CellsTwo categories: (i) simple, non-nucleated prokaryotic cells

(ii) complex, nucleated eukaryotic cells.

Cell Degradation

• Normally worn-out cells are replaced through cell division.

• In humans, after 52 divisions cell division comes to a halt:

“Hayflick” limit -referred to as senescent.

• Cancer cells, do not degrade in this way. Telomerase, present in

large quantities in cancerous cells, rebuilds the telomeres, allowing

division to continue indefinitely.

Growth factor (GF)

Is a signalling molecules capable of stimulating cellular growth,

proliferation and cellular differentiation.

• Usually it is a protein or a steroid hormone.

• GF is important for regulating a variety of cellular processes- cell

differentiation and maturation.

e.g. cytokines and hormones

• GF is used in the treatment of hematologic and oncologic diseases

and cardiovascular diseases like:

e.g. Neutropenia, myelodysplastic syndrome,leukemias, aplastic

anaemia, bone marrow transplantation etc.

• GF is sometimes used interchangeably with the

term cytokine.

• While GF implies a (+) ve effect on cell division,

cytokine is a neutral term with respect to whether

a molecule affects proliferation.

e.g. some cytokines can be GF: G-CSF and GM-CSF,

but Fas ligand is used as "death" signals causing

apoptosis.

Classes of GF

Individual GF proteins tend to occur as members of larger

families of structurally and evolutionarily related proteins.

e.g.

• Bone morphogenetic proteins (BMPs)

• Epidermal growth factor (EGF)

• Erythropoietin (EPO)

• Fibroblast growth factor (FGF)

• Hepatocyte growth factor (HGF)

• Insulin-like growth factor (IGF)

• Myostatin (GDF-8)

• Nerve growth factor (NGF) and other

neurotrophins

• Platelet-derived growth factor (PDGF)

• Thrombopoietin (TPO)

• Transforming growth factor alpha(TGF-α)

• Transforming growth factor beta (TGF-β)

• Vascular endothelial growth factor (VEGF)

Growth Factor Range of Specificity Effects

Epidermal growth

factor (EGF)

Broad Stimulates cell proliferation in many tissues; plays a key role in

regulating embryonic development

Erythropoietin Narrow

Required for proliferation of red blood cell precursors and their

maturation into erythrocytes (red blood cells)

Fibroblast growth

factor (FGF)

Broad Initiates the proliferation of many cell types; inhibits maturation

of many types of stem cells; acts as a signal in embryonic

development

Insulin-like

growth factor

Broad Stimulates metabolism of many cell types; potentiates the effects of other growth factors in promoting cell proliferation

Interleukin-2 Narrow Triggers the division of activated T lymphocytes during the immune response

Characteristics of Growth Factors

• Over 50 different GF have been isolated . A specific

cell surface receptor “recognizes” each growth factor,

its shape fitting that growth factor precisely. When

the growth factor binds with its receptor, the

receptor reacts by triggering events within the cell.

• Some growth factors, like PDGF and epidermal

growth factor (EGF), affect a broad range of cell

types, while others affect only specific types.

Growth

• Implies development, from the time of birth to the time

of maturity and for many species, beyond maturity to

eventual senescence or death.

• Increase in size, height and mass resulting from cell

multiplication and cell expansion, as well as

maturation of tissues.

• Also necessitates programmed cell death, leading to

the production of the final body form.

Cell division

• Growth is a steady, continuous process,

interrupted only briefly at M phase when

the nucleus and then the cell divide in two.

• Cell division/cell cycle, has four major parts

– G1 phase , S phase, G2 phase and M phase

Phases in a Cell cycle

Phases of the cell cycle

other than mitosis, is

often termed as

interphase (12 - 36h)

1 h

12 h

7 h

12 h

Cell cycle

The cell cycle of eukaryotic cells can be divided into four successive

phases:

(i) M phase (mitosis): (1-2 h)

• The nucleus and the cytoplasm divide

• Cell growth and protein production stop at this stage

• Nuclear division (karyokinesis) and cytoplasmic division (cytokinesis),

accompanied by the formation of a new cell membrane.

