General, Organic, and Biochemistry, 8e - PDF

24 General, Organic, and Biochemistry, 8e Bettelheim, Brown Campbell, and Farrell © 2006 Thomson Learning, Inc. All rights reserved 24-1 24 Chapter 24 Chemical Communications: Neurotransmitters and...

24 General, Organic, and Biochemistry, 8e Bettelheim, Brown Campbell, and Farrell © 2006 Thomson Learning, Inc. All rights reserved 24-1 24 Chapter 24 Chemical Communications: Neurotransmitters and Hormones © 2006 Thomson Learning, Inc. All rights reserved 24-2 24 © 2006 Thomson Learning, Inc. All rights reserved 24-3 Fig. 24-CO, p. 608 24 Chemical Communication Terms and definitions: neuron: a nerve cell. neurotransmitter: neurotransmitter a chemical messenger between a neuron and another target cell; neuron, muscle cell or cell of a gland. hormone: a chemical messenger released by an endocrine gland into the bloodstream and transported there to reach its target cell. 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). © 2006 Thomson Learning, Inc. All rights reserved 24-4 24 Chemical Communication A large percent of drugs used in human medicine influence chemical communication (see Table 24.1). 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. © 2006 Thomson Learning, Inc. All rights reserved 24-5 24 Chemical Communication Figure 24.1 Neuron and synapse. © 2006 Thomson Learning, Inc. All rights reserved 24-6 24 © 2006 Thomson Learning, Inc. All rights reserved 24-7 Fig. 24-1, p. 609 24 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. © 2006 actLearning, Thomson directly or through a secondary messenger. Inc. All rights reserved 24-8 24 Acetylcholine The main cholinergic messenger is acetylcholine. O CH3 + CH3 -C-O-CH2 -CH2 -N-CH3 CH3 Acetylcholine (ACh) 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. © 2006 Thomson Learning, Inc. All rights reserved 24-9 24 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 0.1 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. © 2006 Thomson Learning, Inc. All rights reserved 24-10 24 Acetylcholine Action of the acetylcholine (cont’d) The presence of ACh on the postsynaptic receptor triggers a conformational 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 © 2006 Thomson a few milliseconds, the ion channel closes. Learning, Inc. All rights reserved 24-11 24 Acetylcholine in Action © 2006 Thomson Learning, Inc. All rights reserved 24-12 24 Acetylcholine Removal of ACh ACh is removed from the receptor site by hydrolysis catalyzed by the enzyme acetylcholinesterase. O CH3 Acetylcholin- CH3 -C-O-CH2 -CH2 + -N-CH3 + H2 O esterase CH3 Acetylcholine (ACh) O CH3 CH3 -C-O- + HO-CH2-CH2+ -N-CH3 CH3 Acetate Choline This rapid removal allows nerves to transmit more than 100 signals per second. © 2006 Thomson Learning, Inc. All rights reserved 24-13 24 Acetylcholine Control of neurotransmission Acetylcholinesterase is inhibited irreversibly by the phosphonates in nerve gases and some pesticides (ChemCom 24B). It is also inhibited by these two compounds: +CH3 O O +CH3 CH3 NCH2 CH2 OCCH2 CH2 COCH2 CH2 NCH3 CH3 CH3 Succinylcholine Br- Br- CH CH + 3 + 3 CH3 NCH2 (CH2 ) 8 CH2 NCH3 CH3 CH3 © 2006 Thomson Learning, Decamethonium bromide Inc. All rights reserved 24-14 24 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. channels The binding 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 large doses is an antagonist and blocks the action of the receptor. © 2006 Thomson Learning, Inc. All rights reserved 24-15 24 Amino Acids Amino acid messengers Some amino acids are excitatory neurotransmitters; neurotransmitters examples are Glu, Asp, and Cys. Others are inhibitory neurotransmitters; neurotransmitters they reduce neurotransmission. Examples are Gly and these three, none of which is found in proteins. + + + H3 NCH2 CH2 SO3- H3 NCH2 CH2 COO- H3NCH2 CH2 CH2 COO- Taurine -Alanine -Aminobutyric acid (GABA) © 2006 Thomson Learning, Inc. All rights reserved 24-16 24 Amino Acid Messengers Each amino acid has its own receptors: Glu has at least five subclasses of receptors. The best known receptor among these is the N-methyl- D-aspartate (NMDA) receptor. - OOC-CH2 -CH-COO- N-Methyl-D-aspartate NH2+ 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. The gate of this channel is closed by Mg2+ ion. © 2006 Thomson Learning, Inc. All rights reserved 24-17 24 Adrenergic Messengers Monoamine messengers These monoamines transmit signals by a mechanism whose beginning is similar to the action of acetylcholine. HO OH H + NH3 + HO N CH3 H N HO H Epinephrine Serotonin H + HO N + NH3 + NH3 N HO H Dopamine Histamine © 2006 Thomson Learning, Inc. All rights reserved 24-18 24 Adrenergic Messengers When norepinephrine is absorbed onto the receptor site, The active G-protein hydrolyzes GTP. The energy of hydrolysis activates adenylate cyclase. © 2006 Thomson Learning, Inc. All rights reserved 24-19 24 Cyclic AMP (cAMP) cAMP is synthesized in cells from ATP NH2 N N O O O - O P O P O P O CH2 O N N adenylate cyclase O- O- O- H H H H OH OH NH2 Adenosine triphosphate N (ATP) N O CH2 O N N O O H H + -O P O P O- H H O- O- O P O OH - O Cyclic-adenosine Pyrophosphate monophosphate © 2006 ThomsonLearning, (cAMP) Inc. All rights reserved 24-20 24 Adrenergic Messengers cyclic-AMP activates protein kinase by dissociating the regulatory (R) unit from the catalytic (C) unit. © 2006 Thomson Learning, Inc. All rights reserved 24-21 24 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. © 2006 Thomson Learning, Inc. All rights reserved 24-22 24 Adrenergic Messengers Removal of the signal: When the neurotransmitter or hormone dissociates from the receptor, the 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. The amplification through the secondary messenger (cAMP) is relatively slow. It may take from 0.1 s to a few minutes. In cases where transmission must be fast, a neurotransmitter, such as acetylcholine, acts on membrane permeability directly without a second messenger. © 2006 Thomson Learning, Inc. All rights reserved 24-23 24 Adrenergic Messengers Control of neurotransmission: The G-protein—adenylate cyclase cascade in transduction signaling is not limited to monoamine messengers. A variety of other neurotransmitters and peptide hormones use this signaling pathway, including glucagon, vasopressin, luteinizing hormone, enkephalins, and P-protein. A number of enzymes can be phosphorylated by protein kinases and the phosphorylation controls whether these enzymes will be active or inactive. © 2006 Thomson Learning, Inc. All rights reserved 24-24 24 Adrenergic Messengers Removal of neurotransmitter: The body inactivates monoamines by oxidation to an aldehyde, catalyzed by monoamine oxidases (MAOs). OH H OH + HO N CH3 HO NH3 + H HO HO Epinephrine Norepinephrine MAO MAO H2 O H2 O + NH4 + CH3 NH3 OH HO H O © 2006 Thomson Learning, HO Inc. All rights reserved 24-25 24 Adrenergic Messengers The action of histamine is similar to that of other monoamines. It is synthesized from His by decarboxylation. H+ COO- histidine H+ N decarboxylase N NH3 + + H+ NH3 + + CO2 N N H H H1 receptors L-Histidineare found in the respiratory tract where they Histamine 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. © 2006 Thomson Learning, Inc. All rights reserved 24-26 24 Peptidergic Messengers The first brain peptides isolated were the enkephalins. 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 Tyr-Gly-Gly-Phe-Met Leucine enkephalin 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. © 2006 Thomson Learning, Inc. All rights reserved 24-27 24 Peptidergic Messengers All peptidergic messengers, hormones, and neurotransmitters act through secondary messengers. Glucagon, luteinizing hormone, antidiuretic hormone, angiotensin, enkephalin, and substance P use the G- protein-adenylate cyclase cascade. Others such as vasopressin use membrane-derived phosphatidylinositol (PI) derivatives. O H OH - O-P-O H Inositol 1-phosphate OH H O- OH OH H OH H H © 2006 Thomson Learning, Inc. All rights reserved 24-28 24 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. © 2006 Thomson Learning, Inc. All rights reserved 24-29 24 Chemical Communication End Chapter 24 © 2006 Thomson Learning, Inc. All rights reserved 24-30