Ligands & receptors

Types of signaling molecules and the receptors they bind to on target cells.
Intracellular receptors, ligand-gated ion channels, G protein-coupled
receptors, and receptor tyrosine kinases.

Introduction
Just as a journey of a thousand miles begins with a single
step, so a complex signaling pathway inside of a cell begins
with a single key event – the binding of a signaling molecule,
or ligand, to its receiving molecule, or receptor.

Receptors and ligands come in many forms, but they all have
one thing in common: they come in closely matched pairs,
with a receptor recognizing just one (or a few) specific
ligands, and a ligand binding to just one (or a few) target
receptors. Binding of a ligand to a receptor changes its shape
or activity, allowing it to transmit a signal or directly produce
a change inside of the cell

Stages of signal transduction: ligand-receptor binding, signal relay,

response.

This article focuses on the first stage (signal reception).

In this section, we’ll look at different types of receptors and
ligands, seeing how they interact to turn information from
outside the cell into a change inside the cell.

Types of receptors
Receptors come in many types, but they can be divided into
two categories: intracellular receptors, which are found inside
of the cell (in the cytoplasm or nucleus), and cell surface
receptors, which are found in the plasma membrane.

Intracellular receptors
Intracellular receptors are receptor proteins found on the
inside of the cell, typically in the cytoplasm or nucleus. In
most cases, the ligands of intracellular receptors are small,
hydrophobic (water-hating) molecules, since they must be
able to cross the plasma membrane in order to reach their
receptors. For example, the primary receptors for
hydrophobic steroid hormones, such as the sex hormones
estradiol (an estrogen) and testosterone, are intracellular.

When a hormone enters a cell and binds to its receptor, it

causes the receptor to change shape, allowing the receptor-
hormone complex to enter the nucleus (if it wasn’t there
already) and regulate gene activity. Hormone binding
exposes regions of the receptor that have DNA-binding
activity, meaning they can attach to specific sequences of
DNA. These sequences are found next to certain genes in the
DNA of the cell, and when the receptor binds next to these
genes, it alters their level of transcription.
[What's transcription?]
Diagram of a signaling pathway involving an intracellular receptor. The
ligand crosses the plasma membrane and binds to the receptor in the
cytoplasm. The receptor then moves to the nucleus, where it binds
DNA to regulate transcription.
Image credit: "Signaling molecules and cell receptors: Figure 3," by OpenStax College,
Biology (CC BY 3.0).

Many signaling pathways, involving both intracellular and cell

surface receptors, cause changes in the transcription of
genes. However, intracellular receptors are unique because
they cause these changes very directly, binding to the DNA
and altering transcription themselves.

Cell-surface receptors
Cell-surface receptors are membrane-anchored proteins
that bind to ligands on the outside surface of the cell. In this
type of signaling, the ligand does not need to cross the
plasma membrane. So, many different kinds of molecules
(including large, hydrophilic or "water-loving" ones) may act
as ligands.

A typical cell-surface receptor has three different domains,

or protein regions: a extracellular ("outside of cell") ligand-
binding domain, a hydrophobic domain extending through
the membrane, and an intracellular ("inside of cell") domain,
which often transmits a signal. The size and structure of
these regions can vary a lot depending on the type of
receptor, and the hydrophobic region may consist of multiple
stretches of amino acids that criss-cross the membrane.

This diagram shows a G protein-coupled receptor (GPCR), a

type of receptor we'll examine in more detail later in the
article. GPCRs have seven membrane-spanning domains, as
shown by the seven segments crossing the gray region that
represents the plasma membrane.

GPCR with seven transmembrane domains. N-terminus is outside the

cell and C-terminus is inside.
Image modified from "GPCR," by Retama, CC BY-SA 3.0. The modified image is licensed
under a CC BY-SA 3.0 license

There are many kinds of cell-surface receptors, but here we’ll

look at three common types: ligand-gated ion channels, G
protein-coupled receptors, and receptor tyrosine kinases.

Ligand-gated ion channels

Ligand-gated ion channels are ion channels that can open
in response to the binding of a ligand. To form a channel, this
type of cell-surface receptor has a membrane-spanning
region with a hydrophilic (water-loving) channel through the
middle of it. The channel lets ions to cross the membrane
without having to touch the hydrophobic core of
the phospholipid bilayer.

