BIO 345 S18 Chapter 6 S19 (Flipped) S20 - True of False Answers Included - S21

Department of Natural sciences
BIO 345
CELL & MOLECULAR BIOLOGY
Chapter 6: Receptors, second messengers

and signaling pathways
1
Dr. Mohamad RIMA Session # 19, 20, 21
Q/A (1)
• What are the 3 states of a receptor/channel ?
Q/A (1)
• What are the 3 states of a receptor/channel ?
1-Closed/Resting
2-Open/Activated
3-Desensitized
Q/A (2)
• What are the characteristics of cell signaling ?
Q/A (2)
• What are the characteristics of cell signaling ?
1- Specificity
2- Amplification
3- Desensitization
4- Integration
Overview
• Cells are able to respond to environmental
factors.
• Cells process the gathered information and

respond.
• Proteins are at the heart of cellular

communication systems. They are sent,
processed and integrated to deliver specific
messages.
8
Overview
• Communication between cells in multicellular
organisms is mediated mainly by extracellular
signal molecules.
• Signal reception is mediated by cell surface or

intracellular receptor proteins.
• Intracellular signaling proteins process the

signal inside the receiving cell and transform
it into function.
9
Signal transduction
• 3 stages:
1- Reception
2- Transduction
3- Response
10
Overview
• Based on the distance, signal can have different forms: Autocrine,
Paracrine, and endocrine.
Direct membrane–membrane contact

11
Forms of cell signaling
The main difference between the different categories of signaling is the distance that the signal travels
through the organism to reach the target cell.
Paracrine Cells that are near one another communicate i.e., Synaptic signaling
through the release of chemical messengers
Autocrine A cell signals to itself i.e., Secretion of IL-1 by
macrophages
Endocrine When cells need to transmit signals over long i.e., Hormones
distances
Direct Contact The transfer of signaling molecules transmits i.e., Gap junctions, Antigen-
the current state of one cell to its neighbor. This presenting cells.
allows a group of cells to coordinate their
response to a signal that only one of them may
have received
12
Features of signal transduction (1)
Specificity
• This is the first line of defense: Molecule should interact only with the
appropriate targets.
• For example: Protein kinases contain active sites that recognize a specific a.a sequence around the
phosphorylation site on the correct target, and they often contain additional docking sites that
promote a specific, high-affinity interaction with the target.
Amplification
Convert a simple signal into
a complex response.
?
Desensitization
Example : Too much glutamate (neurotransmitter) in the brain -> overexcited nerve cells -> brain cell damage
Integration
Features of signal transduction
• Specificity
• Amplification
• Desensitization
• Integration
From: D. L. Nelson, Lehninger Principles of Biochemistry, IV Edition – Chapter 12 Biosignaling

Signal molecules and receptors
• Extracellular signal molecules bind to specific
receptors on/in the target cells.
• Receptors can be TM or intracellular proteins.
• Most signal molecules are hydrophilic and

unable to cross the target cell’s plasma
membrane directly. They bind to cell-surface
receptors, which in turn generate signals
inside the target cell.
21
• Small hydrophobic molecules diffuse across the PM and bind to
receptors inside the target cell (either in the cytosol or in the nucleus).
22
Hydrophobic signals Hydrophilic signals Gaseous molecules

• Diffuse through the PM when • Most common type of • Act directly on the intracellular
small enough. signaling molecules. enzymatic systems.
• In the blood, they travel bound • Circulate in the blood and bind • No need for receptors
to transport proteins (such as to membrane receptors on
albumin). target cells.
• Bind to intracellular receptors.
Steroids, Thyroid hormones Peptides, proteins Nitric oxide (NO) and Carbon
monoxide (CO)
23
• 3 classes of signal transducers:
(A) Ion-channel-coupled receptors
(transmitter-gated ion channels or
ionotropic receptors)
(B) G-protein-coupled receptors
(C) Enzyme-coupled receptors
24
25
Receptors
Ion-channel-coupled receptors
Transmitter or ligand-gated ion channels / ionotropic receptors
• Belong to a large family of homologous, multipass transmembrane proteins.
• Involved in rapid synaptic signaling between nerve cells and other

electrically excitable targets (nerve and muscle cells).
• Mediated by neurotransmitters that

transiently open or close an ion channel,
changing ion permeability and thereby
excitability of the postsynaptic target
cell.
26
Receptors
• Channels are concentrated in a specialized region of the

postsynaptic membrane at the synapse.
• These channels are insensitive to membrane potential:

