaptic) • More neurotransmitter binds to receptors to open (or close) channels • Greater increase (or decrease) ion permeability • Greater (or lesser) ion flux • Greater depolarization Inhibitory Synapses • Neurotransmitter binds to receptor. • Channels for either K or Cl open hyperpolarizes the cell. • If K channels open, then… K moves out IPSP (inhibitory postsynaptic potential) • If Cl channels open, then either… Cl moves in IPSP Cl stabilizes membrane potential. Fast Inhibitory Synapses Involving K Channels IPSPs are Grade Potentials • Higher freq of APs (presynaptic) • More neurotransmitter released (presynaptic) • More neurotransmitter binds to receptors to open (or close) channels • Greater increase (or decrease) ion permeability • Greater (or lesser) ion flux • Greater depolarization Neural Integration • Divergence/convergence • Summation • The summing of input from various synapses at the axon hillock of the postsynaptic neuron to determine whether the neuron will generate action potentials Divergence Convergence Convergence of Input as a Factor in Summation Temporal Summation from the same Synapse Spatial Summation from Different Synapses Neurotransmitters • • • • • Acetylcholine Biogenic Amines Amino Acid Neurotransmitters Neuropeptides Autonomic Nervous Sysntem Acetylcholine • Found in the CNS and PNS • Most abundant neurotransmitter in PNS. • Synthesis - Acetyl CoA + choline acetylcholine +CoA - Synthesized in cytoplasm of axon terminal - Biosynthetic enzyme: choline acetyltransferase (CAT) • Breakdown - Acetylcholine acetate + choline - Degradation occurs in synaptic cleft - Degradative enzyme: acetylcholinesterase (AchE) Cholinergic Synapse Cholinergic Receptors • Nicotinic - Ionotropic - Found mostly in the skeletal muscle - Some found in the CNS • Muscarinic - Metabotropic - Found mostly in the CNS Actions at Nicotinic Cholinergic Receptors Actions at Muscarinic Cholinergic Receptors Biogenic Amines • Derived from amino acids • Catecholamines – derived from tyrosine - Dopamine - Norepinephrine (noradrenaline) - Epinephrine (adrenaline) • Norepineprine and epinephrine bind adrenergic receptors - Alpha and beta adrenergic receptors - Slow responses at all adrenergic receptors • Adrenergic receptors are G-protein-coupled • Generally linked to second messengers Dopamine • Category: biogenic amine • Postsynaptic effect: Excitatory or inhibitory Fig. 6.11 Dopamine Receptors • Large diversity of metabotropic dopamine receptors (at least 6). • Bound by many antipsychotic drugs Kandel, 2000 Norepinephrine • Category: biogenic amine • Formed from dopamine • also in PNS – sympathetic NS Norepinephrine Receptors • Effect depends on receptor bound – α-receptors α1- vs. α2-receptors (see next slide) – ß-receptors Silverthorn 2004 Receptors can be Located Presynaptically too – This will determine their effect Presynaptic GABAB receptor actions Isaacson, J Epinephrine • Category: biogenic amine • synthesized from norepinephrine • Effect depends on receptor bound – α-receptors – ß-receptors Histamine • Category: biogenic amine • Postsynaptic effect: Excitatory Fig. 6-12 Histamine effects • • • • Receptors are all G-protein coupled In brain, affects arousal and attention In periphery affects inflamation, vasodilation. Why do some cold medicines make you sleepy? (good exam question). Serotonin (5-HT) Category: Biogenic amines • Postsynaptic effect: Excitatory Serotonin effects • Involved in sleep/wakefulness cycle • Most receptors are metabotropic, but one group are ionotropic. • Why does turkey make you sleepy? • SSRI and depression Amino Acid Neurotransmitters • Amino acid neurotransmitters at excitatory Synapses: glutamate • Amino acid neurotransmitters at inhibitory Synapses: GABA (gamma-amino butyric acid) • Category: small-molecule • Glutaminergic neurons • Postsynaptic effect: depends • Very important in CNS • Synthesized from glutamine from glia Glutamate Fig. 6.6 Glutamate Receptors • Ionotropic – NMDA • late EPSP • Glycine & Mg2+ dependent – AMPA • early EPSP – kainate • early EPSP • Metabotropic Kandel 2000 GABA (γ-aminobutyric acid) • Category: small-molecule • GABAergic neurons • Postsynaptic effect: Inhibitory • Made from glucose Fig. 6.8 GABA Receptors • GABAA – Ionotropic – gates Cl- channel • GABAB – Metabotropic – gates K+ channel Fig. 6.9 Neuropeptides • Short chains of amino acids • E.G., endogenous opiates - endorphins – found in the brain, morphine-like - Vasopressin – Anjtidiuretic hormone (ADH) – found in the posterior pituitary Autonomic Nervous System (ANS) • Both branches of the ANS innervate most effector organs • Primary function – regulate organs to maintain homeostasis • Parasympathetic and sympathetic activities tend to oppose each other - Parasympathetic Nervous system – rest - Sympathetic nervous system – fight or flight response Autonomic Pathways Neurotransmitters and their Receptors in the ANS