3. LECTURE- 9-1- RECEPTOR MECHANISMS.ppt

RECEPTOR MECHANISMS

1. RECEPTOR MECHANISMS
•Receptors are
 proteins with high affinity to a
particular
 ligand, usually a hormone or
neurotransmitter, other proteins, light, or
other chemicals.
•The attachment of a ligand to its receptor will
cause a conformational change which will
stimulate an intracellular event, which will
then transduce the effect of the bound ligand.

2. •Receptors exist throughout the body, the
brain, the heart, the kidneys, liver, skin, all
tissue have receptors.
•An example of a receptor is the
 acetylcholine
receptor
 in the heart.
•Acetylcholine binds and causes activation of
a G-protein, which will open K
+
channels and
hyperpolarize the cell membranes.
•A cell can have more than one type of
receptor on its surface, and typically has
thousands of each type of receptor.

6. •Cells have a number of signalling systems that are capable
of responding either to external stimuli or to internal stimuli
• External stimuli acting on cell-surface receptors are coupled
to transducers to relay information into the cell using a
number of different signalling pathways (Pathways 1–17)
• Internal stimuli derived from the endoplasmic reticulum (ER)
or from metabolism activate signalling pathways
independently of external signals (Pathways 18 and 19)
• All of these pathways generate an internal messenger that
then acts through an internal sensor to stimulate the
effectors that bring about different cellular responses.
• The names of these signalling pathways usually reflect a
major component(s) of the pathway

8. EXTRACELLULAR SIGNAL MOLECULES BIND TO SPECIFIC RECEPTORS
•Cells in higher animals communicate by means of
hundreds of kinds of signal molecules.
•E.g. proteins, small peptides, amino acids, nucleotides,
steroids, retinoids, fatty acid derivatives, and gases such
as nitric oxide and carbon monoxide.
•Most of these signal molecules are secreted from the
signaling cell into the extracellular space by exocytosis
•Others are released by diffusion through the plasma
membrane
•some are exposed to the extracellular space while
remaining tightly bound to the signaling cell's surface.

10. Some signal molecules can directly enter cells.
Hydrophobic molecules such as steroid hormones
can enter cells because of their hydrophobic
character. The receptor molecules for these
hormones are inside the cells.
 
Nitric oxide (NO) can also enter cells directly. NO is
released from nitroglycerine and relaxes blood
vessels.
NO often binds to the enzyme which converts GTP
into cyclic GMP, an internal cell signal molecule.

13. Other external cell signals, use one of three
mechanisms to pass the "message" into the cell
interior - a) An ion channel linked receptor, b) a G-
protein linked receptor, c) an enzyme linked
receptor.
 
•G protein receptors are a major pathway for
converting an external signal into an intracellular
message.
 
G proteins consist of three subunits. The large
alpha unit dissociates from the rest of the molecule
and diffuses along the internal cell surface when a
signaling molecule binds to the external receptor
binding site.
 This dissociation is accompanied by
release of GDP and binding of GTP. Binding of GTP
is common in molecular switches.
 

15. G proteins cause K
+
 
channels to open in response to
neurotransmitter binding in heart muscle.
 
•Hormone binding can use a G protein intermediate
to produce changes in concentrations of
intracellular messengers :Cyclic AMP
 is an
important intracellular messenger.
•Adrenaline, glucagon, and ACTH are important
hormones which cause changes in cyclic AMP
concentrations within target cells.
 
•One of the effects of increased concentrations of
cAMP is activation of a kinase. This kinase starts a
cascade of changes in enzymes which results in an
increase in the rate at which glucose is released
from glycogen.

17. EXTRACELLULAR SIGNAL MOLECULES BIND TO SPECIFIC RECEPTORS
•Regardless of the nature of the signal, the target cell responds by
means of a specific protein called a receptor
•Receptor specifically binds the signal molecule and then initiates a
response in the target cell.
•In most cases, these receptors are transmembrane proteins on the
target cell surface.
•When they bind an extracellular signal molecule (a ligand), they
become activated and generate a cascade of intracellular signals that
alter the behavior of the cell.
•In other cases, the receptors are inside the target cell, and the signal
molecule has to enter the cell to activate them
•This requires that the signal molecules be sufficiently small and
hydrophobic to diffuse across the plasma membrane.

19. EXTRACELLULAR SIGNAL MOLECULES CAN ACT OVER EITHER SHORT OR LONG DISTANCES
•Many signal molecules remain bound to the surface of the
signaling cell and influence only cells that contact it.
•Such contact-dependent signaling is especially important
during development and in immune responses.
•Secreted molecules may be carried far afield to act on
distant targets, or they may act as local mediators,
affecting only cells in the immediate environment of the
signaling cell-paracrine signaling.
•For paracrine signals to be delivered only to their proper
target cells, the secreted molecules must not be allowed to
diffuse too far
•they are rapidly taken up by neighboring target cells,
destroyed by extracellular enzymes, or immobilized by the
extracellular matrix.

