Chapter 3: System control and communication as the foundation of individual
health
Chapter 3a: The Control and Communication Network
i) CellCell Communication
Mechanisms of intercellular communication
All body functions require communication between cells. Cells are physically
linked by gap junctions and they communicate through chemical messengers.
Gap junctions link adjacent cells and are formed by plasma membrane proteins
called connexins that form connexons.
Connexons form channels that allow ions and small molecules to pass directly
from one cell to another. The movement of ions through gap junctions electrically
couples the cells, such that electrical signals in one cell are directly transmitted to
the neighboring cells.
The movement of small molecules through gap junctions metabolically couples
the cells such that one cell can provide necessary nutrients to other cells.
Cells communicate via chemical messengers which are all ligands, molecules that
bind to proteins reversibly.
Communication through chemical messengers occurs when one cell releases a
chemical into the interstitial fluid, by secretion, and another cell, the target cell,
responds to the chemical messenger.
The target cell is the cell which a message is aimed at. It responds to chemical
messenger because it has certain proteins called receptors that recognize and bind
the messenger.
The binding of messengers to receptors produces a response in the target cell
through a variety of mechanisms called signal transduction. The strength of the
target cell response increases as the number of bound receptors increases. The
number of bound receptors depends on both the concentration of messenger in the
interstitial fluid and the concentration of receptors on the target cell.
Chemical Messengers
Chemical messengers can be classified into 3 categories: 1) paracrines, 2)
neurotransmitters 3) hormones. Each of these when released in fluid transmit a
signal by binding to receptors on a target cell.
Paracrines are chemicals that communicate with neighboring cells. The target cell
must be close enough that once the paracrine is secreted into the extracellular
fluid, it can reach the target cell by simple diffusion. These generally include
growth factors, clotting factors, and cytokines.
Growth factors are proteins that stimulate proliferation and differentiation of cells.
Clotting factors are peptides usually released from immune cells that function in
coordinating the body’s defense against infections.
Another paracrine messenger is a histamine which is important in allergic
reactions and inflammation and is secreted by mast cells scattered throughout the
body.
Autocrines are a subclass that act on the same cell that secreted them.
Neurotransmitters are chemicals released into interstitial fluid from nervous
system cells called neurons. Neurotransmitters are released from a specialized portion of the neuron called the axon terminal which is near the target cell. The
cell that releases neurotransmitters is called presynaptic neuron whereas the target
cell is called the postsynaptic cell.
Hormones are chemicals released from endocrine glands into the interstitial fluid
where they can then diffuse into the blood. The hormone then travels in the blood
to its target cells which can be distant from the site of hormone release.
Neurohormones are released by neurosecretory cells through a mechanism similar
to neurotransmitter release. They are released into interstitial fluid and then
diffused into the blood.
A messenger’s chemical structure determines its mechanisms of synthesis, release,
transport, and signal transduction. Lipophilic (hydrophobic) molecules are lipid
soluble and readily cross the plasma membrane, but are not water soluble.
Lipophobic (hydrophilic) are water soluble and do not cross the plasma
membrane.
Amino Acid Messengers: glutamate, aspartate, glycine, and gammaaminobutyric
acid are four amino acids classified as chemical messengers. The first 3 are
among the 20 amino acids that are used in protein synthesis, whereas GABA
belongs to gamma amino acids. These are lipophobic.
Amine Messengers: Amines are chemical messengers derived from amino acids
and possess an amino group. These include a group called catecholamines, which
contain a catechol group and are derived from tyrosine. These include dopamine,
norepinephrine, and epinephrine. The first two are neurotransmitters, whereas the
last one is a hormone. Also includes serotonin, thyroid hormone, and histamine.
Most of these are lipophobic, except for thyroid hormones which are lipophilic.
Peptide/protein messengers: most chemicals are polypeptides which are classified
by peptides or proteins based on size. Peptide refers to a chain with less than 50
amino acids, while proteins are longer. These are lipophobic.
