Transcript Chapter 34 Slides

Biochemistry 2/e - Garrett & Grisham
Chapter 34
The Reception and Transmission
of Extracellular Information
to accompany
Biochemistry, 2/e
by
Reginald Garrett and Charles Grisham
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Biochemistry 2/e - Garrett & Grisham
Outline
• 34.1 Hormones and Signal Transduction
Pathways
• 34.2 Signal-Transducing Receptors
Transmit the Hormonal Message
• 34.3 Intracellular Second Messengers
• 34.4 GTP-Binding Proteins” The
Hormonal Missing Link
• 34.5 The 7-TMS receptor
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Outline
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34.6 Specific Phospholipases
34.7 Calcium as a Second Messenger
34.8 Protein Kinase C
34.9 The Single TMS-receptor
34.10 Protein Modules
34.11 Steroid Hormones
SPECIAL FOCUS: Neurotransmission
and Sensory Systems
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Classes of Hormones
(There may be others, but we doubt it...)
• Steroid Hormones - derived from cholesterolregulate metabolism, salt/water balances,
inflammation, sexual function
• Amino Acid Derived Hormones - epinephrine,
etc.- regulate smooth muscle , blood pressure,
cardiac rate, lipolysis, glycogenolysis
• Peptide Hormones - regulate many processes in
all tissues - including release of other hormones
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Signal-Transducing Receptors
Transmit Hormone Message
• Non-steroid hormones bind to plasma
membrane and activate a signaltransduction pathway inside the cell
• Steroid hormones may either
– bind to the plasma membrane
– or
– enter the cell and travel to the nucleus
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Types of Receptors
Three that we know of...
• 7-transmembrane segment receptors
– extracellular site for hormone (ligand)
– intracellular site for GTP-binding protein
• Single-transmembrane segment receptors
– extracellular site for hormone (ligand)
– intracellular catalytic domain - either a tyrosine
kinase or guanylyl cyclase
• Oligomeric ion channels
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Second Messengers
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Many and there may be more!
The hormone is the "first messenger"
The second messenger - Ca2+, cAMP or other
- is released when the hormone binds to its
(extracellular) receptor
The second messenger then activates (or
inhibits) processes in the cytoplasm or nucleus
Degradation and/or clearance of the second
messenger is also (obviously) important
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cAMP and Glycogen
Phosphorylase
Earl Sutherland discovers the first second
messenger
• In the early 1960s, Earl Sutherland showed
that the stimulation of glycogen phosphorylase
by epinephrine involved cyclic adenosine-3',5'monophosphate
• He called cAMP a "second messenger"
• cAMP is synthesized by adenylyl cyclase and
degraded by phosphodiesterase
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How are the hormone receptor
and AC coupled?
• Purified AC and purified receptor, when
recombined, are not coupled.
• Rodbell showed that GTP is required for
hormonal activation of AC
• In 1977, Elliott Ross and Alfred Gilman at Univ.
of Virginia discovered a GTP-binding protein
which restored hormone stimulation to AC
• Hormone stimulates receptor, which activates
GTP-binding protein, which activates AC
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G Proteins
Many new developments in this area
• Two kinds: "heterotrimeric G proteins"
and "small G proteins"
• X-ray diffraction structures for several of
these are only recently available
• Structures shed new light on possible
functions
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Heterotrimeric G Proteins
A model for their activity
• Binding of hormone, etc., to receptor protein in
the membrane triggers dissociation of GDP
and binding of GTP to -subunit of G protein
• G-GTP complex dissociates from G and
migrates to effector sites, activating or
inhibiting
• But it is now clear that G also functions as a
signalling device
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Signalling Roles for G()
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A partial list
Potassium channel proteins
Phospholipase A2
Yeast mating protein kinase Ste20
Adenylyl cyclase
Phospholipase C
Calcium channels
• Receptor kinases
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Stimulatory and Inhibitory G
G proteins may either stimulate or inhibit an
effector.