21. EXTRACELLULAR SIGNAL MOLECULES CAN ACT OVER EITHER SHORT OR LONG DISTANCES
•For complex multicellular organism to coordinate the
behavior of distant cells, sets of specialized cells perform
the role of communication between widely separate parts
of the body.
•The most sophisticated of these are nerve cells, or
neurons, which typically extend long processes that
enable them to contact target cells far away- synaptic
signaling

•A second type of specialized signaling cell that controls
the behavior of the organism as a whole is an endocrine
cell
•These cells secrete hormones into the bloodstream, which
carries the signal to target cells distributed widely
throughout the body- endocrine signaling

22. COMPARISON BETWEEN SYNAPTIC AND ENDOCRINE SIGNALING
1.Because endocrine signaling relies on diffusion and
blood flow, it is relatively slow.
Synaptic signaling can be much faster, as well as more
precise. Nerve cells can transmit information over long
distances by electrical impulses; once released from a
nerve terminal, a NT has to diffuse less than 100 nm to
the target cell.
2. Hormones are greatly diluted in the bloodstream and
interstitial fluid and therefore must be able to act at very
low concentrations.
Neurotransmitters are diluted much less and can achieve
high local concentrations. NT receptors have a relatively
low affinity for their ligand, which means that the NT can
dissociate more rapidly from the receptor to terminate a
response.

23. The speed of a response to an extracellular signal
depends not only on the mechanism of signal
delivery,
but also on the nature of the response in the target
cell.
Where the response requires only changes in
proteins already present in the cell, it can occur in
seconds or even milliseconds.
When the response involves changes in gene
expression and the synthesis of new proteins,
however, it usually requires hours, irrespective of
the mode of signal delivery.

24. Many intracellular signaling proteins behave like molecular switches: on
receipt of a signal they switch from an inactive to an active state, until
another process switches them off. The switching off is just as
important as the switching on.
•The molecular switches fall into two main classes:
1)The largest class consists of protein kinases that are activated or
inactivated by phosphorylation.
A protein kinase, adds one or more phosphate groups to the signaling
protein, and in the other direction by a protein phosphatase, removes
the phosphate groups from the protein.
•Two main types of protein kinases operate as intracellular signaling
proteins.
•The great majority are serine kinases, which phosphorylate proteins
on serines residues.
•Tyrosine kinases, which phosphorylate proteins on tyrosines.

27. 2) The other main class of molecular switches are
GTP-binding proteins.
•These switch between an active state when GTP is
bound
•and an inactive state when GDP is bound.
•Once activated, they have intrinsic GTPase activity
and shut themselves off by hydrolyzing their
bound GTP to GDP
•E.G. large trimeric GTP-binding proteins (G
proteins), which relay the signals from G-protein-
linked receptors

28. •In G-protein-linked or enzyme-linked
receptors, one class of receptor may
activate many of the same signaling
pathways.
•The cell uses groups of interacting signaling
proteins organized into signaling complexes
•The complexes guide the interactions
between the successive components to
achieve precision, speed and efficiency.

30. •Other hormones use the inositol phosphate
pathway (phospholipase C activation). E.g.
vasopressin and thrombin.
•Acetylcholine, a common neurotransmitter, also
uses the inositol phosphate pathway. Inositol
phospholipids are found as part of the the internal
layer of the lipid bilayer membrane.
 
•The inositol pathway is involved with release of Ca
+
+
 
from the ER. This release is involved in many
important biological processes, including
fertilization.
•It is Ca
++
 
release from sarcoplasmic reticulum in
muscle which activates skeletal muscle contraction.

31. •Light absorption by rhodopsin in the eye causes release of
the alpha subunit of a G protein. This causes ion channels to
close and the electrical potential to change across rod and
cone cell membranes.
• It is this electrical potential change which results in an
action potential on an adjacent cell and eventually a signal
sent to the brain via the optic nerve.
•Receptors which activate G proteins have multiple segments
of protein chain which pass through the membrane. These
receptors can change conformation in response to binding
an external messenger and transmit this change across the
membrane.
•However, receptor proteins with a single pass through the
membrane apparently can't transmit a shape change across
membranes. As a result, these types of receptor proteins
work by permitting linking of receptor subunits by a signal
molecule.

35. A CELL CAN REMEMBER THE EFFECT OF SOME SIGNALS
•The effect of an extracellular signal on a target cell can persist well
after the signal has disappeared. The response system displays a
memory.
•A specific example of this is a protein kinase that is activated by Ca2+
to phosphorylate itself and other proteins
•the autophosphorylation keeps the kinase active long after Ca2+ levels
return to normal, providing a memory trace of the initial signal.
•Transient extracellular signals often induce much longer-term changes
in cells during the development of a multicellular organism.
•For example the signals that trigger muscle cell determination turn on
a series of muscle-specific gene regulatory proteins that stimulate the
transcription of their own genes, as well as genes producing many
other muscle cell proteins. In this way, the decision to become a
muscle cell is made permanent.

