Ion pumps and ion channels (K Leak channels) establish the resting potential of a neuron

Resting membrane potential: the voltage (charge) difference between the intracellular and extracellular fluid, when the cell is at rest (i.e not
depolarised by an action potential).

Mechanisms responsible for the resting membrane potential:

Chemical gradients generated by active transport pumps: the concentration of ions are significantly different between the intracellular
and extracellular fluid, eg. the ratio of potassium ions is 35:1.
Selective membrane permeability: the cell membrane is selectively ion-permeable, specifically it is much more permeable to potassium ions
Electrical gradients are generated because potassium leak from the intracellular fluid creates a negative intracellular charge. This charge
attracts potassium ions back into the cell and thus opposes the chemical gradient.
Electrochemical equilibrium develops when electrical and chemical forces are in balance for each specific ion species, and this is described
by the Nernst equation.
The Nernst potential for each ion is the transmembrane potential difference generated when that ion is at electrochemical equilibrium
The total membrane resting potential for all important ion species is described by the Goldman-Hodgkin-Katz equation, which takes into
account the different membrane permeabilities for each ion.
At rest, with normal intracellular and extracellular electrolyte concentrations, the net charge of the intracellular side of the cell membrane is
negative, and is approximately -70 to -90 mV for mammalian neurons.
Gated ion channels alter membrane potential

Resting potential Depolarized Hyperpolarized

Only K+ channel open Voltage-gated Na+ channel open Chemically gated K+ channel open
Outside of cell Na+

K+ channel Voltage-gated Chemically gated

Na+ channel K+ channel

+ + + + + + + + + + + + + + + + + + + + +

– – – – – – – – – + + – – – – – – – – – –

Open Closed Closed

Open Open Closed Open Closed Open

Inside of cell K+

K+ channel open
Membrane potential (mV)

Na+ channel open More K+ channels open

0
Depolarized
–30
Resting potential
–60
Hyperpolarized
–90
Time
Na+ flowing into the More K+ flowing out of
cell depolarizes it. the cell hyperpolarizes it.

45.9 Membranes Can Be Depolarized or Hyperpolarized The rest-ing potential is produced by leak K+ channels. A shift from the
resting potential to a less negative membrane potential, as occurs when Na+ enters the cell through a gated sodium channel, is called
depolarization. Hyperpolarization occurs when the membrane potential becomes more negative, as when additional K+ leaves the cell
through gated K+ chan-nels, which occurs extensively in your brain when you fall asleep.
Graded changes in membrane potential can
integrate information
 Electrical
stimulus

Point A Oscilloscope screen

Point B
Point A

Amplifier
Point B

Outside axon Outside axon

+ + + + + + + + + + + + + + + + + + + + Amplifier
– – – – – – – – – – – – – – – – – – – –
Inside axon Inside axon
– – – – – – – – – – – – – – – – – – – – – – – –
1 2
+ + + + + + + + + + + + + + + + + + + + + + + + Time
Outside axon Outside axon
Point A Point B

(B) Time 1

1 Voltage-gated Na+ channels open in 2 A depolarizing

response to the electrical stimulus, current spreads
generating an action potential. down the axon.

Point A Point B
(C) Time 2

3 Upstream Na+ channels 4 Voltage-gated K+ channels 5 As it travels down the axon, the action
inactivate, making the open, hyperpolarizing the potential stimulates more Na+ channels to
membrane refractory. axon, then close. open in a self-extending forward stream.

Point A Point B
45.11 Action Potentials Travel along Axons (A) There is no loss of signal as an action poten-
tial travels along an axon. (B) When an action potential is stimulated in one region of membrane,
electric current flows to adjacent areas of membrane and depolarizes them. (C) The advancing
wave of depolarization causes more Na+ channels to open, and the action potential is generated
anew in the next section of membrane. Meanwhile, in the region where the action potential has just
fired, the Na+ channels are inactivated and the voltage-gated K+ channels are still open, rendering
this section of the axon refractory. Hence the action potential cannot “back up,” but moves contin-
uously forward along the axon, regenerating itself as it goes.
Ligand Gated Ion Channels- Where are they?