• In the case of adenylyl cyclase, the stimulatory
G protein is known as Gs and the inhibitory G
protein is known as Gi
• Gi may act either by the Gi subunit binding to
AC or by the Gi complex complexing all the Gi
and preventing it from binding to AC
• Read about the actions of cholera toxin and
pertussis toxin
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The ras Gene and p21ras
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An oncogene and its product
a gene first found in rat sarcoma virus
Normal cellular ras protein activates cellular
processes when GTP is bound and is inactive
when GTP has been hydrolyzed to GDP
Mutant (oncogenic) forms of ras have severely
impaired GTPase activity, so remain active for
long periods, stimulating
excessive growth and metabolic activity causing tumors to form
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7-TMS Receptors
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Receptors that interact with G proteins
Seven putative alpha-helical transmembrane
segments
Extracellular domain interacts with hormone
Intracellular domain interacts with G proteins
Adrenergic receptors are typical
Note desensitization by phosphorylation, either
by ARK or by protein kinase A
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Phospholipases Release
Second Messengers
• Inositol phospholipids yield IP3 and DAG
• PLC is activated by 7-TMS receptors
and G proteins
• PLC is activated by receptor tyrosine
kinases (via phosphorylation)
• Note PI metabolic pathways and the role
of lithium
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Other Lipids as Messengers
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Recent findings - lots more to come
More recently than for PI, other
phospholipids have been found to
produce second messengers!
PC can produce C20s, DAG and/or PA
Sphingomyelin and glycosphingolipids
also produce signals
Ceramide (from SM) is a trigger of
apoptosis - programmed cell death
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Ca2+ as a Second Messenger
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Several sources of Ca2+ in cells!
[Ca2+] in cells is normally very low: < 1M
Calcium can enter cell from outside or from ER
and calciosomes
CICR - Calcium-Induced Calcium Release - is
very, very similar to what happens at the foot
structure in muscle cells!
IP3 (made by action of phospholipase C) is the
trigger
See Figures 34.17-34.19
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Calcium Oscillations!
M. Berridge's model of Ca2+ signals
• Ca2+ was once thought to merely rise in
cells to signal and drop when the signal
was over
• Berridge's work demonstrates that Ca2+
levels oscillate in cells!
• The purpose may be to protect cell
components that are sensitive to high
calcium, or perhaps to create waves of
Ca2+ in the cell
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Ca2+-Binding Proteins
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Mediators of Ca2+effects in cells
Many cellular proteins modulate Ca2+
effects
3 main types: protein kinase Cs, Ca2+modulated proteins and annexins
Kretsinger characterized the structure of
parvalbumin, prototype of Ca2+-modulated
proteins
"EF hand" proteins bind BAA helices
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Transduction of two second
messenger signals
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PKC is activated by DAG and Ca2+
Most PKC isozymes have several domains,
including ATP-binding domain, substrate-binding
domain, Ca-binding domain and a phorbol esterbinding domain
Phorbol esters are apparent analogues of DAG
Cellular phosphatases dephosphorylate target
proteins
Read about okadaic acid
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Single TMS Receptors
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Three main classes
Extracellular domain to interact with hormone
Single transmembrane segment
Intracellular domain with enzyme activity
Activity is usually tyrosine kinase or guanylyl
cyclase
Each of these has a "nonreceptor" counterpart
src gene kinase - pp60v-src was first known
Two posttranslational modifications
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Receptor Tyrosine Kinases
Membrane-associated allosteric enzymes
• How do single-TMS receptors transmit
the signal from outside to inside??
• Oligomeric association is the key!