36. A CELL CAN REMEMBER THE EFFECT OF SOME SIGNALS
•In their initial response, these immune cells, known as cytotoxic T
lymphocytes, or CTLs, kill cells infected with pathogens. They also
provide long-term protection against pathogens by "remembering"
which proteins the pathogen makes.
•Targeting the ability of these CTLs to remember the pathogen is one
way vaccines protect against infection.
•IL-12 signal is important in driving that immediate, or effector, immune
response while interferon drives the development of long-term
memory."
(Immunologists identify biochemical signals that help immune cells
remember how to fight infection, May 28, 2009)

37. CELLS CAN ADJUST THEIR SENSITIVITY TO A SIGNAL
•Target cells undergo a reversible process of adaptation, or
desensitization, whereby a prolonged exposure to a stimulus
decreases the cells' response to that level of exposure.
•In chemical signaling, adaptation enables cells to respond to changes
in the concentration of a signaling ligand.
•Desensitization to a signal molecule can occur in various ways
•cell receptors may induce their endocytosis and temporary
sequestration in endosomes.
•Such ligand-induced receptor endocytosis can lead to the destruction
of the receptors in lysosomes, a process referred to as receptor down-
regulation.
•In other cases, desensitization results from a rapid inactivation of the
receptors—for example, by phosphorylation.

38. DIFFERENT CELLS CAN RESPOND DIFFERENTLY TO THE SAME EXTRACELLULAR SIGNAL MOLECULE
•The specific way in which a cell reacts to signal
depends on receptor proteins and intracellular
machinery by which the cell integrates and
interprets the signals it receives.
•Thus, a single signal molecule often has different
effects on different target cells.
•The neurotransmitter acetylcholine, for example,
stimulates the contraction of skeletal muscle cells,
•but it decreases the rate and force of contraction
in heart muscle cells.

39. Acetylcholine receptor
•An acetylcholine receptor (AChR) is an
integral membrane protein that responds to
the binding of acetylcholine, a
neurotransmitter
•This is because the acetylcholine receptor
proteins on skeletal muscle cells are
different from those on heart muscle cells.

41. TYPES OF CELLULAR COMMUNICATION
1. AUTOCRINE
•Cells can send signals to other cells of the same type, as well as to
themselves.
•In such autocrine signaling, a cell secretes signal molecules that can
bind back to its own receptors.
•During development, for example, once a cell has been directed
along a particular pathway of differentiation, it may begin to secrete
autocrine signals to itself that reinforce this developmental decision.
•Autocrine signaling is most effective when performed
simultaneously by neighboring cells of the same type
•and it is likely to be used to encourage groups of identical cells to
make the same developmental decisions.

42. 2. PARACRINE SIGNALING
•Paracrine signaling is a form of cell signaling in which the
target cell is near the signal-releasing cell.
•Both paracrine and autocrine signaling affect neighboring
cells, but whereas autocrine signaling occurs among the
same types of cells, paracrine signaling affects other types
of (adjacent) cells.
•Growth factor and clotting factors are paracrine signaling
agents. The local action of growth factor signaling plays an
especially important role in the development of tissues.
•Usually it is a protein or a steroid hormone. Growth factors
are important for regulating a variety of cellular processes.
Growth factors typically act as signaling molecules
between cells.

43. PARACRINE SIGNALING
•Another way to coordinate the activities of neighboring cells is
through gap junctions.
•These are specialized cell-cell junctions that can form between
closely apposed plasma membranes and directly connect the
cytoplasms of the joined cells via narrow water-filled channels.
•The channels allow the exchange of small intracellular signaling
molecules (intracellular mediators), such as Ca2+ and cyclic AMP
but not of macromolecules, such as proteins or nucleic acids.
•Thus, cells connected by gap junctions can communicate with each
other directly, without having to surmount the barrier presented by
the intervening plasma membranes.
•Gap-junctions have an important role in the signaling processes that
occur between the cells in a developing embryo.
•Like the autocrine signaling, gap-junction communication helps
adjacent cells of a similar type to coordinate their behavior.

44. 3. ENDOCRINE
•Binding of hormone:
•Change In Membrane Permeability- a change in structure
of receptor, usually opening or closing a channel for one
or more ions.
•Activation Of Intracellular Enzyme –activation of
membrane-associated enzyme- second messenger
systems
•Gene Activation –The activated HR complex binds with/
activates specific portions of DNA in the nucleus
•New proteins may appear after hours or days. Steroid
hormones, by contrast, persist in the blood for hours and
thyroid hormones for days.

45. By method of excretion
Exocrine glands are named apocrine glands,
holocrine glands, or merocrine glands based on how
their products are excreted.
Merocrine
 secretion
– cells excrete their substances
by
 exocytosis; for example, pancreatic acinar cells.
Apocrine
 secretion
– a portion of the
 cell
membrane
 that contains the excretion buds off.
Holocrine
 secretion
– the entire cell disintegrates to
excrete its substance; for example, sebaceous
glands of the
 skin and nose.