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Types of Signal Molecules
∗
Steven Telleen
This work is produced by OpenStax-CNX and licensed under the
Creative Commons Attribution License 4.0†
Abstract
This module provides an overview of the major classes of signaling molecules based on their polarity
and chemical structure. It contains content from: Signaling Molecules and Cellular Receptors (m44451)
Ligands produced by signaling cells that subsequently bind to receptors in target cells act as chemical
signals. These chemical signals travel to the target cells to coordinate responses. The types of ligands
that serve as signal molecules are incredibly varied and range from small proteins to small ions like calcium
(Ca2+ ).
Signal molecules fall into a variety of dierent chemical classes. In general, all the signaling molecules
in a given chemical class have similar characteristics in terms of polarity and receptor location (intracellular
versus extracellular); however there are a few notable exceptions. For example, thyroid hormone belongs to
the class of signal molecules known as bioamines. This class of molecule normally is hydrophilic attaching
to cell-surface receptors; however thyroid hormone is an exception and is hydrophobic with intracellular
receptors. An exception to the general receptor location rule has been found with several steroid molecules.
Steroid receptors have long been identied as intracellular. However, recently a class of cell surface receptors
for steroid molecules like estrogen has been identied and described.
Since the vast majority of signal molecules in a chemical class do have the same polarity, this section will
begin by discussing the signal molecule chemical classes based on their polarity.
1 Hydrophilic Signaling Molecules
Water-soluble signal molecules are polar and therefore cannot pass through the non-polar center of the
plasma membrane unaided. Sometimes, they are too large to pass through the membrane at all. Instead,
most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of signal
molecules is quite diverse and most are based on amino acids. In some cases the unmodied amino acid is
the signal molecule, in others the amino acid is modied into a derivative, and in still others amino acids
are combined into peptides and proteins (Figure 1). Some additional small, polar, signal molecules also are
hydrophilic.
∗ Version
1.2: Apr 6, 2015 6:41 pm -0500
† http://creativecommons.org/licenses/by/4.0/
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Figure 1: The majority of hydrophilic signal molecules are based on amino acids. They may be
unmodied amino acids, modied amino acids, or strings of amino acids (peptides or proteins).
1.1 Amino Acids
There are four amino acids that function as signal molecules. They are:
•
•
•
•
Glutamate (made from glucose)
Aspartate (made from glucose)
Glycine (made from 3-phosphoglycerate)
GABA (gamma-Aminobutyric Acid made from glutamate)
All four are neurotransmitters that are synthesized and stored in vesicles by the neurons that release them.
Release is via exocytosis.
1.2 Biogenic Amines
All the members of this group are hydrophilic except thyroid hormone. The biogenic amine molecules all
contain an amine group and are derived by modifying an amino acid. This group can be further dierentiated
by the specic amino acid that is modied to make the signal molecules.
•
•
•
•
Catecholamines (derived from a single tyrosine molecule)
Thyroid Hormone (derived from two tyrosine molecules)
Histamine (derived from histadine)
Serotonin (derived from tryptophan)
All are synthesized in the cytosol of the cells that release them and are stored in vesicles. They are released
through exocytosis. The biogenic amines a cell is able to produce is determined by the specic enzymes that
are active in the synthesizing cell.
1.2.1 Catecholamines
Catecholamines
are derived from a single tyrosine molecule. The best known examples of this group are:
• Dopamine
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• Norepinephrine (Noradrenalin)
• Epinephrine (Adrenalin)
All three are neurotransmitters. Norepinephrine is the primary neurotransmitter of the postsynaptic neurons
in the sympathetic nervous system. Epinephrine is best known as the sympathetic system hormone adrenalin,
and while dopamine also is released with epinephrine from the adrenal medulla, it is better known for its
functions as an inhibitor of antagonist muscle action when released from substantia nigra neurons and as
the reward or pleasure neurotransmitter when released from VTA neurons.
