Lecture Notes
Receptors Functions and Signal Transduction L3
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University:
Kentucky State University -
Course:
CHE 315 | Biochemistry Academic year:
2023
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Views:
378
Pages:
33
Author:
Lily Callahan
Receptors Functions and Signal
Transduction- L3
73 Second Messenger Targets
Enzymes
Protein Kinases
Modulate phosphorylation
Phosphorylation activation or inactivation
Increase phosphorylation
Protein Phosphatases
activated by Ca2+/calmodulin
Decrease phosphorylation ~
74 Second Messengers
Calcium (Ca2+)
Target: calmodulin
Calmodulin protein kinases (protein kinas B)
Cyclic nucleotides
cAMP & cGMP
Target: protein kinases ~
75 Second Messengers
Diacylglycerol (DAG) & inositol triphosphate (IP3)
From membrane lipids
DAG and calcium Protein Kinase C (membrane)
IP3 Ca2+ (endoplasmic reticulum) ~
76 Hormones That Use 2nd Messengers
Hormones cannot pass through plasma
membrane use 2nd messengers.
Catecholamine, polypeptide, and glycoprotein
hormones bind to receptor proteins on the target
plasma membrane.
Actions are mediated by 2nd messengers
(signal-transduction mechanisms).
Extracellular hormones are transduced into
intracellular 2nd messengers.
77 Adenylate Cyclase-cAMP
4. Second Messengers: for Hormones that can’t cross PM
A. cAMP:
i. Production:
ATP converted to cAMP by adenylate cyclase (a large
multipass TM protein). Degraded by cAMP phosphodiesterase
ii. Action:
a. cAMP-dependent protein kinase (protein kinase A
(PKA)). PKA is a tetramer of catalytic and regulatory subunits.
cAMP binding leads to dissociation of regulatory subunits and
release of catalytic subunits which then phosphorylate target
proteins in cytoplasm:
78 Adenylate Cyclase-cAMP
iii. Action:
b. PKA enters the nucleus and phosphorylates CREB
(CRE binding protein), which binds to the cAMP
response element (CRE), a regulatory DNA sequence
associated with specific genes. This results in activation
of transcription of those genes.
iv. Rapid turn on and rapid turn off of cAMP and activation
by cAMP :
Question: what turns off proteins activated by protein
kinases?
v. Amplification of signal at each step of signaling pathway characteristic feature of signal transduction.
79 Second messenger -cAMP
A. cAMP, cont.:
vi. Regulation of adenylate cyclase: Receptors that cause increase in
cAMP do so by activating Gs, a stimulatory protein that activates
adenylyl cyclase. Adenylyl cyclase is turned off by Gi, an inhibitory
protein.
vii. Pathogens alter cAMP production: Cholera toxin active subunit
catalyzes transfer of ADP ribose from intracellular NAD to the
subunit of Gs, causing it to be continuously active, stimulating
adenylyl cyclase indefinitely. This causes ion channels that export
chloride to produce a net effux of Cl- and water, leading to severe
diarrhea characteristic of cholera.
B. cGMP:
1. produced from GTP by guanylyl cyclase;
2. activates cGMP-dependent kinases or other targets
3. example: G-prot. Coupled rhodopsin photoreceptor in rod cells
of retina
80 cAMP production:
From Janeway, Immunobiology, 5th edition
81 Adenylate Cyclase-cAMP
82 Adenylate Cyclase-cAMP
Polypeptide or glycoprotein hormone binds to
receptor protein causing dissociation of subunit
of G-protein.
G-protein subunit binds to and activates
adenylate cyclase.
ATP
cAMP + PPi
cAMP attaches to inhibitory subunit of protein
kinase.
Inhibitory subunit dissociates and activates cAMP
dependent protein kinase (protein kinase A)
83 Adenylate Cyclase-cAMP (continued)
Phosphorylates
enzymes within the
cell to produce
hormone’s effects.
Modulates activity of
enzymes present in
the cell.
Alters metabolism of
the cell.
cAMP inactivated by
phosphodiesterase.
Hydrolyzes cAMP
to inactive
fragments.
84 A. cAMP:
i. Production:
ATP converted to cAMP by
adenylate cyclase.
