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23
General, Organic, and
Biochemistry, 7e
Bettelheim,
Brown, and March
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23-1
23 Chapter 23
Chemical Communication:
Neurotransmitters and
Hormones
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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
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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)
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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
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23-5
23 Introduction
• Neuron and synapse
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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
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Learning,
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• act
directly
or through a secondary messenger
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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
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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
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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
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23-10
23 Acetylcholine
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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
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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-
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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
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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
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+
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
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23-16
23 Adrenergic Messengers
• Monoamine messengers
OH H
+
N CH3
H
HO
HO
NH3
N
H
Serotonin
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+
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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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23-28
23 Chemical Communication
End
Chapter 23
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23-29