Biochemistry

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Biochemistry

• Chapter 24
• Chemical Communications
• Neurotransmitters and Hormones

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Problem Sets

• PS 1
• Sec 24.1 24.4
• 3, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15
• PS 2
• Sec 24.5 24.7
• 18, 19, 23, 24, 25, 26, 28, 29, 30, 33, 35

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24.1 Chemical Communications

• Each cell is an isolated entity
• Need to communicate with other cells in order to
  coordinate activity
• Also needs to communicate internally organelles
  need to coordinate activity
• Communicate by exchanging molecules
• 3 types of molecules Receptors, chemical
  messengers, secondary messengers

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24.1 Communication Molecules

• Receptors
• Proteins on the surface of cells embedded in the
  cell membrane
• Chemical Messengers (ligands)
• Interact with receptors
• Fit into receptor sites like lock-and-key
• Secondary Messengers
• Carry the message from receptor to inside cell
• Amplify the message

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24.1 Some Terminology

• Neuron a nerve cell
• Neurotransmitters compounds that carry messages
  from one neuron to another or from one neuron to
  some other cell
• Example acetylcholine
• Hormones communication molecules secreted by
  endocrine glands
• Example adrenaline

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24.1 Ways Drugs Affect Communication

• Antagonist a drug that blocks the receptor and
  prevents its stimulation
• Agonist a drug that competes with the messenger
  for the receptor site, stimulating the receptor
• Some drugs decrease concentration of the
  messengers by controlling their release
• Others increase concentration of the messengers
  by inhibiting their removal

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24.2 Neurotransmitters

• Axon long fiber part of cell
• Dendrite hair-like receptors
• Synapse fluid-filled space between neurons
• Presynaptic side from which the
  neurotransmitters originate
• Postsynaptic side with receptors for
  neurotransmitters
• Vessicles presynaptic storage sites for
  neurotransmitters

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24.2 Hormones

• Diverse compounds secreted by endocrine glands,
  released into bloodstream, and adsorbed onto
  distant receptor sites
• Difference between neurotransmitters and hormones
  is distance
• Neurotransmitters work on a short distance across
  a synapse (2 x 10-6 cm)
• Hormones act over a large distance through the
  bloodstream
• Some compounds can be both!

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24.2 Classification

• Classified by chemical structure
• Cholinergic, amino acid, adrenergic, peptidergic,
  steroid
• Classified by how they work
• Activate enzymes, affect synthesis of enzymes by
  working on gene transcription, affect membrane
  permeability
• Classified how directly they act
• Some act directly, others require a secondary
  messenger

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24.3 Cholinergic Neurotransmitters

• Acetylcholine O
  CH3
  CH3 C O CH2 CH2 N CH3
  
  CH3
• Often abbreviated ACh

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24.3 Cholinergic Receptors

• Two types Nicotinic and Muscarinic
• Nicotinic Receptors
• Often found at myoneural junctions
• Respond to nicotine
• 5 unit transmembrane protein, ion channel
• Muscarinic Receptors
• Parasympathetic nervous system
• Respond to muscarine
• Use secondary messengers to open ion channels

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24.3 Action of Acetylcholine
ACh attaches, triggering a conformational change
that opens the ion channel
Inside cell, K gt Na
More Na enters than K leaving, so cell builds
up a charge
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24.3 Removal of ACh
ACh must be removed from receptor
Acetylcholinesterase (AChE) hydrolyzes ACh
Operates rapidly enough to allow transmission of
more than 100 nerve signals per second
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24.3 Inhibition of AChE
Nerve agents and pesticides irreversibly bind to
AChE by phosphonylation of a serine near the
active site
Succinylcholine and decamethonium bromide
resemble ACh and fit into the active site of AChE
(competitive inhibitors)
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24.3 Other Means of Controlling ACh
Neurotransmission

• Modulation of the ion channel
• Eg, nicotine prolongs the channels response
• Acts as an agonist in low doses
• In high doses it becomes an antagonist because it
  blocks the action of the receptor
• Neurotoxins like cobra venom and curare work in
  the same way
• Control the supply of ACh
• Botulism prevents release of ACh from vessicles
• Alzheimers impairs the synthesis of ACh

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24.4 Amino Acid Neurotransmitters