Degraded by cAMP
phosphodiesterase
ii. Action:
a. cAMP-dependent protein kinase
(protein kinase A (PKA)). PKA is a tetramer of
catalytic and regulatory subunits. cAMP binding
leads to dissociation of regulatory subunits and
release of catalytic subunits which then
phosphorylate target proteins in cytoplasm:
cAMP production:
85 86 Signals are amplified G-Protein-coupled Receptors
88 Summary of how
cAMP activates
transcription:
(CREB= cAMP Response
Element Binding protein)
89 Phospholipase-C-Ca2+
Binding of Epinephrine to a-adrenergic receptor in
plasma membrane activates a G-protein intermediate,
phospholipase C.
Phospholipase C splits phospholipid into IP3 and
DAG.
Both derivatives serve as 2nd messengers.
IP3 diffuses through cytoplasm to endoplasmic
reticulum (ER).
Binding of IP3 to receptor protein in ER causes
Ca2+ channels to open and release of calcium to the
cytoplasm
90 91 Ca2+- Calmodulin Protein kinas B
(continued)
Ca2+ diffuses into the
cytoplasm.
Ca2+ binds to
calmodulin.
Calmodulin activates
specific protein kinase
enzymes.
Alters the
metabolism of the
cell, producing the
hormone’s effects.
92 ▪ Neurotransmitter Release: exocytosis and endocytosis
1.
Transmitter synthesized and stored
2.
Action Potential
3.
Depolarization: open voltage-gated Ca2+
channels
4.
Ca2+ enter cell
5.
Ca2+ causes vesicles to fuse with
membrane
6.
Neurotransmitter released (exocytosis)
7.
Neurotransmitter binds to postsynaptic
receptors
8.
Opening or closing of postsynaptic
channels
9.
Postsynaptic current excites or inhibits
postsynaptic potential to change
excitability of cell
10.
Retrieval of vesicles from plasma
membrane (endocytosis)
93 ▪ Transmitter Inactivation:
reuptake and enzymatic breakdown
Reuptake by
transporters
(glial cells)
Reuptake by transporters
Enzymatic
breakdown
Neurotransmitter can be recycled in presynaptic terminal
or can be broken down by enzymes within the cell
94 NT – Receptor Binding
Receptors are large, dynamic proteins that
exist along and within the cell membrane.
Dynamic – they can increase in number and
avidity for their neurotransmitter according to
circumstances.
Two Types of Post synaptic Receptors:
Ionotropic receptors: NT binding results in
direct opening of specific ion channels
Metabotropic receptors: binding of NT initiates
a sequence of internal molecular events which in
turn open specific ion channels
95 NT binding -> Membrane Potential
Response
96 Ionotropic Receptors
Work very fast; important role in
fast neurotransmission
1. Each is made of several
subunits (together form the
complete receptor)
2. At center of receptors is
channel or pore to allow
flow of ions
3. At rest - receptor channels
are closed
4. When neurotransmitter
binds -- channel
immediately opens
5. When ligand leaves binding
site -- channel quickly closes
97 Metabotropic Receptors…
Work by activating other
proteins called G
proteins
1. Each is made of
several
transmembrane
regions
2. Stimulate or inhibit
the opening of ion
channels in the cell
membrane
3. Work more slowly
than ionotrophic
receptors
98 Metabotropic Receptors…
1. Stimulate or inhibit
certain effector
enzymes
2. Most effector
enzymes controlled
by G proteins are
involved in synthesis
of second
messengers.
*First messenger:
ligand.
*Second messenger:
effector enzyme
99 Second messengers: Activate Protein Kinases
Can work by affecting:
NT production, no.
synapses formed,
sensitivity of receptors,
or expression of genes
(long term effects).
Can result in
amplification interconnections.
100 Other Metabotropic Receptors
Work more slowly than ionotropic
receptors
1. Though it takes longer for
postsynapic cell to respond,
response is somewhat longerlasting
2. Comprise a single protein subunit,
winding back-and-forth through
cell membrane seven times
(transmembrane domains)
3. They do not possess a channel or
pore
101 102 103 104 PLC- signaling pathway
PKC
Phosphorylates
many substrates,
can activate
kinase pathway,
gene regulation
Receptors Functions and Signal Transduction L3
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