• Physical division of "mother" and "daughter" cells.

• M phase has - prophase, prometaphase, metaphase, anaphase and

telophase leading to cytokinesis.

• Focused on the complex and orderly

division into two similar daughter cells.

• There is a Metaphase Checkpoint that

ensures the cell is ready to complete cell

division.

(ii) S phase (DNA synthesis):

The DNA in the nucleus replicates (once

only)

Cell cycle

(iii & iv) Two gap phases, G1 & G2.

– The G1 phase is a critical stage, allowing

either commitment to a further round of cell

division or withdrawal from the cell cycle

(G0) to embark on a differentiation pathway

• G1 phase is also involved in the control of

DNA integrity before the onset of DNA

replication.

• Synthesis of enzymes for nucleotide and

nucleic acid biosynthesis takes place in

this phase

Cell cycle

Cell cycle

– G2 phase:

The cell checks the completion of DNA replication and

the genomic integrity before cell division starts.

Protein and RNA synthesis that takes place in the S

phase continues to the G2 Phase

significant protein synthesis occurs during this phase,

mainly involving the production of microtubules, which

are required during the process of division, called mitosis.

Control of cell cycle

Note the 3 main sites

Control of the Cell Cycle

Check points: Quality Control of the Cell Cycle

• Eukaryotic cells have gene products that govern

the transition from one phase to the other.

• These are family of proteins in the cytoplasm

e.g. Cyclins

• Their levels in the cell rise and fall with the

stages of the cell cycle.

Check points

• They turn on different cyclin dependent Kinase

(CDKs) and Cell division cyclin kinase (CdCK)

that phosphorylates substrate essential for

progression through the cycle.

• These ensure that all phases of the cell cycle

are executed in the correct order.

Cyclins and CDKs involved in cell cycle progression

Phase Cyclin Kinase Function

G1 Cyclin D CDK 4 & 6 Cell cycle

progression- passing

G1/S boundary

S Cyclin E & A CDK2 Initiation of DNA

synthesis in early S

phase

M Cyclin B & A CDK1 Transition from G2 to

M

Check points

• CDK levels in the cell remain fairly stable, but

each must bind the appropriate cyclin (whose

levels fluctuate) in order to be activated.

• CDK act by adding phosphate groups to a

variety of protein substrates that control

processes in the cell cycle.

Cyclin

• Cell cycle is controlled by various proteins

regulated by the Genes catalytic and target

(Cyclin) unit

• The cyclin units appear transiently at

various sites and disintegrate after passing.

G1 Start S G2 M G1

CDK

G1 CYCLIN

S PHASE

CYCLIN

MITOTIC CYCLIN

G1 CYCLINMITOTIC CYCLIN

G1 Start S G2 M G1

CDK

S PHASE

CYCLIN

TYROSINE

PHOSPHORYLATION

Rb, P53, p16

•

G0- quiescent

• Anaphase-promoting complex (APC)

– triggers the events leading to destruction of

the cohesins thus allowing the sister

chromatids to separate;

– degrades the mitotic cyclin B promoting exit

from mitosis

Check points & mechanism of DNA repair:

Cell has several systems to interrupt the

cell cycle if something goes wrong.

(i) DNA damage checkpoints. These sense DNA damage.

- G1 checkpoint: Damage to DNA inhibits the action

of CDK thus stopping the progression of the cell

cycle until the damage can be repaired

Checkpoints & mechanism of DNA repair

- The common repairing mechanisms are

mismatch repair, base excision repair, nucleotide

excision repair, double strand break repair

- If the damage is so severe that it cannot be repaired,

the cell self-destructs by apoptosis.

(ii) Check point for successful replication of DNA

is present at S phase

(iii) Spindle checkpoints.

– detect any failure of spindle fibers that attach to

kinetochores and arrest the cell in metaphase until

all the kinetochores are attached correctly (M

checkpoint )

– detect improper alignment of the spindle itself and

block cytokinesis

– trigger apoptosis if the damage is irreparable.

