23 23-1 © 2003 thomson learning, inc. all rights reserved general, organic, and biochemistry, 7e...

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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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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

23 23-1 © 2003 thomson learning, inc. all rights reserved general, organic, and biochemistry, 7e...

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