When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic
cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these
receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels,
which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization,
for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.
LIGAND-GATED ION CHANNELS OPEN UPON BINDING WITH CHEMICAL SIGNALS

Na+
Ligand-gated ion channels ACh ACh
δ
• These are sometimes called ionotropic receptors. γ
• They are involved mainly in fast synaptic transmission. α α
• There are several structural families, the commonest Outside
being heteromeric assemblies of four or five subunits, β
with transmembrane helices arranged around a central
aqueous channel.
• Ligand binding and channel opening occur on a
millisecond timescale.
• Examples include the nicotinic acetylcholine, GABA
type A (GABAA), glutamate (e.g. N-methyl-D-aspartatic
acid receptor [NMDA]) and ATP (P2X) receptors.

Inside
(A) ION-CHANNEL-COUPLED RECEPTORS

ions Na+

signal molecule
FIGURE 2–9 The nicotinic acetylcholine (ACh) receptor, a ligand-
plasma gated ion channel. The receptor molecule is depicted as embedded in
membrane
CYTOSOL a rectangular piece of plasma membrane, with extracellular fluid above
and cytoplasm below. Composed of five subunits (two α, one β, one γ,
closed channel open channel
and one δ), the receptor opens a central transmembrane ion channel
when ACh binds to sites on the extracellular domain of its α subunits.
An ion-channel-coupled receptor opens in
response to binding an extracellular signal
molecule.

Table 3.1 The four main types of receptor

Type 1: Ligand-gated
ion channels

Location Membrane
Effector Ion channel
Coupling Direct
Examples Nicotinic acetylcholine
receptor, GABAA receptor
Structure Oligomeric assembly of
subunits surrounding
central pore

Binding of agonist to Opens the ion channels Flow of ions

inotropic receptors (Na+, K+, Ca2+, Cl–) through channels

Tissue Hyperpolarization/
response Depolarization

The onset of action of a drug is fastest through this receptor.

 Pentameric channels Tetrameric channels Trimeric channels

Acetylcholine Serotonin GABA Glycine Glutamate ATP

Na+,K+ Na+ Cl– Cl– Ca2+ Na+,K+ Na+,K+ Na+,K+, Ca2+

Nicotinic ACh 5-HT3 GABAA Gly NMDA AMPA Kainate P2x

GluN1–3 GluA1–4 GluK1–5 P2x1–7

FIGURE 2.8.4 Ligand-gated ion channels. These channels reside in the plasma membrane and respond to specific ligands by allowing specific ions to
cross the membrane. The channels are classified according to their structure and agonist or chemical signal that opens the channel. The names of the
channels are at the bottom of the figure, and alternate naming conventions have been proposed. Each family of channels has multiple isoforms that
depend on the subunit make-up of the channels.
 G Proteins = guanine-nucleotide binding Intracellular signalling proteins

The human genome encodes nearly 200 of G proteins, which differ in size and subunit structure, intra-cellular location,
and function. But all G proteins share a common feature: they can become activated and then, after a brief period, can
inactivate themselves, thereby serving as molecular binary switches with built-in timers.

G proteins turn : ON when bound with GTP, OFF when bound with GDP

GTP + H2O → GDP + Pi (GTP Hydrolysis)

SIGNAL OFF
IN
GDP P

GTP
GDP GTP
hydrolysis
binding
GTP

ON

GTP

SIGNAL
OUT

* 2 Types of G Proteins
(a) Heterotrimeric G Proteins = consists of 3 units a,b,g;
a unit connected by noncovalent bond to b,g which are always
connected together.
Tethered to plasma membrane by lipid anchors, so can only move
along the membrane.
Have intrinsic GTPase activity
There are four major families of G Proteins distinguished by their
different asub-units.