Checkpoints & mechanism of DNA repair

Cancer and Oncogenes

• All the checkpoints examined require the

services of a complex of proteins.

• Mutations in the genes encoding some of these

have been associated with cancer: oncogenes

• Checkpoint failures allow the cell to

continuously divide despite damage to its

integrity?? “developing cancer”

Growth Factors and Cancer

• Two main genes

– Tumor-suppressor Genes

– Proto-oncogenes.

Proto-oncogenes.

• PDGF and many other growth factors, stimulate cell division by

triggering G1 checkpoint by aiding the formation of cyclins

• Genes that normally stimulate cell division are sometimes called

proto-oncogenes because mutations that cause them to be

overexpressed or hyperactive convert them into oncogenes (Greek

onco, “cancer”).

• Even a single mutation (creating a heterozygote) can lead to cancer

if the other cancer preventing genes are non-functional.

– E.g. myc, fos, and jun,

Tumour-suppressor Genes

• They block passage through the G1 checkpoint by

preventing cyclins from binding to Cdk, thus inhibiting

cell division.

• When mutated, they can also lead to unrestrained cell

division, but only if both copies of the gene are mutant.

• Hence, these cancer-causing mutations are recessive.

• Rate of cancer cell growth:

The proportion of cancer cells growing and making new

cells varies. If more than 6 -10% of the cells are making

new cells, the rate of growth is considered

unfavourably high.

• S-phase fraction and Ki-67 tests may be required to

measure rates of cell growth but treatment decisions are

made on other more reliable cancer characteristics.

• "Grade" of cancer cell growth: Patterns of cell growth are rated on

a scale from 1 to 3 (also referred to as low, medium, and high

instead of 1, 2 or 3).

– Calm, well-organized growth with few cells reproducing is considered

grade 1. Disorganized, irregular growth patterns in which many cells

are in the process of making new cells is called grade 3. The lower the

grade, the more favourable the expected outcome.

• Dead cells within the tumour: necrosis (or dead tumour cells) is

one of several signs of excessive tumour growth. It means that a

tumour is growing so fast that some tumour cells die.

Cell growth disorders

• A series of growth disorders can occur at the cellular level and

these underpins much of the subsequent course in cancer,

– group of cells display uncontrolled growth and division

beyond the normal limits,

– invasion (intrusion on and destruction of adjacent tissues),

– metastasis (spread to other locations in the body via lymph or

blood).

LABILE CELL

– cells that multiply constantly throughout life. They spend little

or no time in the quiescent G0 phase of the cell cycle, but

regularly performs cell division .

– E.g. skin cells, cells in the gastrointestinal tract and blood cells

in the bone marrow.

– It is mainly not the segments of the cell cycle that go faster (i.e.,

but rather a short or absent G0 phase.

– higher risk of becoming malignant and develop cancer.

Note:

• Cytotoxic drugs inhibit the proliferation of dividing

cells, with the malignant cells as the desired target.

• This has adverse effect against the cells normally

dividing in the body, and thus impairing normal

body function of skin, GI tract and bone marrow.

Positive Growth Regulators: Promoting Cell Division

• Rous discovered that he could grind up sarcomas and

extract an unidentified substance that, when injected into

healthy chickens, caused cancer.

– not bacteria because it was carefully filtered,

• so something much smaller that could pass through the

filter.

– first animal tumor virus, which was named the Rous sarcoma

virus in honour of its discovery and the type of tumor from

which it was obtained.

Negative Growth Regulators: Inhibiting Cell Division

• For a cell to divide, proto-oncogenes

must be activated to promote the

process, and tumor suppressor genes

must be inactivated to allow the

process to happen.

Example

p53

• This is known as tumour suppressor gene

• The p53 protein senses DNA damage and can halt

progression of the cell cycle in G1 (by blocking the

activity of CDK2).

• If both copies (as mutations in p53 are recessive) of the

p53 gene is mutated the above mechanism fails

• The p53 protein is also a key player in apoptosis,

forcing "bad" cells to commit suicide.

