Plasma membrane receptors transmit signals across the cell membrane via several mechanisms of signal transduction. Receptor mechanisms include ligand-gated ion channels that directly open or close in response to ligand binding, initiating electrical signals. Receptor tyrosine kinases dimerize and autophosphorylate upon ligand binding, activating intracellular kinase cascades. G-protein coupled receptors activate heterotrimeric G-proteins upon ligand binding, initiating second messenger signaling pathways. These receptor mechanisms underlie rapid cellular responses or slower changes in gene expression.

1. CELL SIGNALING
LESSON 2
NEUROCHEMISTRY

2. 2. Plasma Membrane Receptors and
Signal Transduction
• All plasma membrane receptors are proteins with certain
features in common: an extracellular domain that binds
the chemical messenger, one or more membrane-spanning
domains that are α-helices, and an intracellular domain
that initiates signal transduction.

3. • As the ligand binds to the extracellular domain of
its receptor, it causes a conformational change
that is communicated to the intracellular domain
through the α-helix of the transmembrane domain.
• The activated intracellular domain initiates a
characteristic signal transduction pathway .
Signal transduction pathways run in one direction.
From a given point in a signal transduction pathway,
events closer to the receptor are termed “upstream”
and events closer to the response are termed
“downstream.”

5. • In many pathways, the signal is transmitted by a
cascade of protein phosphorylations
• This phosphorylation (kinases) and
dephosphorylation (phosphatases) system acts
as a molecular switch, turning activities on and
off
• Phosphatase - enzymes remove the phosphates

6. Signal molecule
Activated relay
molecule
Receptor
Inactive
protein kinase
1 Active
protein
kinase
1
Inactive
protein kinase
2 Active
protein
kinase
2
Inactive
protein kinase
3 Active
protein
kinase
3
ADP
Inactive
protein
Active
protein
Cellular
response
ATP
PP
Pi
ADP
ATP
PP
Pi
ADP
ATP
PP
Pi
P
P
P

7. The pathways of signal transduction
for plasma membrane receptors
The pathways of signal transduction for plasma
membrane receptors have two major types of
effects on the cell:
1. rapid and immediate effects on cellular ion
levels or activation/inhibition of enzymes
and/or
1. slower changes in the rate of gene expression
for a specific set of proteins. Often, a signal
transduction pathway will diverge to produce
both kinds of effects.

8. Plasma membrane receptors are grouped
into 6 categories:
• Gated ion channels.
• Receptors linked to membrane-bound G-protein -
work through second messengers;
• Receptors with tyrosine kinase (RTK) activity;
• Receptors linked to tyrosine kinases,
• Receptors with tyrosine phosphatase (RTPase)
activity.
• Atrial natriuretic peptide receptor with guanylate
cyclase activity
This classification is based on the receptor's general structure and
means of signal transduction.

9. 1. Ion Channel Receptors or
• Ligand-gated ion channels (LGICs) (ionotropic
receptor) or channel-linked receptor.
• They are are opened or closed in response to
the binding of a chemical messenger (i.e., a
ligand), such as a neurotransmitter.
• Most small-molecule neurotransmitters and
some neuropeptides use ion channel
receptors.
NOTE
The majority of ion channels fall into two broad categories: voltage-gated ion
channels (VGIC) and ligand-gated ion channels (LGIC).

10. Signal
molecule
(ligand)
Gate
closed Ions
Ligand-gated
ion channel receptor
Plasma
membrane
Gate closed
Gate open
Cellular
response

11. • These proteins are typically composed of at least
two different domains: a transmembrane domain
which includes the ion pore, and an extracellular
domain which includes the ligand binding
domain.