When a ligand binds to the extracellular region of the

channel, the protein’s structure changes in such a way that
ions of a particular type, such as Ca2+ or Cl−, can pass
through. In some cases, the reverse is actually true: the
channel is usually open, and ligand binding causes it to close.
Changes in ion levels inside the cell can change the activity
of other molecules, such as ion-binding enzymes and voltage-
sensitive channels, to produce a response. Neurons, or nerve
cells, have ligand-gated channels that are bound by
neurotransmitters.
 Diagram of a ligand-gated ion channel. When the ligand binds to a
closed ion channel in the plasma membrane, the ion channel opens
and ions can pass through it, moving into or out of the cell (down their
concentration gradient).
Image modified from "Signaling molecules and cell receptors: Figure 4," by OpenStax
College, Biology (CC BY 3.0).

G protein-coupled receptors
G protein-coupled receptors (GPCRs) are a large family of
cell surface receptors that share a common structure and
method of signaling. The members of the GPCR family all
have seven different protein segments that cross the
membrane, and they transmit signals inside the cell through
a type of protein called a G protein (more details below).

GPCRs are diverse and bind many different types of ligands.

One particularly interesting class of GPCRs is the odorant
(scent) receptors. There are about 800800800 of them in
humans, and each binds its own “scent molecule” – such as a
particular chemical in perfume, or a certain compound
released by rotting fish – and causes a signal to be sent to
the brain, making us smell a smell!

When its ligand is not present, a G protein-coupled receptor

waits at the plasma membrane in an inactive state. For at
least some types of GPCRs, the inactive receptor is already
docked to its signaling target, a G protein.

G proteins come in different types, but they all bind the

nucleotide guanosine triphosphate (GTP), which they can
break down (hydrolyze) to form GDP. A G protein attached to
GTP is active, or “on,” while a G protein that’s bound to GDP
is inactive, or “off.” The G proteins that associate with GPCRs
are a type made up of three subunits, known
as heterotrimeric G proteins. When they’re attached to an
inactive receptor, they’re in the “off” form (bound to GDP).

Diagram of the cycle of GPCR signaling.

1. When a signaling molecule binds to the GPCR, the G protein alpha

subunit exchanges GDP for GTP.
 2. The alpha subunit dissociates from the beta and gamma subunits
and interacts with other molecules, ultimately triggering a cellular
response. (The beta and gamma subunits may, in some cases,
also participate in signaling.)

3. GTP is hydrolyzed to GDP, and the signaling molecule comes off

of the receptor.

4. The alpha subunit comes back together with the receptor and the
beta and gamma subunits.

The cycle can then repeat when a new ligand-binding event takes
place.
Image modified from "Signaling molecules and cell receptors: Figure 5," by OpenStax
College, Biology (CC BY 3.0).

Ligand binding, however, changes the picture: the GPCR is

activated and causes the G protein to exchange GDP for GTP.
The now-active G protein separates into two pieces (one
called the α subunit, the other consisting of the β and γ
subunits), which are freed from the GPCR. The subunits can
interact with other proteins, triggering a signaling pathway
that leads to a response.

Eventually, the α subunit will hydrolyze GTP back to GDP, at

which point the G protein becomes inactive. The inactive G
protein reassembles as a three-piece unit associated with a
GPCR. Cell signaling using G protein-coupled receptors is a
cycle, one that can repeat over and over in response to
ligand binding.

G protein-coupled receptors play many different roles in the

human body, and disruption of GPCR signaling can cause
disease.
[GPCR signaling and cholera]

Receptor tyrosine kinases

Enzyme-linked receptors are cell-surface receptors with
intracellular domains that are associated with an enzyme. In
some cases, the intracellular domain of the receptor
actually is an enzyme that can catalyze a reaction. Other
enzyme-linked receptors have an intracellular domain that
interacts with an enzyme.

Receptor tyrosine kinases (RTKs) are a class of enzyme-

linked receptors found in humans and many other species.
A kinase is just a name for an enzyme that transfers
phosphate groups to a protein or other target, and a receptor
tyrosine kinase transfers phosphate groups specifically to the
amino acid tyrosine.