• Some amino acids are neurotransmitters
• Includes aas not among the 20 found in proteins
• Includes other than a amino acids
• Excitory neurotransmitters
• Excite the receptors
• Eg glutamic acid, aspartic acid, cysteine
• Inhibitory neurotransmitters
• Reduce neurotransmission
• Eg glycine, b-alanine, taurine, GABA

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24.4 Amino Acid Receptors

• Each aa has its own set of receptors
• Work similar to ACh receptors
• Removal of messengers
• aas not broken down by enzymes like ACh
• Transporter molecule grabs aa and moves it back
  to the presynaptic side of the synapse
• Process is called reuptake

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24.5 Adrenergic Messengers

• Monoamines
• Epinephrine, serotonin, dopamine, histamine
• Action of monoamine messengers
• Messenger adsorbed onto receptor site
• Signal transduction a cascade of events where
  the receptor signal is carried inside the cell
  and amplified into many signals
• E.g., norepinephrine receptors have an associated
  G-protein and guanosine triphosphate (GTP) that
  create a signal cascade when activated

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Norepinephrine attaches to receptor
G protein hydrolyzes GTP energy activates enzyme
that produces cAMP
Protein kinase has 2 subunits R regulatory C
catalytic
cAMP dissociates R subunit from C, which
activates the enzyme
C subunit phosphorylates the protein that is
blocking the ion channel
Phosphorylated protein changes shape, opening the
ion channel
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24.5 Secondary Messengers

• Norepinephrine receptor produces a secondary
  messenger inside cell
• Cyclic AMP (cAMP)
• Manufactured from ATP
• Accomplishes two goals
• Converts an event outside cell to a change inside
  the cell, so primary messenger does not have to
  cross the cell membrane
• Amplifies the signal one molecule on receptor
  site triggers the production of many cAMP
  molecules

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24.5 Control of Neurotransmission

• Secondary messengers are slow
• Takes from 0.1 s to 1 min to activate
• If speed is important, use acetylcholine
• No secondary messengers, so it activates in a
  time scale of milliseconds
• Removal of the signal
• When the neurotransmitter dissociates from the
  receptor, cell halts production of cAMP
• Existing cAMP is hydrolyzed by an enzyme to AMP

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24.5 Removal of Neurotransmitters

• Most adrenergic neurotransmitters are inactivated
  by oxidation to aldehydes
• Done by enzymes called monoamine oxidases (MAOs)
• Many antidepressant drugs are MAO inhibitors
• Prevent the oxidation of monoamines, so their
  concentration increases in the synapses
• Some adrenergic messengers are carried back to
  the presynaptic vessicles

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24.5 Histamines
Found in the brains of mammals
Synthesized from histidine by decarboxylation
Two types of histamine receptors
H1
H2
Found in the respiratory tract
Affect HCl secretion in the stomach
Blocked by dimenhydrinate (Dramamine) and
diphenhydramine (Benadryl)
Blocked by cimetidine and ranitidine (ulcer drugs)
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24.6 Peptidergic Messengers

• Important metabolic hormones
• E.g., insulin, glucagons, vasopressin, oxytocin
• Enkephalins
• First brain peptides identified
• Pentapeptides
• Bind to pain receptors (control pain perception)
• Bind to same receptor sites as morphine

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24.6 Peptidergic Messengers

• Neuropeptide Y
• Affects the hypothalmus
• Acts as a potent orexic (appetite stimulant)
• Anorexic agents block neuropeptide Y receptors
• Substance P
• 11 amino-acid peptide
• Involved in transmission of pain signals
• With injury or inflammation, peripheral nervous
  system releases substance P, which binds to
  receptors on the spinal cord

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24.6 Secondary Messengers

• All peptidergic messengers act through secondary
  messengers
• Many use the G-protein adenylate cyclase cascade
• Others use membrane-derived phosphatidylinositol
  (PI) derivatives
• Activation occurs by phosphorylation
• Still others use calcium ions as secondary
  messengers

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24.7 Steroid Hormones

• Steroids are hydrophobic
• Can diffuse across cell membrane
• No need for receptors on the cell membrane
• Bind with protein receptors in the nucleus
• Steroid-receptor complex binds to DNA
• Influence synthesis of specific proteins
• Slow process takes hours to occur
• Can sometimes act on cell membrane
• Influence ion gate channels
• Much faster response takes seconds