Gas, Gai, Gaq and Ga12/13 s=simulation, i=inhibition

Role of Hetrotrimeric G Proteins : Simulate or inhibit membrane bound enzymes : Adenylyl Cyclase and Phospholipase C
which lead to production of secondary messangers. Regulate secondary messangers.

Spare receptors : GTP bound a unit remains active for tens of seconds enormously amplifying the original signal
which explains the phenomena of spare receptors.

b) Ras superfamily G proteins : Monomers; resemble asubunit; also known as small G proteins; Dont have
intrinsic enzyme activity.
Use : Catelytic receptor
INACTIVE
MONOMERIC GTPase

OFF

GDP GDP P

GEF GAP Figure 16–12 The activity of monomeric

GTP GTPases is controlled by two types of
regulatory proteins. Guanine nucleotide
ON exchange factors (GEFs) promote the
GTP
exchange of GDP for GTP, thereby switching
the protein on. GTPase-activating proteins
(GAPs) stimulate the hydrolysis of GTP to
ACTIVE
MONOMERIC GTPase GDP, thereby switching the protein off.
What happens if GTP is not hydrolyzed?
If a G-protein could not hydrolyze GTP, then it would not be able to deactivate. This failure to deactivate would
result in a constantly active subunit. One example of such a process happening is in the activation of Ras, which,
when constantly active, causes large amounts of MAPK signaling and resultant cancer.

G Protein Coupled Receptor (GPCR)= 7 Transmembrane or Serpentine Receptor:

* are transmembrane proteins with seven membrane spanning regions with extracellular harmon
binding region and extracellular region for interacting with G proteins

The human genome encodes about 350 GPCRs for detecting hormones, growth factors, and other endogenous
ligands, and perhaps 500 that serve as olfactory (smell) and gustatory (taste) receptors.

* Largest family of cell surface receptors

GPCRs have been implicated in many common human diseases, including allergies, depression, blindness,
diabetes, and various cardiovascular defects with serious health consequences. Close to half of all drugs on the
market target one GPCR or another.
Figure 16–15 An activated GPCR (A) plasma membrane
activates G proteins by encouraging EXTRACELLULAR SPACE
the α subunit to expel its GDP and pick
up GTP. (A) In the unstimulated state,
the receptor and the G protein are both
inactive. Although they are shown here as CYTOSOL
separate entities in the plasma membrane, ˜
inactive receptor protein °
in some cases they are associated in a
preformed complex. (B) Binding of an GDP ˛
extracellular signal molecule to the receptor
changes the conformation of the receptor,
which in turn alters the conformation of signal molecule inactive G protein
the bound G protein. The alteration of
the α subunit of the G protein allows it to (B)
activated receptor
exchange its GDP for GTP. This exchange
triggers an additional conformational
change that activates both the α subunit
and a βγ complex, which dissociate to
interact with their preferred target proteins
in the plasma membrane (Movie 16.2). The
receptor stays active as long as the external
signal molecule is bound to it, and it can
therefore activate many molecules of G
protein. Note that both the α and γ subunits
of the G protein have covalently attached
lipid molecules (red ) that help anchor the GDP dissociation
subunits to the plasma membrane.
GTP