They can’t produce self-amplifying excitation; however, they produce
local permeability increase that changes membrane potential.
• The amount of neurotransmitter released and how long

it persists there will determine the response.
27
Receptors
28
Receptors
• Two levels of selectivity:

1. As receptor: highly selective binding sites for the
neurotransmitter released from the presynaptic
terminal.
2. As channel: selective in the type of ions allowed to
across the plasma membrane.
• Ions entering target cell will determine the nature of

the postsynaptic response (inhibitory or excitatory).
29
Receptors
• Not all chemical synapses operate through ionotropic receptors.
• Many neurotransmitters bind to metabotropic receptors, which regulate

ion channels only indirectly through the action of small intracellular
signal molecules.
30
Receptors
• Not all chemical synapses operate through ionotropic receptors.
• Many neurotransmitters bind to metabotropic receptors, which regulate

ion channels only indirectly through the action of small intracellular
signal molecules.

G-protein-coupled receptors
31
Receptors
Ionotropic vs metabotropic receptors
32
Receptors
• Indirectly regulate the activity of a separate target protein (enzyme or ion
channel).
• The interaction between the activated receptor and the target protein is
mediated by trimeric GTP-binding protein (G protein).
• The activation of the target protein can (i) change the concentration of
small intracellular signaling molecules, or (ii) change ion permeability of
the plasma membrane.
33
Receptors
Enzyme-coupled receptors
• Function as enzymes or associate directly with enzymes that they
activate.
• Usually single-pass transmembrane proteins with extracellular ligand-

binding site and intracellular catalytic or enzyme-binding site.
• Heterogeneous: they are either protein kinases or associate with protein

kinases, which phosphorylate specific sets of proteins in the target cell when activated. 34
Cell response (True or False)
• One cell is exposed to hundreds of different signal molecules in its
environment.
• Signal molecules can only be soluble and stimulatory.
• Cell signaling can act in innumerable different combinations.
35
environment.
36
environment.

Signal molecules can be soluble or bound, stimulatory or inhibitory.
37
environment.

Signal molecules can be soluble or bound, stimulatory or inhibitory.

key challenges in cell biology is to determine how a cell integrates all of this signaling information
to respond correctly.
38
Cell response
• Cell often requires multiple signals to
survive (blue arrows) and additional
signals to grow and divide (red arrows)
or differentiate (green arrows).
• When deprived of these signals, the

cell activates apoptosis.
39
• Each signal molecule is specific to each cell type (they can’t have
effects on different types of target cells).
40
effects on different types of target cells)
One signal molecule often has different effects on different types of
target cells.
41
target cells.
• Different responses result from differences in intracellular proteins,

signaling effector proteins, and activated genes.
42
target cells.
• Different responses result from differences in intracellular proteins,

signaling effector proteins, and activated genes.
43
Cell response
The different effects of acetylcholine.
An extracellular signal itself has little information content; it simply induces the
cell to respond according to its predetermined state. 44
The intracellular signaling
• Signals bind cell-surface receptors and
activate intracellular signaling molecules.
• This resulting chain of events changes

effector proteins that are responsible for
modifying the cell behavior.
• Intracellular signaling molecules are small

chemicals (second messengers) that can
diffuse to spread the signal.
Ex. Cyclic AMP and Ca2+ diffusing in the cytosol (water-soluble),
diacylglycerol diffusing in the plane of the PM (lipid-soluble).
45
• Most intracellular signaling molecules are
proteins.
• They generate second messengers or

activate the next signaling or effector
protein in the pathway.
• These proteins behave as molecular

switches. When they receive a signal, they switch from
an inactive to an active state, until another process switches
them off, returning them to their inactive state.
46
• Two types of intracellular signaling proteins that act as molecular
switches: protein kinase and GTP-binding protein.
47
Intracellular signaling
Signaling by phosphorylation
• Largest class of signal molecules consists of proteins
that are activated or inactivated by phosphorylation.
• Protein kinase: covalently adds one or more phosphate

groups to specific amino acids on the signaling protein.
• Protein phosphatase: removes the phosphate groups.
• The activity of any protein regulated by

phosphorylation depends on the balance between the
kinases-phosphatases activities.
48
Intracellular signaling
Signaling by GTP-binding protein