• Extracellular ligand binding
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The Polypeptide Hormones
Common features of synthesis
• All secreted polypeptide hormones are
synthesized with a signal sequence (which
directs them to secretory granules, then out)
• Usually synthesized as inactive
preprohormones ("pre-pro" implies at least
two precessing steps)
• Proteolytic processing produces the
prohormone and the hormone
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Proteolytic Processing
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A mostly common pathway
Proteolytic cleavage of the hydrophobic Nterminal signal peptide sequence
Proteolytic cleavage at a site defined by
pairs of basic amino acid residues
Proteolytic cleavage at sites designated by
single Arg residues
Post-translational modification: C-terminal
amidation, N-terminal acetylation,
phosphorylation, glycosylation
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Gastrin as an Example
Heptadecapeptide secreted by the antral mucosa
of stomach
• Gastrin stimulates acid secretion in stomach
• Product of preprogastrin - 101-104 residues
• Signal peptide cleavage leaves progastrin 80-83 residues
• Cleavage at Lys and Arg (basic) residues and Cterminal amidation leaves gastrin
• N-terminal residue of gastrin is pyroglutamate
• C-terminal amidation involves destruction of Gly
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Protein-Tyrosine Phosphatases
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The enzymes that dephosphorylate Tyr
Some PTPases are integral membrane
proteins
But there are also lots of soluble PTPases
Cytoplasmic PTPases have N-term. catalytic
domains and C-terminal regulatory domains
Membrane PTPases all have cytoplasmic
catalytic domain, single transmembrane
segment and an extracellular recognition site
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Guanylyl Cyclases
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Soluble or Membrane-Bound
Membrane-bound GCs are the other group
of single-transmembrane-segment
receptors (besides RTKs)
Peptide hormones activate the membraneforms
Note speract and resact, from mammalian
ova
Activation may involve oligomerization of
receptors, as for RTKs
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Soluble Guanylyl Cyclases
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Receptors for Nitric Oxide
NO is a reactive, free-radical that acts either as a
neurotransmitter or as a second messenger
NO relaxes vascular smooth muscle (and is thus
involved in stimulation of penile erection)
NO also stimulates macrophages to kill tumor
cells and bacteria
NO binds to heme of GC, stimulating GC activity
50-fold
Read about NO synthesis and also see box on
Alfred Nobel
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Protein Modules in Signal
Transduction
• Signal transduction in cell occurs via
protein-protein and protein-lipid
interactions based on protein modules
• Most signaling proteins consist of two or
more modules
• This permits assembly of functional
signaling complexes
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Localization of Signaling
Proteins
• Adaptor proteins provide docking sites
for signaling modules at the membrane
• Typical case: IRS-1 (Insulin Receptor
Substrate-1)
– N-terminal PH domain
– PTB domain
– 18 potential tyrosine phosphorylation sites
– PH and PTB direct IRS-1 to receptor
tyrosine kinase - signaling events follow!
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Signaling Pathways from
Membrane to the Nucleus
• The complete path from membrane to
nucleus is understood for a few cases
• See Figure 34.38
• Signaling pathways are redundant
• Signaling pathways converge and
diverge
• This is possible with several signaling
modules on a signaling protein
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Module Interactions Rule!
• The interplay of multiple modules on
many signaling proteins permits a
dazzling array of signaling interactions
• See Figure 34.40
• We can barely conceive of the probable
extent of this complexity
• For example, it is estimated that there
are more than 1000 protein kinases in
the typical animal cell - all signals!
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Steroid Hormones
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Glucocorticoids, mineralocorticoids, vitamin D
and the sex hormones
May either act at nucleus or at plasma
membrane
Steroids are hydrophobic and cannot diffuse
freely to nucleus
Receptor proteins carry steroids to the nucleus
Steroid receptor proteins are all apparently
members of a gene superfamily and have
evolved from a common ancestral precursor
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Steroid Receptor Proteins
• Hydrophobic domain near C-terminus that
interacts with steroid itself
• Central, hydrophilic domain that binds to DNA
• Central DNA-binding domains are homologous
to one another, with 9 conserved Cys residues
• Three pairs of Cys residues are in Cys-X-X-Cys
sequences - as in Zinc-finger domains
• Steroid-receptor complex may bind to DNA or to
transcription factors
• Thyroid hormone receptor proteins are similar
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Extracellular Effects
of steroid hormones
• Two lines of evidence: action of steroids on
calcium channels and other membrane proteins
and the speed of certain steroid hormone effects
• Example: testosterone rapidly stimulates
transport of glucose, calcium and amino acids
into rat kidney cells
• Several demonstrations now of tight binding of
steroid probes to GABA receptor and other
proteins
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Cells of Nervous Systems
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Neurons and Neuroglia (Glial Cells)
Neurons contain processes, including an
axon and dendrites
Axon is covered with myelin sheath and
cellular sheath, except at nodes of Ranvier
The axon ends in synaptic termini, aka
synaptic knobs or synaptic bulbs
Three kinds of neurons: sensory neurons,
motor neurons and interneurons
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Ion Gradients
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The source of electrical potentials in neurons
Nerve impulses consist of electrical signals that
are transient changes in the electrical potential
differences (voltages) across neuron membrane
Know resting concentrations
Learn to use the equation for actual potential
difference in the box on page S-43
Difference between Nernst potential and actual
potential represents a thermodynamic push
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The Action Potential
A somewhat misleading name - it refers to the
series of changes in potential that constitute a
nerve impulse
• Small depolarization (from -60 to -40 mV) opens
voltage-gated ion channels - Na flows in
• Potential rises to +30 mV, Na channels close, K
channels open. K streams out, lowering potential
• Action potentials flow along the axon to the
synapse
• Number and frequency important, not intensity
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Voltage-Gated Na, K
Channels
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Clustered in Nodes of Ranvier
See Figure 34.52 for Na, K channel effectors
Arrangement of Na channel in membrane is like
DHP receptor in muscle
See Figure 34.55 for diagram of how the
channel is formed in membrane
These channels are voltage-sensitive - voltage
changes cause conformational changes and
gating
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Communication at the
Synapse
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A crucial feature of neurotransmission
Ratio of synapses to neurons in human
forebrain is 40,000 to 1!