Steroid messengers: derived from cholesterol. All of the body’s steroid
messengers function as hormones. They are lipophilic.
Eicosanoid messengers: include paracrines that are produced by the cells. These
are lipophilic.
Amino Acids: The four amino acids that function as neurotransmitters must be
synthesized within the neuron that will secrete them. Glutamate and aspartate are
synthesized from glucose. Glycine is synthesized from a glycolytic intermediate.
GABA is synthesized from glutamate in a single reaction catalyzed by the enzyme
glutamic acid decarboxylase.
Amines: All except thyroid hormones are synthesized in the cytosol by a series of
enzyme catalyzed reactions. Note the chart on page 115. Following synthesis,
amines are packaged into cytosolic vesicles where they are stored until their
release is triggered. Release occurs by exocytosis.
Peptides and proteins: these synthesize by having cytosolic mRNA serve as the
template that codes for the amino acid sequence in the peptide or protein.
Translation of this mRNA begins on ribosomes free in the cytosol. Steps on page
116.
Steroids: these are synthesized from cholesterol in a series of reactions catalyzed
by enzymes located in the smooth endoplasmic reticulum or mitochondria. Cholesterol as a result is modified slightly and is capable of crossing the plasma
membrane.. They are stored into the cell as soon as they are synthesized.
Eicosanoids: synthesized on demand and released immediately due to being
lipophilic. First step involves an enzyme called phospholipase A2 which is
activated in response to chemical signals of various kinds. When active, this
enzyme catalyzes the release of arachidonic acid from membrane phospholipids.
Once this is released from the membrane, the final product depends on the
complement of enzymes present in the cell. To become an eicosanoid, an
arachidonic acid binds with either cyclooxygenase or lipoxygenase.
Cyclooxygenase is the first enzyme in the cyclooxygenase pathway that leads the
synthesis of prostacyclins, prostaglandins, or thromboxanes. Lipoxygenase is the
first enzyme in the lipoxygenase pathway that leads the synthesis of leukotrienes.
A messenger must first reach and then bind to receptors on the target cell for the
signal to be transmitted. The messenger is released from a cell near the target cell,
such that the messenger reaches the receptors by simple diffusion.
Hormones can be transported in the blood either in dissolved form or bound to
carrier proteins. The messenger must be hydrophilic to be in dissolved form.
Hydrophobic hormones are transported primarily in bound form, a certain fraction
of the hormone molecules dissolve in plasma. For each such hormone an
equilibrium develops in the bloodstream between the amount of hormone that is
bound to a carrier protein in the form of a complex and the amount of free
hormone that is dissolved in the plasma.
Signal transduction mechanisms
receptors show specificity for the messenger, they generally bind only one
messenger or a class of messengers. The binding is brief and reversible and is
similar to enzymesubstrate interactions. Affinity is the strength of the binding
between a messenger and its receptor.
A single messenger can often bind to more than one type of receptor and these
receptors may have different affinities for the messenger.
A single target cell may have receptors for more than one type of messenger.
The magnitude of a target cell’s response to a chemical messenger depends on
three things: 1) the messenger’s concentration 2) the number of receptors present
3) the affinity of the receptor for the messenger.
The response of a target cell generally increases as the concentration of messenger
increases. As messenger concentration increases, the reaction is driven to the
right. As the concentration of messenger increases, the proportion of bound
receptors increases until all receptors have messengers bound to them.
The target cell’s response also depends on the number of receptors it possesses.
The more receptors there are, the more likely that it is that a messenger will bind
to a receptor. At any given concentration of messenger, the number of bound
receptors will be greater when more receptors are present and the response will be
greater.
The number of receptors that a target cell possesses can vary under different
circumstances as a result of the synthesis of new receptors or turnover of old
receptors. Upregulation, an increase in the number of receptors compared to
normal conditions, occurs when cells are exposed to low messenger concentrations for a prolonged period. Downregulation, a decrease in the number
of receptors occurs when a messenger concentrations are higher than normal for a
prolonged period.