1.2.2 Thyroid Hormone
Thyroid Hormone is derived from two tyrosine molecules. Thyroid hormone molecules dier from others
in the class by being hydrophobic rather than hydrophilic, and like most other hydrophobic signals its mode
of action is intracellular. Even though thyroid hormone is hydrophobic and has intracellular receptors the
molecules do not passively diuse across the plasma membrane but must be actively transported across to
reach their receptors. Thyroid hormone can act on almost all cells in the body and is involved in setting the
metabolic rate and in cell growth and division.
1.2.3 Histamine
Histamine is derived from the amino acid histadine. It is best know for its paracrine signaling function in
the immune response which causes inammation and the symptoms of many allergies. However, it also is an
important signal molecule involved in both GI signaling and as a neurotransmitter. In the GI tract histamine
acts as an enteroendocrine hormone that stimulates the release of gastric acid. As a neurotransmitter
histamine release from the hypothalamus increases wakefulness and prevents sleep. It also has been implicated
in a number of other neural functions including schizophrenia and proper libido and erectile function in males.
1.2.4 Seratonin
is derived from the amino acid tryptophan. It is found in the GI tract, blood platelets, and the
central nervous system. Serotonin is involved in a variety of important functions. In the GI tract and blood
platelets the general function is to cause smooth muscle contraction. However, the most publicized function
of serotonin is its association with general mood and mood disorders in the central nervous system.
The connection of serotonin to feelings of well being, or lack of well being (like depression and anxiety),
has led to the marketing of a number of psycopharmaceutical drugs designed to increase serotonin levels
in the brain. The most well known are the Selective Serotonin Reuptake Inhibitors (SSRIs) that block the
reuptake channels in the presynaptic cells thereby increasing the time and concentration of serotonin in the
synapse. This pathway is the one targeted by the most common antidepressant drugs like Prozac and Zoloft.
Serotonin
1.3 Peptides and Proteins
The majority of signal molecules are peptides and small proteins. Both are made of a chain of amino acids,
the dierence being the number of amino acids that make up the molecule. Generally, if the signal molecules
has fewer than 50 amino acids it is considered a peptide. If it has more it is considered a protein. All interact
with extracellular cell-membrane receptor proteins.
The peptides and proteins are synthesized as inactive larger molecules called prepropeptides in the rough
ER of the cell that releases them. A portion of this molecule is cleaved o by an enzyme leaving a still
inactive propeptide that is released in a transport vesicle and may undergo additional processing in the Golgi
apparatus. The nal version of the propeptide is stored in a vesicle and activated when another enzyme
cleaves additional amino acids from the molecule before it is released by exocytosis. Like the previously
discussed hydrophilic signal molecules, peptide and protein signal molecules are synthesized by the cell that
releases them and the specic signal molecule synthesized depends on the enzymes and transcription factors
that are active in the synthesizing cell.
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2 Small Hydrophobic Signaling Molecules
Small hydrophobic ligands can directly diuse through the plasma membrane and interact with internal
receptors. Two important members of this class of ligands are the steroid hormones and eicosanoids. Other
hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic
ligands must bind to hydrophilic carrier proteins while they are being transported through the bloodstream.
2.1 Steroids
are lipids that have a hydrocarbon skeleton with four fused rings; dierent steroids have dierent
functional groups attached to the carbon skeleton. Cholesterol is the precursor of steroid hormones and an
important structural component of biological membranes (Figure 2). Steroid hormones include the female sex
hormone, estradiol, which is a type of estrogen; the male sex hormone, testosterone; and the stress hormone,
cortisol, released by cells in the adrenal cortex. They are not stored, but are synthesized on demand from
cholesterol in the plasma membrane.
Steroids
Figure 2: Steroid hormones all retain the central four-carbon ring of their precursor, cholesterol but have
dierent modications to the functional groups. Because these molecules are small and hydrophobic, they
can diuse directly across the plasma membrane into the cell, where they interact with internal receptors,
although some also bind to cell-surface receptors.
2.2 Eicosanoids
also are synthesized on demand from a phospholipid called, arachidonic acid, that is found
in the plasma membrane. There are two major pathways that use the arachidonic acid as a precursor: the
cyclooxygenase pathway and the lipoxygenase pathway.