Note :

• More than half of all human cancers do, in fact,

harbor p53 mutations and have non functioning

p53 protein.

p53

Note:

• Inappropriate division of a clone of cells at the

inappropriate time lead to hypertrophy/ hyperplasia/

neoplasia

• Cell cycle is controlled by Genes, which secretes growth

and inhibitory stimuli with contact inhibition (cell to

cell)

• Any errors in the entry or exit in the cell cycle could

cause a tumour

Control at different

stages of the cell cycle

G0Phase

• A cell may leave the cell cycle,

temporarily or permanently.

i.e. it exits the cycle at G1 and enters a

stage designated G0

• G0 cell is often called "quiescent“-not

proliferating.

• Many G0 cells are in resting stage and

does not divide; but they carry out their

functions in the organism.

e.g. secretion, attacking pathogens.

• G0 to G1 requires growth factor

G0Phase

• If G0 cells are terminally differentiated: they will never

reenter the cell cycle but instead will carry out their

function in the organism until they die.

e.g. Terminally differentiated neurons cannot undergo

cell-cycle re-entry.

Note: Epithelial cells divide more than twice a day,

Liver cells divide only once every year or two,

spending most of their time in G0 phase

• Most of the lymphocytes in human blood

are in G0.

However, with proper stimulation, such

as encountering the appropriate antigen,

they can be stimulated to reenter the cell

cycle and proceed on to new cycle.

G0Phase

• G0 represents not simply the absence of signals

for mitosis but an active repression of the

genes needed for mitosis.

• Cancer cells cannot enter G0 and are destined

to repeat the cell cycle indefinitely.

Note: Normal cell exist in G0 more than cancer

cells

Sexual reproduction

• Notice that when meiosis starts, the two copies of sister chromatids

number 2 are adjacent to each other. During this time, there can be

genetic recombination events. Parts of the chromosome 2 DNA gained

from one parent will swap over to the chromosome 2 DNA molecule that

received from the other parent

• It is these new combinations of parts of chromosomes that provide the

major advantage for sexually reproducing organisms by allowing for new

combinations of genes and more efficient evolution.

Specialization & Communication of Cells

• Larger the organism, the greater the need for different types

of cells with different structures and functions.

• Specialized types of cells that are especially suited to

specific duties ensures that all the processes necessary for

the life of the organism are carried out quickly and

efficiently.

• Specialized cells fulfil a wide variety of needs in

multicellular organisms.

• Secondly principle that applies to all multicellular organisms is that of cell communication.

• With the diversity of cells & tissues found in a multicellular organism, they must have some way to coordinate their activities, and must be able to communicate with one another.

Cell – cell Interactions

• Cell-cell commu­nication allows an individual cell to

determine its position in the body, to adjust its

metabolism to suit its particular func­tion, and to

grow and divide at the proper time, in concert with

its neighbours

• Cells must be ready to respond to essential signals in

their environment by releasing small signalling

molecules, which are received by target cells.

Ligand-Receptor Interactions

• Molecules that activate (or, in some cases,

inhibit) receptors :

– hormones

– neurotransmitters

– cytokines

– growth factors but all of these are called

receptor ligands

Types of Signalling

• distant locations in a multicellular organism e.g. endocrine

signalling by hormones;

• nearby cells

e.g. paracrine stimulation by cytokines;

• secreted by themselves ( = autocrine stimulation)

• also respond to molecules on the surface of adjacent cells

e.g. producing contact inhibition

• Some cell-to-cell communication requires direct cell-cell contact.

• Some cells can form gap junctions that connect their cytoplasm to

the cytoplasm of adjacent cells.

– E.g. gap junctions between adjacent cells allows for action potential

propagation from the cardiac pacemaker region of the heart to spread

and co-ordinately cause contraction of the heart.

• Notch signalling mechanism -juxtacrine signalling (also known as

contact dependent signalling) in which two adjacent cells must

make physical contact in order to communicate.

Synaptic Signalling• Neurons communicate with distant cells but they are not

carried to the responding cells by the circula­tory

system.