• Switch between an on-state when GTP is bound and an
off-state when GDP is bound.
• In the on-state, they usually have intrinsic GTPase

activity and shut themselves off by hydrolyzing their
bound GTP to GDP.
• They are regulated by

1. GTPase-activating proteins (GAPs) drive the proteins into off-state by increasing the
rate of hydrolysis of bound GTP.
2. Guanine nucleotide exchange factors (GEFs) activate GTP-binding proteins by
promoting the release of bound GDP, which allows a new GTP to bind. 49
True or False
• Eukaryotic cells are characterized by their expression of one kinase
and one phosphatase.
The human genome encodes about 520 protein kinases and about 150
protein phosphatases (ex. Serine/threonine kinases, tyrosine kinases)
50
True or False
protein phosphatases (ex. Serine/threonine kinases, tyrosine kinases).
NOT all molecular switches depend on phosphorylation or GTP binding
(AMP and Ca2+ or ubiquitylation)
51
True or False
• All molecular switches depend on phosphorylation or GTP binding.

(AMP and Ca2+ or ubiquitylation)
52
True or False
• All molecular switches depend on phosphorylation or GTP binding.

(i.e., AMP, Ca2+ or Ubiquitination).
53
Signal-response relation
The response persistence is variable and regulated (reversible):
• Ex. Transient response (< second) is present in some synapses.
• Ex. Prolonged or permanent response is required in cell fate decisions
during development.
• The duration and reversibility of a response are regulated by
numerous mechanisms (i.e., positive or negative feedback).
54
Signal-response relation
• Signal processing: i.e., Simple signal is converted into an oscillatory
response, via a repeating series of transient intracellular signals.
• Integration: i.e., Specific combinations of extracellular signals are

required to stimulate complex behaviors such as cell survival and
proliferation.
• Coordination of multiple responses: i.e., Single signal stimulates

both grow and division. This coordination depends on mechanisms
for distributing a signal to multiple effectors, by creating branches in
the signaling pathway. 55
Signal-response speed
All responses have the same speed ?
56
All responses have the same speed ? No
• Extracellular signal can lead to slow or rapid responses.
57
58
• Slow: If the response requires changes in
gene expression and synthesis of new
proteins.
i.e., cell growth and division.
• Fast: Not involving changes in gene

transcription. They may involve the rapid
phosphorylation of effector proteins.
i.e., cell movement, secretion, or metabolism.
Synaptic responses are even quicker
(milliseconds).
59
• Some signaling systems generate
both rapid and slow responses
allowing the cell to respond quickly
to a signal while simultaneously
initiating a more long-term,
persistent response.
60
Changing sensitivity to signal
• Cells and organisms are able to detect changes in the concentrations of
an extracellular signal molecule.
• This is accomplished through a reversible process of adaptation, or

desensitization. (Prolonged exposure to a stimulus decreases the cells’ response to
that level of stimulus).
• The machinery resets itself to become less sensitive

to the same level of the signal. Sudden increase in the
signal reactivates the cell for a short period of time
before the negative feedback kicks in.
61
• Different forms of adaptation:
62
• Different forms of adaptation:
1. Inactivation of the receptors (i.e., by phosphorylation)
2. Receptor endocytosis and temporary sequestration in endosomes.
3. Receptor endocytosis followed by the destruction of the receptors in lysosomes
(receptor down-regulation). (In other cases, activated receptors continue to signal
after they have been endocytosed).
4. Changes in intracellular signaling proteins involved in signal transduction.
5. Production of an inhibitor protein that blocks the signal.
63
True or false
• Cells can emit and receive signals.
• Ion-channel-coupled receptors are similar to voltage-gated ion

channels.
64
True or false

channels.
65
True or false

channels.
(voltage-gated channels are sensitive to action potentials, unlike Ion-channel-
coupled receptor).
66
Receptors
• Largest family of cell-surface receptors.
Half of known drugs work through GPCRs or their signaling pathways.
• They mediate most responses to signals (i.e., hormones, neurotransmitters, …)
• Responsible for sensation (vision, smelling and taste).
• Diversity : more than 800 GPCRs in humans, and in mice ~ 1000 responsible of
smelling only.
67
Receptors
• They can be activated by broad scale of molecules :
Proteins, small peptides, derivatives of a.a and fatty acids, photons and
molecules that can be sensed.
• The same signal molecule can activate many different GPCRs (i.e., adrenaline).
• Despite their functional diversity GPCRs have a similar structure:

