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23 General, Organic, and Biochemistry, 7e Bettelheim, Brown, and March © 2003 Thomson Learning, Inc. All rights reserved 23-1 23 Chapter 23 Chemical Communication: Neurotransmitters and Hormones © 2003 Thomson Learning, Inc. All rights reserved 23-2 23 Introduction • There are three principal types of molecules used for communications • Receptors: proteins embedded in the surface membranes of cells • Chemical messengers: chemicals that interact with receptors; also called ligands • Secondary messengers: chemicals that carry a message from a receptor to the inside of a cell and amplify the message © 2003 Thomson Learning, Inc. All rights reserved 23-3 23 Introduction • Other terms and definitions • neuron: a nerve cell • neurotransmitter: a compound involved in communication between neurons or between a neuron and a target tissue; it acts across a synapse • hormone: a compound that is synthesized in one location, travels large distances, usually in the blood, and then acts at a remote location (see Table 23.2) • the distinction between a neurotransmitter and a hormone is physiological, not chemical; it depends on whether the molecule acts over a short distance (across a synapse) or over a long distance (from the secretory organ, through the blood, to its site of action) © 2003 Thomson Learning, Inc. All rights reserved 23-4 23 Introduction • A large percent of drugs used in human medicine influence chemical communication (see Table 23.1) • antagonist: a molecule that blocks a natural receptor and prevents its stimulation • agonist: a molecule that competes with a natural messenger for a receptor site; it binds to the receptor site and elicits the same response as the natural messenger • a drug may decrease or increase the effective concentration of messenger © 2003 Thomson Learning, Inc. All rights reserved 23-5 23 Introduction • Neuron and synapse © 2003 Thomson Learning, Inc. All rights reserved 23-6 23 Chemical Messengers • There are five classes of chemical messengers • cholinergic messengers • amino acid messengers • adrenergic messengers • peptidergic messengers • steroid messengers • Messengers are also classified by how they work; they may • activate enzymes • affect the synthesis of enzymes • affect the permeability of membranes © 2003 Thomson Learning, Inc. • act directly or through a secondary messenger All rights reserved 23-7 23 Acetylcholine • The main cholinergic messenger is acetylcholine O CH3 CH3 -C-O-CH2 -CH2 + -N-CH3 CH3 Acetylch oline (A Ch ) • Cholinergic receptors • there are two kinds of receptors for acetylcholine • we look at the one that exists in motor end plates of skeletal muscles or in sympathetic ganglia © 2003 Thomson Learning, Inc. All rights reserved 23-8 23 Acetylcholine • Storage and release of acetylcholine (ACh) • the nerve cells that bring messages contain ACh stored in vesicles • the receptors on muscle neurons are called nicotinic receptors because nicotine inhibits them • the message is initiated by calcium ions, Ca2+ • when Ca2+ concentration becomes more that about 10-4 M, the vesicles that contain ACh fuse with the presynaptic membrane of nerve cells and empty ACh into the synapse • ACh travels across the synapse and is absorbed on specific receptor sites © 2003 Thomson Learning, Inc. All rights reserved 23-9 23 Acetylcholine • Action of the acetylcholine (cont’d) • the presence of ACh on the postsynaptic receptor triggers a conformation change in the receptor protein • this change opens an ion channel and allows ions to cross membranes freely • Na+ ions have higher concentration outside the neuron and pass into it • K+ ions have higher concentration inside the neuron and leave it • this change of Na+ and K+ ion concentrations is translated into a nerve signal • after a few milliseconds, the ion channel closes © 2003 Thomson Learning, Inc. All rights reserved 23-10 23 Acetylcholine © 2003 Thomson Learning, Inc. All rights reserved 23-11 23 Acetylcholine • Removal of ACh • ACh is removed from the receptor site by hydrolysis catalyzed by the enzyme acetylcholinesterase Acetylch olin O CH3 es teras e CH3 -C-O-CH2 -CH2 + -N-CH3 + H2 O CH3 A cetylcholine (ACh) O CH3 CH3 -C-O- + HO-CH2 -CH2 +-N-CH3 CH3 Choline Acetate • this rapid removal allows nerves to transmit more than 100 signals per second © 2003 Thomson Learning, Inc. All rights reserved 23-12 23 Acetylcholine • Control of neurotransmission • acetylcholinesterase is inhibited irreversibly by the phosphonates in nerve gases and some pesticides (ChemCom 23B) • it is also inhibited by these two compounds O O +CH3 +CH3 CH3 NCH2 CH2 OCCH2 CH2 COCH2 CH2 NCH3 CH3 CH3 Succinylcholine Br- © 2003 Thomson Learning, Inc. All rights reserved Br CH CH + 3 + 3 CH3 NCH2 (CH2 ) 8 CH2 NCH3 CH3 CH3 Decameth on ium bromide 23-13 23 Acetyl Choline • Control of transmission (cont’d) • another control is to modulate the action of the ACh receptor • because ACh enables ion channels to open and propagate signals, the channels themselves are called ligand-gated ion channels • the attachment of the ligand to the receptor is critical to signaling • nicotine in low doses is a stimulant; it is an agonist because it prolongs the receptor’s biochemical response • nicotine in high doses is an antagonist and blocks the action of the receptor © 2003 Thomson Learning, Inc. All rights reserved 23-14 23 Amino