• The site at which the neurotransmitters are released is

called a chemical synapse. While paracrine signals cross

interstitial fluid between cells, neurotransmitters cross

the synapse and persist only.

• Adjacent cells can signal others by direct contact, while

nearby cells that are not touching can communi­cate by the

release of paracrine signals. Two sys­tems mediate

communica­tion over much longer dis­tances: the endocrine

system releases hormones that are carried by circulating

body fluids to distant cells; in ani­mals, the nervous system

se­cretes neurotransmitters from long cellular extensions

that end close to the re­sponding cells.

• Signalling molecules may trigger: an immediate change in

the metabolism of the cell (e.g., increased glycogenolysis

when a liver cell detects adrenaline);

• an immediate change in the electrical charge across the

plasma membrane (e.g., the source of action potentials);

• a change in the gene expression — transcription — within

the nucleus. (These responses take more time.)

Pathways by which a Chemical Signal Turns on Gene Expression

• Two categories of signalling molecules

(i) steroids and nitric oxide diffuse into the cell & bind

internal receptors.

(ii) Proteins & peptides bind to receptors displayed at the

surface of the cell.

– These are transmembrane proteins: extracellular

portion binds the ligand & intracellular portion activates

proteins in the cytosol that eventually regulate gene

transcription in the nucleus.

Receptors

• When a signalling molecule reaches a

target cell, cell have a specific means of

receiving it and acting on its message.

• This responsibility is carried out by a

class of proteins called receptors.

• Cell surface receptors are glycoproteins that are

embedded or otherwise attached to the cell's

plasma membrane and have a binding site for

specific ligands (cytokines, hormones, growth

factors, neurotransmitters, adhesion molecules,

etc.), exposed to the extracellular environment.

• Ligand binding to a cell surface receptor generally

leads to a biological signal

Protein binding diagram

• The steroid–receptor complex acts on

specific genes, activating the production

of the proteins they encode

e.g. genes that are activated by progesterone

in target cells in the uterus, for example,

encode proteins that are necessary for the

proper growth of the uterine lining.

• How does nitric oxide serve as a signal to lower blood

pressure?

• State five molecules that act intra-cellularly to alter

gene expression

Cortisol, oestrogen, progesterone, vitamin D &

thyroid hor­mone

• State five molecules that act on the surface receptors.

Insulin, glucagon, GH, adrenalin, PDGF

• How Cell Surface Receptors Initiate Changes inside the Cell

• specific chemical reactions are triggered inside a

cell by an external signal, causing a series of

protein activations known as a signal cascade-

signal transduction.

• Cell surface receptors transduce ligand signals by a variety

of mechanisms such as receptor clustering, activation of a

hidden enzymatic activity, opening of ion channels, etc

1. Cell surface receptors trigger signal cascades by binding

external signalling molecules, changing shape, and then

activating or inactivating specific proteins inside the cell.

e.g. G proteins and enzyme-catalyzed phosphorylation or

specific nucleotides such as GTP.

2. biological signal that is propagated towards the cell

interior, result in

proliferation, differentiation, apoptosis, degranulation, etc.

Cell surface receptors

• Chemically gated ion channels are multipass transmembrane proteins

that form a pore in the cell mem­brane. This pore is opened or closed by

chemical signals.

• Enzymic receptors are single-pass transmembrane proteins that bind the

signal on the extracellular surface and contain a catalytic region on their

cytoplasmic portion that initiates enzymatic activity inside the cell.

• G protein-linked receptors bind to the signal outside the cell and to G

proteins inside the cell. (~ The G protein-linked receptor is a seven-pass

transmembrane protein.

•

Chemically Gated Ion Channels

• Integral protein has a pore that con­nects

the extracellular fluid with the cytoplasm

where ions pass through it, so the protein

func­tions as an ion channel.

• Ion chan­nels open or close when

neurotransmitter molecules bind to the

protein.

Enzyme Receptors

• Binding of a signal molecule to the receptor activates

the enzyme. In almost all cases, these enzymes are

protein kinases, that add phosphate groups.