Eicosandoids
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Figure 3: Eicosanoids begin as the plasma membrane phospholipids and that are modied by two
dierent pathways. The cyclooxygenase pathway creates prostaglanins, prostacyclins, and thromboxanes.
The lipoxygenase pathway creates leukotrienes. (Modied from Jfdwol gure on Wikimedia Commons.)
Cyclooxygenase pathway: results in three classes of molecules depending on the specic enzymes
activated. these are prostaglandins, prostacyclins, and thromboxanes Prostaglandins can have hormonelike functions, but they are produced by many cells around the body rather than specic organs like most
other hormones. Their eects also can be dramatically dierent in dierent tissue types. Prostacyclins
act as paracrines and are synthesized by cells in blood vessel walls and are potent vasodilators. They also
inhibit platelet aggregation and act as an anti-clotting agent in healthy endothelium. Thromboxanes,
also paracrines, are rleased by platelets and have the reverse eect to prostacyclins. They are potent
vasoconstrictors and promote platelet aggregation. The cyclooxygenase pathway is often abbreviated as
COX, and an important class of analgesic and anti-inammatory drugs called COX-inhibitors target this
pathway. The COX pathway inhibitors also go by the name Non-Steroidal Anti-Inammatory drugs or
NSAIDs and include aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and a host of other drugs that
target dierent aspects of the pathway.
Lipoxygenase pathway: produces a class of signal molecules called leukotrienes, because they are
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produced by certain types of leukocytes (white blood cells). They function as paracrines and trigger inammation. They often are released with both histamines and prostaglandins, which also trigger inammation.
In addition, leukotrienes trigger contractions in the smooth muscle lining the bronchioles and therefore play
a signicant role in creating the symptoms of asthma. There are asthma drugs on the market that target
leukotrienes by either inhibiting the the lipoxygenase pathway or by blocking the leukotriene receptors.
3 Other Signaling Molecules
(Ca2+ ) control many diverse and critical cellular processes ranging from muscle contraction
to exocytosis to gene transcription to apoptosis. Many of the signaling activities are intracellular acting as
second messengers, although they also are one of the ions used for direct intercellular communication through
gap junctions. Numerous proteins in intracellular signal transduction pathways are modulated directly or
indirectly by calcium. Prominent examples include kinases and phosphatases, transcription factors, and
calmodulin. Because of their critical role, calcium levels must be tightly controlled both inside and outside
the cell.
Nitric oxide (NO) is a gas that also acts as a signaling molecule. It is able to diuse directly across the
plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation
of the tissue. NO has a very short half-life and therefore only functions over short distances. Nitroglycerin, a
treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand),
thus restoring blood ow to the heart. NO has become better known recently because the pathway that
it aects is targeted by prescription medications for erectile dysfunction, such as Viagra (erection involves
dilated blood vessels).
Non-coding RNA (ncRNA)molecules have been shown to have both intercellular signaling and catalytic
functions. They have additional capabilities not found in other types of signaling molecules in that they do
not just rely on the transduction pathways of the receiving cell, but can carry encoded information in the
signal. As such they can modify the splicing and translation of mRNA and they have been shown to play
roles in the regulation and structure of many cellular processes.
Calcium ions
4 Exogenous Signal Molecules
Signal molecules are not just generated by our cells. They naturally occur all around us and exogenous
signals regularly enter our bodies through our gastrointestinal and respiratory tracts. Because cells of all
species use many of the same signal molecules these molecules often induce a response in our body that can
aect both our physical function and our behavior. They can be benecial or deadly, but they all work by
activating or blocking existing receptors in our cells.
When the signal molecule is produced by our body we call it an endogenous signal. When the signal
molecule is produced by an external organism, or articially, we call it an exogenous signal. Many receptors
are named for the exogenous signals that were used to identify them, for example nicotinic (from tobacco),
muscarinic (from mushrooms), cannabinoid (from cannabis). They all have endogenous counterparts.
Exogenous signal molecules can be divided into the four major sources:
•
•
•
•
Bacterial
Multicellular tissue
Pheromones
Synthetic molecules
Bacteria (as well as parasites) produce and release a variety of signal molecules in the GI tract that can
be absorbed and cause both physical and behavior changes in the host. When the changes are benecial
we call the organism a probiotic. When they are detrimental they are dened as a disease or disorder.