The target cell response also depends on the affinity of its receptors for the
messenger. When a messenger is present at a given concentration, receptors with
higher affinity are more likely to become bound than are receptors with lower
affinity.
Target cells possessing high affinity receptors will respond more strongly to a
given messenger, all else being equal.
Ligands that bind to receptors and produce a biological response and agonists.
Ligands that bind to receptors and do not produce a biological response are
antagonists. These two compete with each other, decreasing the likelihood that
the binding of agonist to receptor will occur and bring about a response.
Receptors for lipophilic messengers are usually located in the cytosol or nucleus
of target cells and are readily accessible because these messengers easily permeate
the plasma membrane.
1. If a receptor is located in the nucleus then the hormone diffuses into the
nucleus and binds to it forming a hormone receptor complex.
2. If a receptor is located in the cytosol then the hormone binds to it there,
forming a hormone receptor complex that then enters the nucleus.
3. Inside the nucleus, the complex binds to a certain region of DNA called the
hormone response element which is located at the beginning of a specific
gene.
4. Binding of the complex to the HRE activates or deactivates the gene which
affects transcription of mRNA and ultimately increases or decreases synthesis
of the protein coded by the gene.
5. The mRNA moves into the cytosol
6. The mRNA is translated by ribosomes to yield proteins.
Lipophobic messengers cannot permeate the plasma membrane to any major
degree. Their receptors are located on the plasma membrane with the binding site
facing the extracellular fluid. The receptors for these messengers fall into three
general categories: channellinked receptors, enzymelinked receptors, and G
protein linked receptors.
Channel linked receptors: The permeability of the plasma membrane is
determined by the presence of ion channels. These are very specific and are
proteins which can be regulated between open and closed states. Ion channels that
open or close in response to the binding of a chemical to a receptor or to the
channel are called ligand gated channels. Channellinked receptors are a type of
ligandgated channel in which the ligand is a messenger that binds to a receptor.
These are either fast channels, in which the receptor and channel are the same
protein, or slow channels, in which the receptor and channel are separate proteins
but are coupled together by a G protein.
Fast ligandchannels are proteins that function as both receptors and ion channels.
The binding causes the channel to open, increasing the membrane’s permeability
for that specific ion. Open ion channels allow a specific ion or class of ions to
move across the plasma membrane down its electrochemical gradient. Ion movement into or out of the cell can have two effects on the target cell: 1) ions
entering and leaving can change the electrical properties of the cell 2) entering
ions can interact with proteins inside the cell to induce a response such as muscle
contraction, secretion, change in metabolism or altered transport of substance.
The opening of most ion channels causes effects by changing the electrical
properties of the target cell. In other cases, fast ligandgated channels exert their
effects by opening calcium channels. When these open, calcium ions enter the
cell. The calcium can trigger a variety of responses by interacting with
intracellular proteins, including muscle contraction, secretion of a product by
exocytosis and functioning as a second messenger (an intracellular messenger
produced by the binding of an extracellular messenger to a receptor).
Intracellular calcium levels are maintained at their normal levels by 3 processes
that remove calcium ions from the cytosol: 1) active transport of calcium across
the plasma membrane 2) sequestration of calcium by binding with proteins in the
cytosol and 3) active transport of calcium into certain organelles such as the
smooth endoplasmic reticulum and mitochondria.
Enzymelinked receptors: function both as enzymes and as receptors. These are
transmembrane proteins with the receptor side facing the interstitial fluid and the
enzyme side facing the cytosol. These enzymes are activated when a messenger
binds to the receptor which allows them to catalyze intracellular reactions. Most
are tyrosine kinases which catalyze the addition of a phosphate group to the side
chains of tyrosine in certain locations in target proteins.
1. the messenger binds to the receptor, changing its conformation
2. the conformation change activates the tyrosine kinase
3. the tyrosine kinase then catalyzes phosphorylation of an intracellular protein.
4. Phosphorylation of the protein changes its activity by covalent regulation bringing
about a response in the target cell.