• Each receptor is a single-pass transmembrane protein

(the amino acid chain passes through the plasma

membrane only once); the portion that binds to the

signal molecule is outside the cell, and the por­tion

that carries out the enzyme activity is exposed to the

cytoplasm.

G Protein-linked Receptors

• Receptors in this category are members of the largest

superfamily of surface receptors. Each is a seven-pass trans-

membrane protein

• signal molecule binds the receptor protein changes shape,

causing the associated G protein to bind GTP and become

activated.

• The activated G protein then diffuses away from the

recep­tor, starting a chain of events that ultimately brings

about the response of the cell.

G Protein-linked Receptors

How Cell Surface Receptors Initiate Changes inside

the Cell

• Cell response to an external signal is known as signal

transduction.

• The signal is transferred, or transduced, from the outside to

the inside of the cell.

• It triggers a series of chemical reactions that activate

proteins inside the cell-referred to as a signal cascade.

• Each type of signalling molecule binds to a specific type of

receptor on the cell surface, causing a specific signal

cascade that activates specific proteins.

G proteins

• Bind to and are regulated by nucleotides

with a guanine base:

• When a G protein is bound to GDP, it is

inactive. When an inactive G protein binds

to an activated receptor, however, it is able

to release GDP and bind GTP from the

cytosol.

G-Protein-Coupled Receptors (GPCRs)

• Many ligands that alter gene expression by

binding GPCRs:

– protein and peptide hormones

e.g. TSH, ACTH.

– Serotonin and GABA (which affect gene

expression in addition to their role as

neurotransmitters)

Turning GPCRs Off

• A cell must also be able to stop responding to a signal. Several

mechanisms cooperate in turning GPCRs off. When activated, the

Gα subunit of the G protein swaps GDP for GTP. However, the Gα

subunit is a GTPase and quickly converts GTP back to GDP

restoring the inactive state of the receptor. The receptor itself is

phosphorylated by a kinase, which not only reduces the ability of

the receptor to respond to its ligand but recruits a protein; β-

arrestin, which further desensitizes the receptor, and triggers the

breakdown of the second messengers of the GPCRs: cAMP for

some GPCRs, DAG for others.

G protein diagram

Cytokine Receptors

• Most of these fall into one or the other of two major families:

1. Receptor Tyrosine Kinases (RTKs) and

2. Receptors that trigger a JAK-STAT pathway.

• Receptor Tyrosine Kinases (RTKs)

The receptors are transmembrane proteins that span the plasma

membrane just once.

• Some ligands that trigger RTKs:

e.g. Insulin, Vascular Endothelial Growth Factor , PDGF,EGF, FGF, M-CSF

Amplifying and Combining Signals inside the Cell

• The activation of many proteins at each step of a

signal cascade greatly amplifies the original signal.

Signal cascades that modify existing proteins inside

the cell occur in a matter of seconds; those that

activate genes to produce new proteins can take

several hours. Certain proteins can participate in

multiple signal cascades, allowing the cell to

integrate different external signals.

Defeating Deadly Bacterial Toxins

• Knowing how signal cascades are affected by deadly bacterial toxins will allow biologists to design drug therapies that specifically block their effects.

Signal Transducers

Signal Amplification & Adhering Cell

• Both enzyme-linked and G protein-linked receptors receive

signals at the surface of the cell

• signals are relayed to the cytoplasm or the nucleus by

second messengers, which influence the activity of one or

more enzymes or genes and so alter the behavior of the cell.

• They uses a chain of other protein messengers to amplify

the sig­nal as it is being relayed to the nucleus.

Amplifying & Combining Signals inside the Cell

• Imagine a situation in which a single hormone or growth factor binds to a cell surface receptor. If this binding event resulted in the activation or phosphorylation of only one protein inside the cell, many binding events at the cell surface would be needed in order to bring about any significant change in the cell. To avoid such an inefficient arrangement, most signal cascades greatly amplify the initial signal. A signal cascade is like a huge avalanche on a snow-covered mountain that is started by one small icicle falling off a tree at the top of the slope.

•

Communicating Cell Junctions

• cell recognition proteins allow specific kinds of cells to bind to each other to make direct physical contact called cell junction.