target protein
plasma membrane EXTRACELLULAR
SPACE

CYTOSOL GTP
activated
GTP ˜ subunit activated
activated
˜° complex °˛ complex
activated
˛ subunit
EFFECTOR ACTIVATION
ACTIVATION OF A TARGET
PROTEIN BY THE ACTIVATED
˛ SUBUNIT
Figure 16–16 The G protein α subunit
switches itself off by hydrolyzing its
bound GTP to GDP. W When an activated
α subunit interacts with its target protein,
GTP it activates that target protein for as long
as the two remain in contact. (In some
cases, the α subunit instead inactivates
HYDROLYSIS OF GTP BY THE ˛ SUBUNIT
its target; not shown.) The α subunit then
P INACTIVATES THIS SUBUNIT AND CAUSES IT hydrolyzes its bound GTP to GDP—an event
TO DISSOCIATE FROM THE TARGET PROTEIN that takes place usually within seconds of
G-protein activation. The hydrolysis of GTP
inactivates the α subunit, which dissociates
from its target protein and—if the α subunit
had separated from the βγ complex (as
GDP shown)—reassociates with a βγ complex to
re-form an inactive G protein. The G protein
is now ready to couple to another activated
INACTIVE ˛ SUBUNIT REASSEMBLES WITH ˜° receptor, as in Figure 16−15B. Both the
COMPLEX TO RE-FORM AN INACTIVE G PROTEIN activated α subunit and the activated βγ
complex can interact with target proteins
in the plasma membrane. See also
Movie 16.2.

GDP

inactive G protein
inactive
target protein
TARGETS FOR G PROTEINS
The main targets for G proteins, through which GPCRs
control different aspects of cell function (see Table 3.3), are:
• adenylyl cyclase, the enzyme responsible for cAMP
formation;
• phospholipase C, the enzyme responsible for inositol
phosphate and diacylglycerol (DAG) formation;
• ion channels, particularly calcium and potassium
channels;
• Rho A/Rho kinase, a system that regulates the activity (membrane
of many signalling pathways controlling cell bound)
growth, proliferation and motility, smooth muscle
contraction, etc.;
• mitogen-activated protein kinase (MAP kinase), a system
that controls many cell functions, including cell
division and is also a target of several kinase-linked
receptors.

first messenger → receptor → G proteins → effector → protein kinases → target proteins.

Many G Proteins Activate Membrane-bound Enzymes

That Produce Small Messenger Molecules
Binding of Coupling of G protein GDP bound to α subunit
agonist to receptors to the receptors exchanges with GTP

Dissociation of G protein
subunits from occupied
receptor; α-GTP also
dissociates from βγ subunit

α-GTP and βγ subunits

are released

Stimulation of GTPase Bind to target enzyme/ion

associated with α subunit channel

GTP GDP Effects produced depends on the

type of G protein (Gs, Gi, Gq and
Go), which associates with agonist
α subunit associates with βγ subunit occupied receptor (see below)

Gs Gi Gq !"
! " ! !/"

Adenylyl cyclase Adenylyl cyclase Phospholipase C Enzymes and ion channels,

e.g. all GPCRs

↑cAMP, ↓cAMP, ↑IP3 and ↑DAG,

e.g. β-adrenergic e.g. α2-adrenergic e.g. muscarinic (M1)
receptors receptors in smooth muscle receptors
Gs = G stimulatory : Gi = Inhibitory; q, 12, 13 have no meaning

TABLE 42–3 Classes & Functions of Selected G-Proteinsa

Class or Type Stimulus Effector Effect

Gs
αs Glucagon, β-adrenergics ↑Adenylyl cyclase Glyconeogenesis, lipolysis, glycogenolysis

↑Cardiac Ca2+, Cl–, and Na+ channels Olfaction

αolf Odorant ↑Adenylyl cyclase

Gi
αi-1,2,3 Acetylcholine, α2-adrenergics ↓Adenylyl cyclase Slowed heart rate

↑Potassium channels
M2 cholinergics ↓Calcium channels
αo Opioids, endorphins ↑Potassium channels Neuronal electrical activity

αt Light ↑Cgmp phosphodiesterase Vision

Gq
αq M1 cholinergics
α1-Adrenergics ↑Phospholipase C-β1 ↓Muscle contraction
α11 α 1-Adrenergics ↑Phospholipase C-β2 ↓Blood pressure
G12
α12 Thrombin Rho Cell shape changes
Some G Proteins Directly Regulate Ion Channels
acetylcholine +
plasma membrane closed K channel

(A)

GTP activated
βγ complex
activated α subunit +
+
K CHANNEL open K channel
+
OPENING K
EXTRACELLULAR SPACE
(B)
CYTOSOL