Acids • Amino acid messengers • some amino acids are excitatory neurotransmitters; examples are Glu, Asp, and Cys • others are inhibitory neurotransmitters; examples are Gly and these three + H3 NCH2 CH2 SO3 Taurine © 2003 Thomson Learning, Inc. All rights reserved + H3 NCH2 CH2 COO -Alan ine + H3 NCH2 CH2 CH2 COO -Aminobu tyric acid (GABA) 23-15 23 Amino Acid Messengers • Receptors • Glu has at least five subclasses of receptors • the best known among these is the N-methyl-Daspartate (NMDA) receptor - N -Meth yl-D -asp artate OOC-CH2 -CH-COONH2 + CH3 • this receptor is a ligand-gated ion channel • when Glu binds to the receptor, the ion channel opens, Na+ and Ca2+ ions flow in, and K+ ions flow out • NMDA is an agonist and also stimulates the receptor © 2003 Thomson Learning, Inc. All rights reserved 23-16 23 Adrenergic Messengers • Monoamine messengers OH H + N CH3 H HO HO NH3 N H Serotonin © 2003 Thomson Learning, Inc. All rights reserved + NH3 + HO HO Epinep hrine HO OH N orepinep hrine H + N HO HO NH3 D opamine + NH3 + N H Histamine 23-17 23 Adrenergic Messengers • When norepinephrine is absorbed onto the receptor site • the active G-protein hydrolyzes GTP • the energy of hydrolysis activates adenylate cyclase © 2003 Thomson Learning, Inc. All rights reserved 23-18 23 Cyclic AMP (cAMP) • cAMP is synthesized in cells from ATP NH2 N O O O N O P O P O P O CH2 O O- O- O H H H H OH OH Aden os ine triphosph ate (ATP) © 2003 Thomson Learning, Inc. All rights reserved N ad enylate cyclase N NH2 N N O CH2 O N H H H H O OH O P OCyclic-ad enosine mon op hosph ate (cAMP) N O O + -O P O P OOOPyrophosp hate 23-19 23 Adrenergic Messengers • cyclic AMP activates protein kinase by dissociating the regulatory (R) unit from the catalytic (C) unit © 2003 Thomson Learning, Inc. All rights reserved 23-20 23 Adrenergic Messengers • the catalytic unit phosphorylates the ion-translocating protein that blocks the channel ion flow • the phosphorylated ion-translocating protein changes its shape and position and opens the ion gate © 2003 Thomson Learning, Inc. All rights reserved 23-21 23 Adrenergic Messengers • Removal of the signal • when the neurotransmitter or hormone dissociates from the receptor, adenylate cyclase stops the synthesis of cAMP • the cAMP already produced is destroyed by the enzyme phosphodiesterase, which catalyzes the hydrolysis of one of the phosphodiester bonds to give AMP © 2003 Thomson Learning, Inc. All rights reserved 23-22 23 Adrenergic Messengers • Control of neurotransmission • the G-protein-adenylate cyclase cascade in transduction signaling is not limited to monoamine messengers • among the other neurotransmitters and peptide hormones using this signaling pathway are glucagon, vasopressin, luteinizing hormone, enkephalins, and Pprotein • a number of enzymes can be phosphorylated by protein kinases and the phosphorylation controls whether these enzymes are active or inactive © 2003 Thomson Learning, Inc. All rights reserved 23-23 23 Adrenergic Messengers • Removal of neurotransmitter • the body inactivates monoamines by oxidation to an aldehyde, catalyzed by monoamine oxidases (MAOs) HO OH H + N CH3 H HO Epinep hrine OH HO HO MAO NH3 + N orepinep hrine MAO OH HO © 2003 Thomson Learning, Inc. All rights reserved HO H O 23-24 23 Adrenergic Messengers • Histamine - H + N COO NH3 N H L-Histid ine + + H+ h istidine d ecarboxylase H + N NH3 + + CO2 N H Histamine • H1 receptors are found in the respiratory tract where they affect the vascular, muscular, and secretory changes associated with hay fever and asthma; antihistamines that block H1 receptors relieve these symptoms • H2 receptors are found mainly in the stomach and affect the secretion of HCl; cimetidine and ranitidine block H2 receptors and thus reduce acid secretion © 2003 Thomson Learning, Inc. All rights reserved 23-25 23 Peptidergic Messengers • The first brain peptides isolated were the enkephalins • these pentapeptides are present in certain nerve cell terminals • they bind to specific pain receptors and seem to control pain perception Tyr-Gly-Gly-Phe-Leu Leucine enkephalin Tyr-Gly-Gly-Phe-Met Methionine enkephalin • Neuropeptide Y, a potent orexic, affects the hypothalamus • Substance P, an 11-amino acid peptide is involved in the transmission of pain signals © 2003 Thomson Learning, Inc. All rights reserved 23-26 23 Peptidergic Messengers • All peptidergic messengers, hormones, and neurotransmitters act through secondary messengers • glucagon, luteinizing hormone, antidiuretic hormone, angiotensin, enkephalin, and substance P use the Gprotein-adenylate cyclase cascade • others such as vasopressin use membrane-derived phosphatidylinositol (PI) derivatives Inositol 1-phosp hate © 2003 Thomson Learning, Inc. All rights reserved O O-P-O O H H OH OH OH H OH H H H OH 23-27 23 Steroid Messengers • A large number of hormones are steroids • these hormones are hydrophobic and, therefore, cross plasma membranes by diffusion • steroid hormones interact inside cells with protein receptors • most of these receptors are located in the nucleus, but small numbers also exist in the cytoplasm • once inside the nucleus, the steroid-receptor complex can either bind directly to DNA or combine with a transcription factor © 2003 Thomson Learning, Inc. All rights reserved 23-28 23 Chemical Communication End Chapter 23 © 2003 Thomson Learning, Inc. All rights reserved 23-29