A messenger that uses the tyrosine kinase signal transduction is the hormone
insulin.
Others are guanylate cyclases which catalyze the conversion of GTP to the 2 nd
messenger cGMP which then activates a protein kinase which catalyzes
phosphorylation of a protein.
G proteinlinked receptors: these work by activating special membrane proteins
called G proteins. These are located on the intracellular side of the plasma
membrane where they function as links between the G proteinlinked receptor and
other proteins in the plasma membrane called effectors. These include ion
channels and enzymes. G proteins get their name from their ability to bind
guanosine, nucleotides, and have three subunits: alpha, beta, and gamma.
In active state, alpha subunit separates from the beta and gamma subunits leaving
a beta gamma dimer. The alpha and sometimes beta move to the effectors causing
a change in the effectors activity. G proteins can be classified into 3 types: 1)
those that affect ion channels 2) stimulatory G proteins 3) inhibitory G proteins.
Both of these are associated with the activation and inhibition of enzymes called
amplifier enzymes.
Slow ligandgated ion channels are regulated by G protein which cause the
channels to open or close in response to a messenger binding to its receptor. Two differences between the two types of channels: 1) at fast ligand gated
channels, messenger binding to channellinked receptors only opens the channel
os it increases the permeability of the target cell for the specific ion. G protein
linked ion channels can either be open or closed by messenger binding to the
receptor. 2) binding of a messenger to channel linked receptors produces an
immediate and brief response in the target cell.
cAMP second messenger system: the mechanisms of action of cAMP are as
follows:
a) the first messenger binds to the receptors, activating a Gs protein.
b) The G protein releases the alpha subunit which binds to and activates the enzyme
adenylate cyclase.
c) Adenylate cyclase catalyzes the conversion of ATP to cAMP
d) cAMP activates protein kinase A, also called cAMP dependent protein kinase.
e) The protein kinase catalyzes the transfer of a phosphate group from ATP to a
protein thereby altering the protein’s activity.
f) Altered protein activity causes a response in the cell
Termination of the actions of cAMP requires its degradation by the enzyme cAMP
phosphodiesterase. The enzymes that dephosphorylate a protein are called
phosphoprotein phosphatases.
The concentration of cAMP in a cell is determined by the rates of synthesis and
breakdown. When synthesis is faster, the concentration increases.
cGMP second messenger system: It is commonly associated with G proteins and
it activates protein kinase G.
Phosphatidlinositol second messenger system: A membrane phospholipid
undergpes an enzyme catalyzes reaction that liberates two second messengers,
DAG and IP3, the latter stimulates release of the third second messenger calcium.
The action of this system:
a) the messenger binds to its receptors, activating a G protein.
b) The G protein releases the alpha subunit which binds to and activates the
enzyme phospholipase C.
c) Phospholipase C catalyzes the conversion of PIP2 to DAG and IP3 each of
which functions as a second messenger.
d) DAG remains in the membrane and activates the enzyme protein kinase C.
e) Protein kinase C catalyzes the phosphorylation of a protein.
f) The phosphorylates protein brings about a response in the cell.
Also,
D2) IP3 moves into the cytosol
E2) IP3 triggers the release of calcium from the ER.
Does one of these two,
F2) It acts on proteins to stimulate contraction or secretion
F3) Acts as a second messenger by binding to calmondulin activating a protein kinase
that phosphorylates a protein that produces a response in the cell.
Signal Amplification in chemical messenger systems:
Second messenger systems have the ability of small changes in concentration of a
chemical messenger to elict marked responses to target cells. Diagram on page 129.
Long Distance communication via the nervous and endocrine systems
crucial that the cells in one region of the body be able to communicate with cells
in distant regions. Body has the endocrine and nervous system.
The nervous system consists of neurons and support cells called glial cells.
Neurons can communicate long distances, first by transmitting electrical signals
along the cell and then by trandmitting chemical signals through the release of a
neurotransmitter from the axon termi
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