GTP

Figure 16–17 A Gi protein directly

G-PROTEIN couples receptor activation to the
P INACTIVATION; opening of K+ channels in the plasma
+
K CHANNEL +
membrane of heart pacemaker cells.
CLOSING closed K channel (A) Binding of the neurotransmitter
acetylcholine to its GPCR on the heart cells
results in the activation of the G protein, Gi.
(C) (B) The activated βγ complex directly opens
a K+ channel in the plasma membrane,
increasing its permeability to K+ and thereby
inactive making the membrane harder to activate
G protein GDP and slowing the heart rate. (C) Inactivation
of the α subunit by hydrolysis of its bound
GTP returns the G protein to its inactive
state, allowing the K+ channel to close.

The adenylyl cyclase/cAMP system
cAMP is a nucleotide synthesised within the cell from
ATP by the action of a membrane-bound enzyme, adenylyl
cyclase. It is produced continuously and inactivated by
hydrolysis to 5′-AMP by the action of a family of enzymes
known as phosphodiesterases (PDEs). Many different drugs,
hormones and neurotransmitters act on GPCRs and increase
or decrease the catalytic activity of adenylyl cyclase (see
Fig. 3.10), thus raising or lowering the concentration of
cAMP within the cell.
Cyclic AMP regulates many aspects of cellular function
including, for example, enzymes involved in energy
metabolism, cell division and cell differentiation, ion
transport, ion channels and the contractile proteins in smooth
muscle. These varied effects are, however, all brought about
by a common mechanism, namely the activation of protein
kinases by cAMP (known as cyclic AMP-dependent protein
kinases) in eukaryotic cells. One important cyclic AMP-
dependent protein kinase is protein kinase A (PKA). Protein
kinases regulate the function of many different cellular
proteins by controlling protein phosphorylation. Fig. 3.11
shows how increased cAMP production in response to
β-adrenoceptor activation affects enzymes involved in
glycogen and fat metabolism in liver, fat and muscle cells.
The result is a coordinated response in which stored energy
in the form of glycogen and fat is made available as glucose
to fuel muscle contraction.
1 Epinephrine
binds to its
specific b-adrenergic
receptor. receptor
N Outside

Adenylyl
cyclase

C Inside

GDP GTP GTP ATP

Gsb
Gsa Gsa
Gsg
GDP

2 Hormone-receptor 3 Activated Gsa 4 Adenylyl 5 cAMP 6 Phosphorylation

complex causes separates from cyclase activates of cellular
the GDP bound to Gsbg, moves to catalyzes the cAMP PKA. proteins by PKA
Gsa to be replaced adenylyl cyclase, formation causes the
by GTP, activating and activates it. of cAMP. cellular response
Gsa. Many Gsa cyclic nucleotide to epinephrine.
subunits may be phosphodiesterase
activated by one
occupied receptor.
5-AMP 7 cAMP is degraded,
reversing the
PKA = cyclic-AMP-dependent protein kinase (PKA). activation of PKA.

activated Figure 15–27 How a rise in intracellular

adenylyl cyclase cyclic AMP concentration can alter
signal molecule activated α
gene transcription. The binding of an
subunit of extracellular signal molecule to its GPCR
stimulatory G plasma activates adenylyl cyclase via Gs and
protein (Gs) membrane thereby increases cAMP concentration in
the cytosol. This rise activates PKA, and
the released catalytic subunits of PKA
CYTOSOL can then enter the nucleus, where they
phosphorylate the transcription regulatory
GTP
protein CREB. Once phosphorylated,
activated GPCR CREB recruits the coactivator CBP, which
stimulates gene transcription. In some
ATP cases, at least, the inactive CREB protein is
bound to the cyclic AMP response element
cyclic AMP (CRE) in DNA before it is phosphorylated
(not shown). See Movie 15.2.