➢ Single polypeptide chain that multipass the membrane often with a ligand-binding site.
➢ They all use G proteins to transmit the signal into the cell
68
Receptors
• Trimeric GTP-binding protein (G proteins) are composed of three
subunits, α, β, and γ. G proteins have similar structure and mechanism.
• G protein can be physically associated with the

receptor before the receptor is activated, or it binds
only after the receptor activation.
• Various types of G proteins: arising from the

specificity for GPCRs and the targets.
• Extracellular signals binds to GPCR that undergoes a conformational

change that activates G protein. This couples the receptor to enzymes or
ion channels in the membrane.
69
Receptors
Molecular mechanism
• In unstimulated state, the α subunit has GDP bound and the G

protein is inactive.
• When a GPCR is activated, it acts like a guanine nucleotide

exchange factor (GEF) and induces the release of bound GDP,
allowing GTP binding.
• GTP binding causes an activating conformational change in

the α subunit, releasing the G protein from the receptor and
triggering the dissociation of the GTP-bound α subunit from
the beta-gamma dimer.
• Both parts diffuse laterally to interact with their targets

(enzymes and ion channels in the plasma membrane), which
relay the signal onward. 70
Receptors
Molecular mechanism
• The α subunit is a GTPase and becomes inactive when it hydrolyzes GTP to GDP.
• GTP hydrolysis is quick because this GTPase activity of α subunit is greatly enhanced by
the binding of second protein, which can be either the target protein or a specific
regulator of G protein signaling (RGS).
• RGS proteins act as α-subunit-specific GTPase-activating proteins (GAPs).

They help shutting off G-protein-mediated responses in all eukaryotes.
• 25 RGS proteins encoded in the human genome.
71
Receptors
Downstream effectors
• G proteins regulate the activity of several downstream effectors.
Pathway Second messengers

Adenylate cyclase cAMP
Phospholipase Cβ diacylglycerol (DAG) + triphosphate
inositol (PI3)
Phospholipase A2 Arachidonic acid
Transducin phosphodiesterase cGMP (visual signals)
72
GPCRs
cAMP
as second messengers
• Cyclic AMP (cAMP) is an intracellular second messenger to

a wide variety of hormones and neurotransmitters.
• cAMP is synthesized from ATP by an enzyme called adenylyl

cyclase, and it is rapidly and continuously destroyed by
cyclic AMP phosphodiesterases.
73
GPCRs
cAMP
• Adenylyl cyclase is a large, multipass

transmembrane protein with its catalytic domain on
the cytosolic side of the plasma membrane.
• Activated GPCRs activates adenylyl cyclase via

stimulatory G-protein (Gs) → increase in cAMP.
• Other extracellular signals, acting through different

GPCRs, inhibits adenylyl cyclase via inhibitory G
protein (Gi) → decrease in cAMP.
74
GPCRs
cAMP
• Gs and Gi are targets for bacterial toxins.
• Cholera toxin, produced by the Vibrio Cholerae, is an

enzyme that alters the α subunit (it can’t hydrolyze its
bound GTP) causing its permanent activation and
stimulation of adenylyl cyclase.
• The prolonged elevation in cAMP in intestinal cells causes a

large efflux of Cl– and water → diarrhea.
75
GPCRs
cAMP
What is the main downstream effector of cAMP ?
• In most animal cells, cAMP activates cAMP-dependent protein kinase (PKA).
76
GPCRs
cAMP
• PKA consists of a complex of two catalytic

subunits and two regulatory subunits (also
called A-kinase) that are important for localizing
the kinase inside the cell.
• This kinase phosphorylates specific serines or

threonines of target proteins modulating their
activity. 77
GPCRs
cAMP
• PKA consists of a complex of two catalytic subunits and two

regulatory subunits (also called A-kinase) that are important
for localizing the kinase inside the cell.
78
GPCRs
cAMP
• Binding of cAMP to the regulatory

subunits alters their conformation,
causing them to dissociate from the
complex.
• Released catalytic subunits are thereby

activated to phosphorylate (serines or
threonines) of target proteins modulating
their activity.
79
GPCRs
cAMP
80
GPCRs
cAMP
• Activated PKA translates into the nucleus.
• Specific transcription regulator called CRE-

binding (CREB) is phosphorylated by PKA.
• CREB recognizes cis-regulatory sequence, called

the cAMP response element (CRE).
• Phosphorylated CREB, recruits a transcriptional

coactivator, CREB-binding protein (CBP),
stimulating the transcription of the target genes.
(ex. Somatostatin hormone)
81
GPCRs
Regulation of ion channels