Chemical synapses are different from electrical
Neurotransmitters facilitate cell-cell
communication at the synapse
Note families of neurotransmitters in Table
34.6
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The Cholinergic Synapse
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A model for many others
Synaptic vesicles in synaptic knobs contain
acetylcholine (10,000 molecules per vesicle)
Arriving action potential depolarizes membrane,
opening Ca channels and causing vesicles to fuse
with plasma membrane
Acetylcholine spills into cleft, migrates to adjacent
cells and binds to receptors
Toxin effects: botulism toxin inhibits Ac-choline
release, black widow's latrotoxin protein
overstimulates
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Two Classes of Ac-Ch Receptor
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Nicotinic and muscarinic
As always, toxic agents have helped to identify
and purify hard-to-find biomolecules
Nicotinic Ac-Ch receptors are voltage-gated ion
channels
Muscarinic Ac-Ch receptors are transmembrane
proteins that interact with G proteins
Acetylcholinesterase degrades Ac-Ch in cleft
Transport proteins and V-type H+-ATPases
return Ac-Ch to vesicles - called reuptake
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Other Neurotransmitters
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Excitatory and inhibitory
Glutamate is good example: nerve impulse
triggers Ca-dependent exocytosis of glutamate
Glutamate is either returned to neuron, or carried
into glial cells, converted to Gln and taken back to
the neuron from which it was released
See 4 types of glutamate receptors in Fig. 34.68
NMDA receptor is best understood for now
Note phencyclidine (angel dust) story
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GABA and Glycine
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Inhibitory Neurotransmitters
Inhibitory neurotransmitters diminish the actions
of activating neurotransmitters
See Figure 34.70 for glutamate degradation
Excitatory glutamate is broken down to inhibitory
GABA, which is broken down to non-signals
GABA & glycine receptors are chloride channels
Glycine receptor is site of action of strychnine
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Catecholamine
Neurotransmitters
• Epinephrine, norepinephrine, dopamine and
L-dopa are all neurotransmitters
• Synthesized from tyrosine - see Fig. 34.72
• Excessive production of dopamine (DA) or
hypersensitivity of DA receptors produces
psychotic symptoms and schizophrenia
• Lowered production and/or loss of DA
neurons are factors in Parkinsonism
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Neurological Disorders
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Depression, Parkinsonism, etc.
Defects in catecholamine processing are
responsible for many neurological disorders
Norepinephrine and dopamine systems are keys
Breakdown of NE and DA by catechol-O-methyl
transferase and monoamine oxidase
Reuptake by specific transport proteins
MAO inhibitors are antidepressants
Tricyclics - antidepressants that block reuptake
Cocaine blocks reuptake, prolongs effects of DA
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Peptide Neurotransmitters
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Lots more to learn here!
Likely to be many peptide NTs
Concentrations are low; purification is hard
Roles are complex
Endorphins and enkephalins are natural opioids
Endothelins affect smooth muscle contraction,
vasoconstriction, mitogenesis, tissue changes
Vasoactive intestinal peptide stimulates AC (to
make cAMP) via G proteins, and its effects are
synergistic with those of other neurotransmitters
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Sensory Transduction
• Similarities between sight, taste, smell
• Specialized sensory cells translate stimulus into
electrical signals in adjacent neurons
• Vision is the paradigm system
• Absorption of light quanta by rhodopsin
isomerizes retinal (11-cis to all-trans)
• Light is absorbed by rhodopsin in the outer
segments of rod and cone cells
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