Recognizing bacteria as an important source of benecial as well as detrimental signal molecules is fairly
recent and is undergoing intense focus from a number of angles. New eects both physical and behavioral
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continue to be identied and explored through research studies. While many may be benecial on the borders
of the body, if the bacteria (or parasite) manages to get into the interior of our body (blood and other body
uids) it will cause disease.
Multicellular tissue signals, depending on the type, can enter the body via several dierent pathways.
They can be ingested and absorbed through the intestines; they can be inhaled and absorbed in the lungs,
or they can be injected directly into the tissue or bloodstream. Many are actively pursued by the receiving
organism because of the signal's eect. For example caeine is purposefully consumed by people all over the
world. The same is true of nicotine, THC and CBD (in cannabis), psilocybin (in mushrooms), mescalin (in
cactus), opium (in poppies), and a host of other naturally produced substances. Other signal molecules from
multicellular tissue enter the body without conscious participation, for example the anticoagulant paracrines
in the saliva of mosquitoes and other blood feeding insects that cause the swelling and itching from their
bites.
Pheromones are signal molecules secreted or excreted into the environment with the express function of
aecting the behavior of other individuals of the same species. Pheromones often are involved in mediating
territorial and sexual behaviors. This form of social communication has been well studied in a variety of
animals from insects to mammals. For example, the urine of dogs contains pheromones that are used to
mark territory. By smelling the pheromones, other dogs can not only tell which dog or dogs have marked
the spot, but how long ago each dog was there, and even aspects of the physiological states of the dogs that
marked it. There is evidence that humans, like other mammals, also produce pheromones, especially from
apocrine glands around the nipples, in the groin area, and in the axillary regions. However, the complexity
of chemicals from these glands has made it dicult to isolate any specic molecule as a denite human
pheromone signal molecule.
Synthetic molecules are molecules that are not derived or copied directly from naturally produced signal molecules, but have bioactive signaling capabilities. Many of our synthetic materials, particularly plastics
and pesticides unintentionally have released molecules that mimic naturally occurring signal molecules. Many
can be shown to enter the body although not all the eects are easily seen. Some are known to mimic estrogen and have been blamed for both physical and behavioral changes in humans. Others have been explicitly
designed for psychotropic eects both medicinal and illegal.
5 Section Summary
are ligands that bind to receptor proteins and stimulate an action by the cell. They can
be divided into two categories based on the polarity of the molecule, hydrophilic and hydrophobic. In
general, hydrophilic signal molecules interact with receptors on the surface of the plasma membrane and
hydrophobic signal molecules interact with receptors inside the cell that regulate cellular transcription.
Hydrophilic signal molecules are generated by the cells that release them and are stored in vesicles until release. Most are either amino acids, biogenic amines (derivatives of amino acids), or peptides/proteins (strings of amino acids). Biogenic amines are classied by the amino acid from which
they are derived: catecholamines (single tyrosine), thyroid hormone (two tyrosines), histamine (histadine),
and serotonin (tryptophan). Some additional small, polar molecules not based on amino acids also act as
hydrophilic signal molecules.
Hydrophobic signal molecules also are generated by the cells that release them, but are generated on
demand from plasma membrane lipids rather than stored in vesicles. Steroids are derived from cholesterol
and include the sex hormones and the stress hormone cortisol. Eicosanoids are derived from the membrane
phospholipid, arachidonic acid. They fall into two classes depending on the initial enzyme used to modify the
arachidonic acid. The cyclooxygenase (COX) pathway gives rise to the prostaglandins, prostacyclins,
and thromboxanes. The lipoxygenase pathway gives rise to the leukotrienes.
There are many additional endogenous molecules that act as signaling molecules. These include
calcium ions (Ca2+ ), nitric oxide (NO), and non-coding RNA molecules (ncRNA). Exogenous molecules
also can interact with cellular receptors and aect physical and mental activities. These include molecules
release by bacteria, multicellular tissue, pheromones, and synthetic chemicals.
Signal molecules
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