How does RTK signaling work? In a typical example, signaling

molecules first bind to the extracellular domains of two
nearby receptor tyrosine kinases. The two neighboring
receptors then come together, or dimerize. The receptors
then attach phosphates to tyrosines in each others'
intracellular domains. The phosphorylated tyrosine can
transmit the signal to other molecules in the cell.
 Diagram of receptor tyrosine kinases, showing ligand binding and
receptor autophosphorylation.

When signaling molecules bind to two nearby receptors, the receptors

dimerize (pair up).
The paired receptors phosphorylate one another on tyrosine residues in
the intracellular domain (the portion of the protein inside of the cell.

The phosphorylated receptors can interact with other proteins in the

cell to trigger signaling pathways leading to a response.
Image modified from "Signaling molecules and cell receptors: Figure 7," by OpenStax
College, Biology (CC BY 3.0).

In many cases, the phosphorylated receptors serve as a

docking platform for other proteins that contain special types
of binding domains. A variety of proteins contain these
domains, and when one of these proteins binds, it can initiate
a downstream signaling cascade that leads to a cellular
response.

Receptor tyrosine kinases are crucial to many signaling

processes in humans. For instance, they bind to growth
factors, signaling molecules that promote cell division and
survival. Growth factors include platelet-derived growth
factor (PDGF), which participates in wound healing, and nerve
growth factor (NGF), which must be continually supplied to
certain types of neurons to keep them alive^88start
superscript, 8, end superscript. Because of their role in
growth factor signaling, receptor tyrosine kinases are
essential in the body, but their activity must be kept in
balance: overactive growth factor receptors are associated
with some types of cancers.

Types of ligands
Ligands, which are produced by signaling cells and interact
with receptors in or on target cells, come in many different
varieties. Some are proteins, others are hydrophobic
molecules like steroids, and others yet are gases like nitric
oxide. Here, we’ll look at some examples of different types of
ligands.
Ligands that can enter the cell
Small, hydrophobic ligands can pass through the plasma
membrane and bind to intracellular receptors in the nucleus
or cytoplasm. In the human body, some of the most
important ligands of this type are the steroid hormones.

Familiar steroid hormones include the female sex hormone

estradiol, which is a type of estrogen, and the male sex
hormone testosterone. Vitamin D, a molecule synthesized in
the skin using energy from light, is another example of a
steroid hormone. Because they are hydrophobic, these
hormones don’t have trouble crossing the plasma membrane,
but they must bind to carrier proteins in order to travel
through the (watery) bloodstream.

Chemical structures of estradiol and testosterone. Both have four fused

hydrocarbon rings. The two hormones differ in the double bond
patterns of the rings and in the functional groups attached to them.
Image modified from "Signaling molecules and cell receptors: Figure 8," by OpenStax
College, Biology (CC BY 3.0).

Nitric oxide (NO) is a gas that acts as a ligand. Like steroid

hormones, it can diffuse directly across the plasma
membrane thanks to its small size. One of its key roles is to
activate a signaling pathway in the smooth muscle
surrounding blood vessels, one that makes the muscle relax
and allows the blood vessels to expand (dilate). In fact, the
drug nitroglycerin treats heart disease by triggering the
release of NO, dilating vessels to restore blood flow to the
heart.

NO has become better-known recently because the pathway

that it affects is targeted by prescription medications for
erectile dysfunction, such as Viagra.

Ligands that bind on the outside of the

cell
Water-soluble ligands are polar or charged and cannot readily
cross the plasma membrane. So, most water-soluble ligands
bind to the extracellular domains of cell-surface receptors,
staying on the outer surface of the cell.

Peptide (protein) ligands make up the largest and most

diverse class of water-soluble ligands. For instance, growth
factors, hormones such as insulin, and certain
neurotransmitters fall into this category. Peptide ligands can
range from just a few amino acids long, as in the pain-
suppressing enkephalins, to a hundred or more amino acids
in length.

Enkephalin: a short peptide ligand of sequence Tyr-Gly-Gly-Phe-Met.

As mentioned above, some neurotransmitters are proteins.

Many other neurotransmitters, however, are small,
hydrophilic (water-loving) organic molecules. Some
neurotransmitters are standard amino acids, such as
glutamate and glycine, and others are modified or non-
standard amino acids.