• three types of cell junctions

– tight junctions

– desmosomes

– gap junctions

• Cell junctions can be classified into three functional groups:• 1. Occluding junctions seal cells together in an epithelium in a way that

prevents even small molecules from leaking from one side of the sheet to the other.

• E.g. tight junctions (vertebrates only) & septate junctions (invertebrates mainly)

2. Anchoring junctions mechanically attach cells (and their cytoskeletons) to their neighbors or to the extracellular matrix.

• E.g cell-cell junctions (adherens junctions)• cell-matrix junctions (focal adhesions)

3. Communicating junctions mediate the passage of chemical or electrical signals from one interacting cell to its partner.

• The major kinds of intercellular junctions within each group are listed in Table 16.1. We discuss each of them in turn, except for chemical synapses, which are formed exclusively by nerve cells and are considered in other course unit.

• gap junctions, chemical synapses, plasmodesmata (plants only)

Cell recognition and adhesion involve proteins at the cell surface

• Membrane glycoprotein (80% sugar) that is partlyembedded in the plasm is responsible for cell recognition.

• protein has specific chemical groups exposed on itssurface where they can interact with other substances,including other proteins.

• Two types.

(i) homotypic: The same molecule sticks out of bothcells, & exposed surfaces bind to eachother.

(ii)heterotypic: binding of cells with differentproteins.

e.g. Male and female cells recognize each other

Gap Junctions

• Allow small molecules to pass directly from Cell to Cell

• In EM appears as 2 adjacent cells separated by a narrow gap (2–4 nm)

• The gap is spanned by channel-forming proteins (connexins) to form

(connexons)

• allow inorganic ions and other small water-soluble molecules to pass

directly from the cytoplasm of one cell to the other,

• couple the cells both electrically and metabolically to share small

molecules. But not macromolecules (e.g proteins, NA)

Function of gap junctions

• In nerve cells - electrically coupled, allowing action

potentials to spread rapidly from cell to cell, without the

delay that occurs at chemical synapses.

e.g when speed and reliability are crucial-in certain escape

responses in fish and insects.

• Synchronizes the contractions

– heart muscle cells in heart

– smooth muscle cells involved in the peristaltic movements of the

intestine.

• Gap junctions also occur in tissues that do not contain

electrically excitable cells.

– e.g. Release of noradrenaline from sympathetic nerve endings in

response to a fall in blood glucose levels stimulates hepatocytes

to increase glycogen breakdown and release glucose into the

blood.

• Note: Not all the hepatocytes are innervated by

sympathetic nerves, when glucose level fall, however by

means of the gap junctions that connect hepatocytes, the

signal is transmitted .

• The normal development of ovarian follicles

also depends on gap-junction-mediated.

• Cell coupling via gap junctions also seems to be

important in embryogenesis.

Permeability of Gap Junctions Can Be Regulated

• Like ion channels, individual gap-junction channels do not

remain continuously open; instead, they flip between open

and closed states.

• The permeability of gap junctions is rapid (within seconds)

and reversibly reduced by decrease cytosolic pH (not

known) / increase cytosolic [free Ca2+ ] to very high levels.

• They are dynamic structures that can undergo a reversible

conformational change that closes the channel in response

to changes in the cell.

• Purpose of Ca2+ control: when a cell is damaged, its

plasma membrane become leaky, fluid, such as Ca2+

and Na+, and then move into the cell, and valuable

metabolites leak out.

• If the cell were to remain coupled to its healthy

neighbours, the large influx of Ca2+ into the damaged

cell causes its gap-junction channels to close

immediately, effectively isolating the cell and

preventing the damage from spreading to other cells.

• Gap-junction communication can also be regulated by

extracellular signals.

E.g. neurotransmitter dopamine, for example, reduces gap-

junction communication between a class of neurons in the

retina in response to an increase in light intensity. This

reduction in gap-junction permeability helps the retina

switch from using rod photoreceptors, which are good

detectors of low light, to cone photoreceptors, which detect

color and fine detail in bright light.