inactive PKA
activated
PKA

CYTOSOL

NUCLEUS

nuclear pore
activated PKA

activated, phosphorylated CREB

inactive CREB
CREB-binding P
protein (CBP) activated target gene

cyclic AMP response

element (CRE) GENE TRANSCRIPTION
 Cyclic-AMP-Dependent Protein Kinase (PKA) Mediates Most of
the Effects of Cyclic AMP
In most animal cells, cAMP exerts its effects mainly by activating cyclic-AMP-
dependent protein kinase (PKA). This kinase phosphorylates specific serines or
threonines on selected target proteins, including intracellular signaling proteins
and effector proteins, thereby regulating their activity. The target proteins differ
from one cell type to another, which explains why the effects of cAMP vary so
markedly depending on the cell type (see Table 15–1).

TAble 15–1 Some Hormone-induced Cell Responses Mediated by Cyclic AMP

Target tissue hormone Major response
Thyroid gland Thyroid-stimulating hormone (TSH) Thyroid hormone synthesis
and secretion
Adrenal cortex Adrenocorticotrophic hormone Cortisol secretion
(ACTH)
Ovary Luteinizing hormone (LH) Progesterone secretion
Muscle Adrenaline Glycogen breakdown
Bone Parathormone Bone resorption
Heart Adrenaline Increase in heart rate and
force of contraction
Liver Glucagon Glycogen breakdown
Kidney Vasopressin Water resorption
Fat Adrenaline, ACTH, glucagon, TSH Triglyceride breakdown

The effect of this phosphorylation on cell function depends

on the identity of the cell and the proteins that are phosphorylated.
In muscle cells, for example, PKA activates an enzyme necessary
to break down glycogen and inhibits another enzyme necessary to
synthesize glycogen. This leads to an increase in glucose available
to the muscle. By contrast, in the kidney the action of PKA leads
to the production of water channels that can increase the permea-
bility of tubule cells to water.
Disruption of cAMP signaling can have a variety of effects.
The symptoms of the disease cholera are due to altered cAMP
levels in cells in the gut. The bacterium Vibrio cholerae produces
a toxin that binds to a GPCR in the epithelium of the gut, causing
it to be locked into an “on” state. This causes a large increase in
intracellular cAMP that, in these cells, causes Cl– ions to be trans-
ported out of the cell. Water follows the Cl–, leading to diarrhea
and dehydration characteristic of the disease.
 The Inositol Phospholipid Pathway Triggers a Rise in Intracellular Ca2+

signal molecule inositol Figure 16–23 Phospholipase C activates

phospholipid plasma two signaling pathways. Two messenger
activated GPCR activated membrane
phospholipase C diacylglycerol molecules are produced when a membrane
inositol phospholipid is hydrolyzed by
activated phospholipase C. Inositol
1,4,5-trisphosphate (IP3) diffuses through
P the cytosol and triggers the release of Ca2+
P
GTP
from the ER by binding to and opening
P activated
special Ca2+ channels in the ER membrane.
P PKC The large electrochemical gradient for
P
Ca2+ across this membrane causes Ca2+
activated G protein (Gq) inositol to rush out of the ER and into the cytosol.
1,4,5-trisphosphate Ca 2+
P Diacylglycerol remains in the plasma
(IP3) open Ca2+ membrane and, together with Ca2+, helps
channel
activate the enzyme protein kinase C (PKC),
CYTOSOL which is recruited from the cytosol to the
endoplasmic cytosolic face of the plasma membrane
reticulum (Movie 16.4). PKC then phosphorylates
ER LUMEN its own set of intracellular proteins, further
propagating the signal. At the start of the
pathway, both the α subunit and the βγ
complex of the G protein Gq are involved in
activating phospholipase C.