• G proteins do not act exclusively on membrane-bound enzymes that alter the
concentration of cyclic AMP or Ca2+ in the cytosol.
• They can directly activate/inactivate ion channels; therefore, altering ion permeability
and hence the electrical excitability of the membrane.
• Ex: Acetylcholine (Ach) released by the vagus nerve reduces the heart rate. This effect is
mediated by a special class of Ach receptors that activate the Gi protein:
➢ α subunit of Gi inhibits adenylyl cyclase
Inhibitory effect of acetylcholine on the heart
➢ βγ subunits bind to K channels
+
82
GPCRs
Regulation of ion channels

• Ex: Acetylcholine (Ach) released by the vagus nerve reduces the heart rate. This effect is
mediated by a special class of Ach receptors that activate the Gi protein:
➢ α subunit of Gi inhibits adenylyl cyclase
➢ βγ subunits bind to K+ channels
Inhibitory effect of acetylcholine on the heart
83
Receptors
• Transmembrane proteins characterized by extracellular ligand-binding
domain and intracellular catalytic domain or enzyme-linked domain.
• They often activate some of the same

signaling pathways as GPCRs.
• The most common: tyrosine kinases

receptor.
84
Receptor Tyrosine Kinases

• Many extracellular signals act through
receptor tyrosine kinases (RTKs).
• Diversity: 60 human RTKs are classified

into 20 structural superfamilies.
85

• In the absence of extracellular signals, most RTKs exist as monomers in (the internal
kinase domain is inactive).
• Binding of the signal to the ligand-binding domain brings two monomers together and
activates the tyrosine kinase domain.
• These phosphorylations promotes the complete activation of the domains and create
phosphotyrosine docking sites for various intracellular signaling proteins that transmit
the signal.
86

• Dimerization stimulates kinase activity by a variety of mechanisms:
1. Dimerization simply brings the kinase domains close to each other in an
orientation that allows them to phosphorylate each other on specific
tyrosines in the kinase active sites, thereby promoting conformational
changes that fully activate both kinase domains (ex. Insulin receptor).
2. The kinase is not activated by phosphorylation but by conformational

changes through interactions between the two kinase domains outside
their active sites (ex. epidermal growth factor (EGF) receptor).
87

• In the absence of EGF, the receptor is
inactive (monomer).
• EGF binding results in a conformational
change that promotes dimerization of
the external domains.
• Dimerization orients the internal kinase
domains into an asymmetric dimer, in
which one kinase domain (the
“activator”) pushes against the other
kinase domain (the “receiver”), thereby
causing an activating conformational
change in the receiver.
88

• The active receiver domain
phosphorylates multiple tyrosines in
both receptors, generating docking
sites for signaling proteins.
89
90
Receptors
Overlapping signaling pathways

• RTKs and GPCRs activate some of the same
intracellular signaling pathways.
Ex. IP3 pathway triggered phospholipase C.
• Even when they activate different pathways, the

different pathways can converge on the same target
proteins.
• Interactions between the pathways help in

extracellular signals to modulate and coordinate each
other’s effects.
91
Alternative signaling routes in gene expression
• The receptor Notch
• Diffusing Extracellular signals
92
Alternative signaling
The receptor Notch

• Notch signaling is widely described in animal development.
• It controls cell fate choices and regulates pattern formation during

the development of most tissues, and in tissue renewal.
• Main components : delta (signal) and Notch (receptor).

