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23-1© 2003 Thomson Learning, Inc.All rights reserved
General, Organic, and General, Organic, and Biochemistry, 7eBiochemistry, 7e
Bettelheim,Bettelheim,
Brown, and MarchBrown, and March
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23-2© 2003 Thomson Learning, Inc.All rights reserved
Chapter 23Chapter 23
Chemical Communication:Chemical Communication: Neurotransmitters and Neurotransmitters and
HormonesHormones
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IntroductionIntroduction• There are three principal types of molecules used
for communications• Receptors:Receptors: proteins embedded in the surface
membranes of cells• Chemical messengers:Chemical messengers: chemicals that interact with
receptors; also called ligands• Secondary messengers:Secondary messengers: chemicals that carry a
message from a receptor to the inside of a cell and amplify the message
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IntroductionIntroduction• Other terms and definitions
• neuron:neuron: a nerve cell• neurotransmitterneurotransmitter: a compound involved in
communication between neurons or between a neuron and a target tissue; it acts across a synapse
• hormone: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)
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IntroductionIntroduction• A large percent of drugs used in human medicine
influence chemical communication (see Table 23.1)• antagonist:antagonist: a molecule that blocks a natural receptor
and prevents its stimulation• agonist: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
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IntroductionIntroduction• Neuron and synapse
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Chemical MessengersChemical 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• act directly or through a secondary messenger
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AcetylcholineAcetylcholine• The main cholinergic messenger is acetylcholine
• 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
CH3-C-O-CH2-CH2-N-CH3
CH3
CH3
O
Acetylcholine (ACh)
+
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AcetylcholineAcetylcholine• 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
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AcetylcholineAcetylcholine• 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
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AcetylcholineAcetylcholine
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AcetylcholineAcetylcholine• Removal of ACh
• ACh is removed from the receptor site by hydrolysis catalyzed by the enzyme acetylcholinesterase
• this rapid removal allows nerves to transmit more than 100 signals per second
CH3-C-O-CH2-CH2-N-CH3
CH3
CH3
OH2O
CH3-C-O-
OHO-CH2-CH2-N-CH3
CH3
CH3
Acetylcholine (ACh)
+ +
Acetylcholin-esterase
+ +
Acetate Choline
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AcetylcholineAcetylcholine• 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
CH3NCH2CH2OCCH2CH2COCH2CH2NCH3
CH3
CH3 O O
CH3
CH3
CH3NCH2(CH2)8CH2NCH3
CH3
CH3
CH3
CH3Br-Br-
+ +
++
Succinylcholine
Decamethonium bromide
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Acetyl CholineAcetyl 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 channelsligand-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
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Amino AcidsAmino Acids• Amino acid messengers
• some amino acids are excitatory neurotransmittersexcitatory neurotransmitters; examples are Glu, Asp, and Cys
• others are inhibitory neurotransmittersinhibitory neurotransmitters; examples are Gly and these three
H3NCH2CH2SO3- H3NCH2CH2COO
- H3NCH2CH2CH2COO-
Taurine -Alanine -Aminobutyric acid(GABA)
+ + +
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Amino Acid MessengersAmino Acid Messengers• Receptors
• Glu has at least five subclasses of receptors• the best known among these is the N-methyl-D-
aspartate (NMDA) receptor
• 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
-OOC-CH2-CH-COO-
NH2+
CH3
N-Methyl-D-aspartate
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Adrenergic MessengersAdrenergic Messengers• Monoamine messengers
HO
N
NH3+
H
HO
HONH3
+
N
N
H
H
NH3+
Epinephrine
Serotonin Dopamine Histamine
+
+
Norepinephrine
HO
HO
NOH
HO
HO
NH3+
OHCH3
H
H
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Adrenergic MessengersAdrenergic Messengers• When norepinephrine is absorbed onto the
receptor site• the active G-protein hydrolyzes GTP• the energy of hydrolysis activates adenylate cyclase
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Cyclic AMP (cAMP)Cyclic AMP (cAMP)• cAMP is synthesized in cells from ATP
N
NN
N
NH2
O
OHO
HHH
CH2
H
O
POO-
Cyclic-adenosinemonophosphate
(cAMP)
N
NN
N
NH2
O
OHOH
HHH
CH2
H
OPO-
O-O O P O P
O
O- O-
O
Adenosine triphosphate(ATP)
adenylatecyclase
+ PO-
O-O O P O-
O
O-
Pyrophosphate
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Adrenergic MessengersAdrenergic Messengers• cyclic AMP activates protein kinase by dissociating the
regulatory (R) unit from the catalytic (C) unit
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Adrenergic MessengersAdrenergic 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
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Adrenergic MessengersAdrenergic 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
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Adrenergic MessengersAdrenergic 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 P-protein
• a number of enzymes can be phosphorylated by protein kinases and the phosphorylation controls whether these enzymes are active or inactive
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Adrenergic MessengersAdrenergic Messengers• Removal of neurotransmitter
• the body inactivates monoamines by oxidation to an aldehyde, catalyzed by monoamine oxidases (MAOs)
HO
HO
NH3+
OH
MAO
HO
HO
NOH
CH3
H
H
MAO
HO
HO
HOH
Epinephrine
+
Norepinephrine
O
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Adrenergic MessengersAdrenergic Messengers• 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
N
N
H
H
NH3+
COO-
H+ N
N
H
H
NH3+ CO2
Histamine
+
+
+ histidinedecarboxylase+
L-Histidine
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Peptidergic MessengersPeptidergic 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
• Neuropeptide Y, a potent orexic, affects the hypothalamus
• Substance P, an 11-amino acid peptide is involved in the transmission of pain signals
Tyr-Gly-Gly-Phe-LeuLeucine enkephalin
Tyr-Gly-Gly-Phe-MetMethionine enkephalin
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Peptidergic MessengersPeptidergic 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-P-O
OHOHOH
OH
OHH
H H
H
H
H
O
O-Inositol 1-phosphate
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Steroid MessengersSteroid 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
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End End Chapter 23Chapter 23
Chemical CommunicationChemical Communication