Phospholipase C/inositol phosphate system

Activation of M1, M3, 5-HT2, peptide and a1-adreno-
receptors, via Gq, cause activation of phospholipase
C, a membrane-bound enzyme, which increases the
rate of degradation of phosphatidylinositol (4,5)
bisphosphate into diacylglycerol (DAG) and inositol
(1,4,5) triphosphate (IP3). DAG and IP3 act as second
messengers. IP3 binds to the membrane of the endo-
plasmic reticulum, opening calcium channels and in-
creasing the concentration of calcium within the cell.
Increased calcium levels may result in smooth muscle
contraction, increased secretion from exocrine glands,
increased hormone or transmitter release, or increased
force and rate of contraction of the heart. DAG, which
remains associated with the membrane owing to its
hydrophobicity, causes protein kinase C to move
from the cytosol to the membrane where DAG can
regulate the activity of the latter. There are at least
six types of protein kinase C, with over 50 targets
including:

• Release of hormones and neurotransmitters

• Smooth muscle contraction
• Inflammation
• Ion transport
• Tumour promotion.

Guanylyl cyclase system The cGMP pathway

cGMP is also a second messenger. It is produced from guanosine triphosphate (GTP) by guanylate
cyclase and degraded to GMP by a phosphodiesterase. Guanylate cyclases are activated by nitric oxide and
peptide signaling molecules.
The best characterized role of cGMP is in photo-receptor rod cells of the retina, where it converts light
signals to nerve impulses.

The cGMP also goes on to cause activation of protein kinase G which in turn phosphorylates contractile
proteins and ion channels.
Effectors controlled by G proteins
Two key second messenger pathways are controlled by
receptors via G proteins:
• Adenylyl cyclase/cAMP:
– can be activated or inhibited by pharmacological ligands,
depending on the nature of the receptor and G protein;
– adenylyl cyclase catalyses formation of the intracellular
messenger cAMP;
– cAMP activates protein kinases such as protein kinase
A (PKA) that control cell function in many different
ways by causing phosphorylation of various enzymes,
carriers and other proteins.
• Phospholipase C/inositol trisphosphate (IP3)/diacylglycerol
(DAG):
– catalyses the formation of two intracellular
messengers, IP3 and DAG, from membrane
phospholipid;
– IP3 acts to increase free cytosolic Ca2+ by releasing
Ca2+ from intracellular compartments
– increased free Ca2+ initiates many events, including
contraction, secretion, enzyme activation and
membrane hyperpolarisation;
– DAG activates various protein kinase C (PKC)
isoforms, which control many cellular functions by
phosphorylating a variety of proteins.
Receptor-linked G proteins also control:
• Ion channels:
– opening potassium channels, resulting in membrane
hyperpolarisation;
– inhibiting calcium channels, thus reducing
neurotransmitter release.
• Phospholipase A2 (and thus the formation of arachidonic
acid and eicosanoids).
The main postulated roles of GPCRs in controlling
enzymes and ion channels are summarised in Fig. 3.14.

Receptors G proteins

Target Guanylyl Adenylyl

enzymes Phospholipase C
cyclase cyclase

Second
cGMP cAMP IP3 DAG AA
messengers

↑[Ca2+]i Eicosanoids

Protein
PKG PKA PKC Released
kinases
as local
hormones

Enzymes, Contractile Ion

Effectors
transport proteins, etc. proteins channels
Guanylyl cyclase system
Fig. 3.14 G protein and second messenger control of cellular effector systems. Not shown in this diagram are signalling pathways
where arrestins, rather than G proteins, link G protein–coupled receptors to downstream events (see text and Fig. 3.15). AA, arachidonic
acid; DAG, diacylglycerol; IP3, inositol trisphosphate.

What does phospholipase A2 do?

Phospholipase A2 (PLA2) catalyzes the hydrolysis of membrane glycerophospholipids to liberate arachidonic acid (AA), a
precursor of eicosanoids. Eicosanoids are lipid-based signaling molecules that play a unique role in innate immune
responses. The multiple types of eicosanoids, such as prostaglandins (PGs) and leukotrienes (LTs), allow the innate immune
cells to respond rapidly to bacterial invaders.