Notch is a single-pass transmembrane protein that requires proteolytic
processing to function.
Delta is a single-pass transmembrane protein.
93
The receptor Notch

• Notch binds to Delta on another cell.
• Activated plasma-membrane-bound
protease (γ-secretase) cleaves the
cytoplasmic tail of Notch.
• This transcription regulator translocates
into the nucleus and activates target genes.
• This latent transcription regulator and provides the

most direct signaling pathway known from a cell
surface receptor to the nucleus.
94
The receptor Notch

• Play a major role in the production of Drosophila neural cells:
• These cells will arise as isolated single cells within

epithelial precursor cells.
• When a precursor cell commits to become a
neural cell, it signals to its neighbors via Notch
signaling not become neural. Therefore,
neighboring cells develop into epidermal cells.
The process is called lateral inhibition.
By binding to the Notch receptor on a neighboring

cell, Delta signals to the neighbor not to become
neural. 95
Diffusing Extracellular signals

• Various small, hydrophobic signals diffuse directly across the plasma membrane of
target cells and bind to intracellular receptors that are transcription regulators.
• Ex. steroid hormones, thyroid hormones, retinoids, and vitamin D.
• Although their chemical and functional differences, they act by a similar mechanism:
They bind to their respective intracellular receptors and alter their abilities to control the
gene transcription. Thus, these proteins serve as intracellular receptors and intracellular
effectors for the signal.
• The receptors are all structurally related, being part of nuclear receptor superfamily.
96

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Department of Natural sciences

Chapter 6: Receptors, second messengers

• Cells process the gathered information and

• Proteins are at the heart of cellular

• Signal reception is mediated by cell surface or

• Intracellular signaling proteins process the

Direct membrane–membrane contact

From: D. L. Nelson, Lehninger Principles of Biochemistry, IV Edition – Chapter 12 Biosignaling

• Receptors can be TM or intracellular proteins.

• Most signal molecules are hydrophilic and

Hydrophobic signals Hydrophilic signals Gaseous molecules

• Belong to a large family of homologous, multipass transmembrane proteins.

• Involved in rapid synaptic signaling between nerve cells and other

• Mediated by neurotransmitters that

• Channels are concentrated in a specialized region of the

• These channels are insensitive to membrane potential:

• The amount of neurotransmitter released and how long

• Two levels of selectivity:

• Ions entering target cell will determine the nature of

• Not all chemical synapses operate through ionotropic receptors.

• Many neurotransmitters bind to metabotropic receptors, which regulate

• Not all chemical synapses operate through ionotropic receptors.

• Many neurotransmitters bind to metabotropic receptors, which regulate

Ionotropic vs metabotropic receptors

• Usually single-pass transmembrane proteins with extracellular ligand-

• Heterogeneous: they are either protein kinases or associate with protein

• Signal molecules can only be soluble and stimulatory.

• Cell signaling can act in innumerable different combinations.

• Signal molecules can only be soluble and stimulatory.

• Cell signaling can act in innumerable different combinations.

• Signal molecules can only be soluble and stimulatory.

• Cell signaling can act in innumerable different combinations.

• Signal molecules can only be soluble and stimulatory.

• Cell signaling can act in innumerable different combinations.

• When deprived of these signals, the

• Different responses result from differences in intracellular proteins,

• Different responses result from differences in intracellular proteins,

• This resulting chain of events changes

• Intracellular signaling molecules are small

• They generate second messengers or

• These proteins behave as molecular

• Protein kinase: covalently adds one or more phosphate

• The activity of any protein regulated by

Signaling by GTP-binding protein

• In the on-state, they usually have intrinsic GTPase

• They are regulated by

• All molecular switches depend on phosphorylation or GTP binding.

• All molecular switches depend on phosphorylation or GTP binding.

• Integration: i.e., Specific combinations of extracellular signals are

• Coordination of multiple responses: i.e., Single signal stimulates

• Fast: Not involving changes in gene

• This is accomplished through a reversible process of adaptation, or

• The machinery resets itself to become less sensitive

• Ion-channel-coupled receptors are similar to voltage-gated ion

• Ion-channel-coupled receptors are similar to voltage-gated ion

• Ion-channel-coupled receptors are similar to voltage-gated ion

• They mediate most responses to signals (i.e., hormones, neurotransmitters, …)

• Responsible for sensation (vision, smelling and taste).

• Despite their functional diversity GPCRs have a similar structure:

• G protein can be physically associated with the

• Various types of G proteins: arising from the

• Extracellular signals binds to GPCR that undergoes a conformational

• In unstimulated state, the α subunit has GDP bound and the G