12. • LGIC is regulated by a ligand and is usually very selective to
one or more ions like Na+, K+, Ca2+, or Cl-.
• Such receptors located at synapses convert the chemical
signal of presynaptically released neurotransmitter directly
and very quickly into a postsynaptic electrical signal.
• Many LGICs are additionally modulated by allosteric
ligands, by channel blockers, ions, or the membrane
potential.
• Ligand-gated ion channels are likely to be the major site at
which anaesthetic agents and ethanol have their effects,
halthough unequivocal evidence of this is yet to be
established

14. Voltage-gated ion channels
• Voltage-gated ion channels are a class of
transmembrane ion channels that are activated by
changes in electrical potential difference near the
channel; these types of ion channels are especially
critical in neurons.
• They have a crucial role in excitable neuronal and
muscle tissues, allowing a rapid and co-ordinated
depolarization in response to triggering voltage
change. Found along the axon and at the synapse,
voltage-gated ion channels directionally propagate
electrical signals.

16. Example: nicotinic acetylcholine receptor
• The prototypic ligand-gated ion channel is the
nicotinic acetylcholine receptor.
• The job of a neurotransmitter is to change the
membrane potential of the postsynaptic cell and
to do it quickly.
• The fastest and most direct mechanism is binding
of the neurotransmitter to a ligand-gated ion
channel in the plasma membrane.
• The nicotinic acetylcholine receptor in the
neuromuscular junction is a classic example.

18. • This receptor is a channel for the monovalent
cations sodium and potassium, with five
subunits that each contribute to the channel
(Fig.). The channel is closed in the resting
state, opening only when acetylcholine binds.
Opening of the channel causes a rapid influx
of sodium down its electrochemical gradient,
which depolarizes the membrane.

19. This receptor is a ligand-
gated channel for small
cations (Na+, K+).
Acetylcholine binds with
positive cooperativity to
the two α subunits.
Each of the five
polypeptides traverses
the membrane four
times, and one of the
transmembrane helices
in each subunit
contributes to the “gate”
in the channel.
Structure of the nicotinic acetylcholine receptor in the
neuromuscular junction.

22. Voltage-gated ion channels
Voltage-gated ion channels are a class of transmembrane ion channels
that are activated by changes in electrical potential difference near the
channel; these types of ion channels are especially critical in neurons.
They generally are composed
of several subunits arranged
in such a way that there is a
central pore through which
ions can travel down their
electrochemical gradients.
The channels tend to be ion-
specific, although similarly
sized and charged ions may
sometimes travel through
them.

23. • Examples include:
• the sodium and potassium voltage-gated
channels of nerve and muscle.
• the voltage-gated calcium channls that play a
role in neurotransmitter release in presynaptic
nerve endings.

25. • CLINICAL CORRELATION
• Lambert–Eaton Myasthenic Syndrome
Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune
disease in which the body raises antibodies against voltage
gated calcium channels (VGCC) located on presynaptic nerve
termini.
Upon depolarization of presynaptic neurons, calcium channels
at presynaptic nerve termini open, permitting the influx of
calcium ions. This increase in calcium ion concentration initiates
events of the synapsin cycle and leads to release of
neurotransmitters into synaptic junctions. When autoantibodies
against VGCC react with neurons at neuromuscular junctions,
calcium ions cannot enter and the amount of acetylcholine
released into synaptic junctions is diminished.

26. Receptor tyrosine kinases
• Kinases are the class of enzymes which
transfer the terminal phosphate group from
ATP to a substrate.
• In particular, tyrosine kinases transfer the
phosphate to a tyrosine residue.

28. Signal
molecule
a Helix in the
membrane
Signal-binding site
Tyr
Tyr
Tyr Tyr
Tyr
Tyr
Tyrosines
Receptor tyrosine
kinase proteins
(inactive monomers)
CYTOPLASM
Tyr
Tyr
Tyr Tyr
Tyr
Tyr Tyr
Tyr
Tyr Tyr
Tyr
Tyr
Tyr
Tyr
Tyr Tyr
Tyr
Tyr
Activated tyrosine-
kinase regions
(unphosphorylated
dimer)
Signal
molecule
Dimer
Fully activated receptor
tyrosine-kinase
(phosphorylated
dimer)
Tyr
Tyr
Tyr Tyr
Tyr
Tyr
P
P
P
P
P
P
ATP 6 ADP
Tyr
Tyr
Tyr Tyr
Tyr
Tyr
P
P
P
P
P
P
Inactive
relay proteins
Cellular
response 2
Cellular
response 1
Activated relay
proteins
6

