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CHEMICAL COMMUNICATION
HORMONES & NEUROTRANSMITTERS
Introduction
• 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
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 (by controlling its release) or increase (by inhibiting its removal from receptors) the effective concentration of messenger
Other terms and definitionsneuron:neuron: a nerve cellneurotransmitterneurotransmitter: a compound involved in communication between neurons or between a neuron and a target tissue; it acts across a synapsehormone: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)
Fig. 23.1, p.573
Neuron and synapse
• 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
CLASSES OF CHEMICAL MESSENGERS
Cholinergic - acetylcholine – neurotransmitter, transfers nerve impulse to muscle cells
Amino acid – simple amino acids & modified amino acids – neurotransmitters
Adrenergic - monoamines similar to epenephrine (adrenalin) - neurotransmitters & hormones
Peptidergic – peptides & proteins – neurotransmitters & hormones
Steroid - steroids - hormones & neurotransmitters
ACETYLCHOLINE
Acetylcholine• 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)
+
Acetylcholine – synthesized in presynaptic cell, stored in vesicles. Release is triggered by the buildup of Ca2+ ions.
Acetylcholine moves across the synapse & forms a complex with receptor. Opens a channel for ion flow & creates a flow of charge by exchanging Na+ and K+ - this constitutes a nerve impulse.
Acetylcholine is broken down & removed from the receptor by acetylcholinesterase.
• Storage and release of acetylcholine (ACh)
– the message is initiated by calcium ions, Ca2+
– the nerve cells that bring messages contain ACh stored in vesicles
– 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
Chem Connect 23A, p.578
• 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
Acetylcholine
Acetylcholine• 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-O
HO-CH2-CH2-N-CH3
CH3
CH3
Acetylcholine (ACh)
+ +
Acetylcholin-esterase
+ +
Acetate Choline
• 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
• 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 ligand-gated ion channelschannels
– 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
Amino Acids• Amino acid messengers
– some amino acids are excitatory excitatory neurotransmittersneurotransmitters; 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)
+ + +
Amino 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
Adrenergic 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
G protein hydrolyzes GTP,activating adenylate cyclase which forms cAMP
cAMP activates protein kinase; ATP phosphorylates catalytic unit
Catalytic unit phosphorylates ion-translocating protein, & opens ion gates.
Adrenergic Messengers
• When norepinephrine is absorbed onto the receptor site– the active G-protein hydrolyzes GTP– the energy of hydrolysis activates adenylate
cyclase
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
Adrenergic Messengers
– cyclic AMP activates protein kinase by dissociating the regulatory (R) unit from the catalytic (C) unit
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
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
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 P-protein
– a number of enzymes can be phosphorylated by protein kinases and the phosphorylation controls whether these enzymes are active or inactive
Adrenergic 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
• 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
• 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 signalsTyr-Gly-Gly-Phe-LeuLeucine enkephalin
Tyr-Gly-Gly-Phe-MetMethionine enkephalin
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-P-O
OHOHOH
OH
OHH
H H
H
H
H
O
O-Inositol 1-phosphate
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
Modes of hormone action
Activate enzymes ex. – epinephrine
Alter gene transcription & the synthesis of enzymes ex. – steroids
Alter the permeability of membranes ex. - insulin