29. • Signal transduction may involve two types of
tyrosine kinase:
1. receptors with inherent tyrosine kinase activity
(RTKs), for example insulin receptor; Receptors with
tyrosine kinase (RTK) activity
2. receptors, which recruit cytoplasmic tyrosine
kinases, for example growth hormone, leptin
operating through Janus kinase (JAK). Receptors
linked to tyrosine kinases,

34. Receptor tyrosine phosphatase
• CD45
1. It is a large（180-220 kDa）cell surface
molecule expressed by all leukocytes,
including T cell.
2. Its cytoplasmic domain has tyrosine
phosphatase activity.

35. G-Protein-Coupled Receptors
The G-protein-coupled receptors (also known as
heptahelical receptors) contain seven-membrane
spanning domains which are a-helices .
Although there are hundreds of hormones and
neurotransmitters that work through heptahelical
receptors, the extracellular binding domain of each
receptor is specific for just one polypeptide
hormone, catecholamine, or neurotransmitter (or its
close structural analogue).

36. Fig. Heptahelical receptors

37. Segment that
interacts with
G proteins
Signal-binding site
G-protein-linked receptor

38. Out
In
G
7 transmembrane
domain receptor
2nd messengers
NH2
COOH

39. • Heptahelical receptors initiate signal
transduction through heterotrimeric G-
proteins (proteins which are activated upon
binding GTP) composed of α-, β-, and γ-
subunits.
• However, different types of heptahelical
receptors bind different G-proteins, and
different G-proteins exert different effects on
their target proteins

40. Heterotrimeric G-proteins
• The function of heterotrimeric G-proteins is illustrated in Fig.
using a hormone that activates adenylyl cyclase (e.g. glucagon or
epinephrine).
• While the α-subunit contains bound GDP, it remains associated
with the β- and γ-subunits, either free in the membrane or
bound to an unoccupied receptor (see Fig, part 1).
• When the hormone binds, it causes a conformational change in
the receptor that activates GDP dissociation and GTP binding.
The exchange of GTP for bound GDP causes dissociation of the α
-subunit from the receptor and from the βγ -subunits (see Fig. ,
part 2).
• The GTP- α -subunit binds its target enzyme in the membrane,
thereby changing its activity. In this example, the α -subunit
binds and activates adenylyl cyclase, thereby increasing synthesis
of cAMP (see Fig. , part 3).

42. • With time, the Gα-subunit inactivates itself by
hydrolyzing its own bound GTP to GDP and Pi.
This action is unrelated to the number of cAMP
molecules formed. When this occurs, the GDP-
α -subunit dissociates from its target protein,
adenylyl cyclase (see Fig. part 4). It reforms the
trimeric G-protein complex, which may return
to bind the empty hormone receptor.

43. The secreted chemical
messenger (hormone, cytokine,
or neurotransmitter) is the first
messenger, which binds to a
plasma membrane receptor
such as the heptahelical
receptors. The activated
hormone-receptor complex
activates a heterotrimeric G-
protein (via an exchange of GTP
for the bound GDP) and via
stimulation of membrane-
bound enzymes, different G-
proteins lead to generation of
one or more intracellular
second messengers, such as
cAMP, diacylglycerol (DAG), or
inositol triphosphate (IP3).
G-protein-coupled receptors and second
messengers.

44. • There are a large number of different
heterotrimeric G-protein complexes, which are
generally categorized according to the activity of
the α-subunit. The 20 or more different isoforms of
Gα fall into four broad categories: GαS, G αi, G αq/11,
G α12/13. GαS refers to α -subunits which, like the
one in Fig., stimulate adenylyl cyclase (hence the
“s”). Gα subunits that inhibit adenylyl cyclase are
called G αi. or Gi protein -G α i/0. The βγ-subunits
likewise exist as different isoforms, which also
transmit messages. Gaqs subunits activate
phospholipase Cβ, which generates second
messengers based on phosphatidylinositol.